Breast Cancer Research: 2002-2006
     
N Engl J Med. 2006 Nov 2;355(18):1851-62.
Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer.
Poole CJ, Earl HM, Hiller L, Dunn JA, Bathers S, Grieve RJ, Spooner DA, Agrawal RK, Fernando IN, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, Harvey P, McAdam K, Foster L, Leonard RC, Twelves CJ; NEAT Investigators and the SCTBG.
Cancer Research UK Clinical Trials Unit, Institute for Cancer Studies, University of Birmingham, Birmingham, United Kingdom. poolecj@aol.com

BACKGROUND: The National Epirubicin Adjuvant Trial (NEAT) and the BR9601 trial examined the efficacy of anthracyclines in the adjuvant treatment of early breast cancer. METHODS: In NEAT, we compared four cycles of epirubicin followed by four cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF) with six cycles of CMF alone. In the BR9601 trial, we compared four cycles of epirubicin followed by four cycles of CMF, with eight cycles of CMF alone every 3 weeks. The primary end points were relapse-free and overall survival. The secondary end points were adverse effects, dose intensity, and quality of life. RESULTS: The two trials included 2391 women with early breast cancer; the median follow-up was 48 months. Relapse-free and overall survival rates were significantly higher in the epirubicin-CMF groups than in the CMF-alone groups (2-year relapse-free survival, 91% vs. 85%; 5-year relapse-free survival, 76% vs. 69%; 2-year overall survival, 95% vs. 92%; 5-year overall survival, 82% vs. 75%; P<0.001 by the log-rank test for all comparisons). Hazard ratios for relapse (or death without relapse) (0.69; 95% confidence interval [CI], 0.58 to 0.82; P<0.001) and death from any cause (0.67; 95% CI, 0.55 to 0.82; P<0.001) favored epirubicin plus CMF over CMF alone. Independent prognostic factors were nodal status, tumor grade, tumor size, and estrogen-receptor status (P<0.001 for all four factors) and the presence or absence of vascular or lymphatic invasion (P=0.01). These factors did not significantly interact with the effect of epirubicin plus CMF. The overall incidence of adverse effects was significantly higher with epirubicin plus CMF than with CMF alone but did not significantly affect the delivered-dose intensity or the quality of life. CONCLUSIONS: Epirubicin plus CMF is superior to CMF alone as adjuvant treatment for early breast cancer. (ClinicalTrials.gov number, NCT00003577 [ClinicalTrials.gov].). Copyright 2006 Massachusetts Medical Society.

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Anticancer Drugs. 2006 Nov;17(10):1201-9.
A randomized phase II trial comparing preoperative plus perioperative chemotherapy with preoperative chemotherapy in patients with locally advanced breast cancer.
Rocca A, Peruzzotti G, Ghisini R, Viale G, Veronesi P, Luini A, Intra M, Pietri E, Curigliano G, Giovanardi F, Maisonneuve P, Goldhirsch A, Colleoni M.
aUnit of Research in Medical Senology bDepartment of Medicine cDivision of Pathology dUniversity of Milan School of Medicine eDivision of Senology fDivision of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy.

The aim of this study was to investigate in a randomized trial the activity of perioperative chemotherapy in patients treated with preoperative chemotherapy for locally advanced breast cancer and to compare it with the preoperative chemotherapy alone. Patients with cT2-3 N0-2 M0 histologically proven breast cancer, with estrogen receptors and progesterone receptors in less than 20% of cells, or with absence of progesterone receptors, received epirubicin 25 mg/m days 1 and 2, cisplatin 60 mg/m day 1, and fluorouracil 200 mg/m daily as continuous infusion. Responding patients were randomized to continue fluorouracil until 2 weeks after surgery (perioperative chemotherapy) or to stop fluorouracil 1 week before surgery. Fifty-eight patients completed six courses of epirubicin, cisplatin and fluorouracil, and were randomized to perioperative chemotherapy (29 patients) or to control (29 patients). The median Ki-67 index remained stable (32-27.5%) in the perioperative chemotherapy arm (P=0.3) and decreased from 55 to 22.5% in the control arm (P=0.01). The rate of pathological complete remission was 41% in both arms (P=1.0). No significant difference in terms of disease-free survival and overall survival was observed between the two arms. Perioperative chemotherapy failed to show an increase in the pathological complete remission rate. A biological effect on Ki-67 expression was demonstrated.

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Anticancer Drugs. 2006 Nov;17(10):1193-1200.
Ten years of experience with weekly chemotherapy in metastatic breast cancer patients: multivariate analysis of prognostic factors.
Nistico C, Cuppone F, Bria E, Fornier M, Giannarelli D, Mottolese M, Novelli F, Natoli G, Cognetti F, Terzoli E.
Departments of aMedical Oncology bBiostatistics and cPathology, Regina Elena National Cancer Institute, Roma, Italy dBreast Cancer Medicine Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Weekly chemotherapy administration represents an emerging option for the treatment of metastatic breast cancer. In order to identify clinical and biological prognostic factors for outcome, we performed a multivariate analysis in a 10-year experience of weekly chemotherapy for metastatic breast cancer patients. The original databases of phase II trials of metastatic breast cancer patients who had undergone first-line weekly chemotherapy were collected. Clinical and biological covariables were screened for a possible relationship with time to progression and overall survival in a Cox model. From 1990 to 2003, 184 patients were enrolled in three consecutive phase II studies, to evaluate activity and tolerability of weekly epirubicin with lonidamine or vinorelbine or paclitaxel. All patients were evaluable for clinical variables; histological samples were available in 40 patients. At a median follow-up of 24 months, median time to progression was 9 months (95% confidence interval 8-10) and median overall survival was 34 months (95% confidence interval 24-42). Independent variables were response (hazard ratio 2.34, P<0.0001), receptor status (hazard ratio 1.62, P=0.01) and performance status (hazard ratio 2.31, P<0.0001) for time to progression, and response (hazard ratio 1.86, P=0.005), performance status (hazard ratio 2.81, P<0.0001), dominant metastatic site (hazard ratio 2.27, P<0.0001) and enrollment period (hazard ratio 2.51, P=0.001) for overall survival. Although no biological factors were entered into the Cox model owing to the small sample size, some subpopulations showed a negative trend in survival. In our series of patients who had undergone weekly chemotherapy for metastatic breast cancer, independent prognostic factors for survival improvement were responders, performance status 0-1, nonvisceral dominant metastatic site and enrollment period. A greater sample population is needed to extensively screen for biological prognostic factors.

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J Clin Oncol. 2006 Nov 1;24(31):4956-62.
Similar efficacy for ovarian ablation compared with cyclophosphamide, methotrexate, and fluorouracil: from a randomized comparison of premenopausal patients with node-positive, hormone receptor-positive breast cancer.
Ejlertsen B, Mouridsen HT, Jensen MB, Bengtsson NO, Bergh J, Cold S, Edlund P, Ewertz M, de Graaf PW, Kamby C, Nielsen DL.
Department of Oncology, Bldg 5012 Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark. ejlertsen@rh.dk

PURPOSE: To compare the efficacy of ovarian ablation versus chemotherapy in early breast cancer patients with hormone receptor-positive disease. PATIENTS AND METHODS: We conducted an open, randomized, multicenter trial including premenopausal breast cancer patients with hormone receptor-positive tumors and either axillary lymph node metastases or tumors with a size of 5 cm or more. Patients were randomly assigned to ovarian ablation by irradiation or to nine courses of chemotherapy with intravenous cyclophosphamide, methotrexate, and fluorouracil (CMF) administered every 3 weeks. RESULTS: Between 1990 and May 1998, 762 patients were randomly assigned, and the present analysis is based on 358 first events. After a median follow-up time of 8.5 years, the unadjusted hazard ratio for disease-free survival in the ovarian ablation group compared with the CMF group was 0.99 (95% CI, 0.81 to 1.22). After a median follow-up time of 10.5 years, overall survival (OS) was similar in the two groups, with a hazard ratio of 1.11 (95% CI, 0.88 to 1.42) for the ovarian ablation group compared with the CMF group. CONCLUSION: In this study, ablation of ovarian function in premenopausal women with hormone receptor-positive breast cancer had a similar effect to CMF on disease-free and OS. No significant interactions were demonstrated between treatment modality and hormone receptor content, age, or any of the well-known prognostic factors.

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Breast Cancer Res Treat. 2006 Oct 26; [Epub ahead of print]
Predictors and outcomes of contralateral prophylactic mastectomy among breast cancer survivors.
Graves KD, Peshkin BN, Halbert CH, Demarco TA, Isaacs C, Schwartz MD.
Cancer Control Program, Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3300 Whitehaven Street, NW, Suite 4100, Washington, DC, 20007, USA, kdg9@georgetown.edu.

BACKGROUND: Women affected with breast cancer who carry a BRCA1 or BRCA2 (BRCA1/2) mutation are at risk of developing contralateral breast cancer. To reduce the risk of contralateral breast cancer, some patients opt for prophylactic surgery of the unaffected breast (contralateral prophylactic mastectomy, CPM) in addition to mastectomy of the affected breast. METHODS: We conducted the present study to determine the predictors and outcomes of CPM in the year following BRCA1/2 genetic counseling and testing. Four hundred and thirty-five women affected with unilateral breast cancer who received positive or uninformative BRCA1/2 genetic test results completed assessments prior to genetic counseling and testing and 1, 6, and 12 months after receipt of results. RESULTS: Prior to testing, 16% had undergone CPM (in conjunction with mastectomy of the affected breast). In the year following testing, 18% with positive test results and 3% with uninformative test results opted for CPM. CPM following testing was associated with a positive genetic test result, younger age at cancer diagnosis [odds ratio (OR) = 0.94], and higher cancer-specific distress at baseline (OR = 3.28). CPM was not associated with distress outcomes at 12 months. CONCLUSIONS: Following a positive test result, 18% of women previously affected with unilateral breast cancer had a CPM. Women affected with breast cancer at a younger age, particularly those with positive genetic test results and higher cancer-specific distress, are more likely to choose CPM than women who receive uninformative test results and who are less distressed and older at diagnosis. CPM does not appear to impact distress outcomes.

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Cancer. 2006 Oct 23; [Epub ahead of print]
Identifying breast cancer patients most likely to benefit from aromatase inhibitor therapy after adjuvant radiation and tamoxifen.
Freedman GM, Anderson P, Li T, Ross E, Swaby R, Goldstein L.
Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

BACKGROUND.: The purpose of the current study was to examine patient selection for an aromatase inhibitor in breast cancer patients who were free from adverse events 5 years after treatment with tamoxifen. METHODS.: In all, 471 women were treated with breast-conserving surgery, axillary lymph node dissection, and radiation. Eligibility included T1-2 disease, tamoxifen use, follow-up of >/=5 years, no prior breast cancer, and freedom from all events at 5 years of follow-up. Patients treated with chemotherapy more often had T2 disease and positive lymph nodes, and were aged <60 years compared with patients treated with tamoxifen alone. No patient during the period of the current study (1982-1999) received an aromatase inhibitor. The median follow-up was 8.25 years. RESULTS.: There were 36 events: 10 contralateral breast cancers (CBCs) and 26 recurrences (8 local, 1 regional, and 17 distant). The 10-year risk of locoregional recurrence was 2.5%, the 10-year risk of CBC was 3.6%, and the 10-year risk of distant metastasis was 4.4%. The event-free survival rate for all patients was 93%. Only >/=4 positive lymph nodes and premenopausal status were found to be independent variables for decreased event-free survival on multivariate analysis. The overall survival rate was 89%. Only younger age and lower lymph node status were found to be significant predictors of improved overall survival. CONCLUSIONS.: In the current study, a 40% reduction in recurrence/CBC with the addition of an aromatase inhibitor after 5 years of tamoxifen treatment would have had a marginal benefit of 1% to 2%. Women who were premenopausal and patients with >/=4 positive lymph nodes would have the greatest absolute benefit of >3% in the 10-year event-free survival rate from extended therapy. The decision needs to be individualized for patients aged >/=60 years based on their initial lymph node status and the presence of comorbidities that could lower their 5-year life expectancy. Cancer 2006. (c) 2006 American Cancer Society.

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Am Surg. 2006 Oct;72(10):935-8.
Success of neoadjuvant chemotherapy in conversion of mastectomy to breast conservation surgery.
Kaufmann P, Dauphine CE, Vargas MP, Burla ML, Isaac NM, Gonzalez KD, Rosing D, Vargas HI.
Harbor-UCLA Medical Center, Torrance, California, USA.

Neoadjuvant chemotherapy (NC) in patients with breast cancer results in high response rates and has been used with the purpose of reducing tumor size and achieving breast conservation (BC) in individuals who initially require mastectomy. Our objective is to determine the success of NC in achieving BC in women who initially were not candidates for BC. We conducted a cohort study of women with invasive breast cancer who required mastectomy but desired BC surgery. Outcomes measured were tumor response and rates of BC. Thirty-seven women had a mean age of 45 years. Mean tumor size was 51 mm, and 62 per cent were larger than 4 cm. Tumors were predominantly infiltrating ductal carcinoma (83.3%) and high grade (62.2%). Cyclophosphamide, doxorubicin, and 5-fluorouracil with or without taxotere were most commonly used (86%). Complete clinical and pathologic responses were seen in 32.4 per cent and 10.8 per cent of patients, respectively. BC was achieved in 56.7 per cent of cases. Only initial tumor size predicted tumor regression and success of BC (P = 0.014). Neither tumor histology nor biologic markers predicted tumor response. In conclusion, NC is an effective alternative in achieving tumor reduction and BC in selected patients who require mastectomy but desire BC surgery.

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Cochrane Database Syst Rev. 2006 Oct 18;(4):CD005212.
Sequencing of chemotherapy and radiation therapy for early breast cancer.
Hickey BE, Francis D, Lehman MH.
Queensland Radium Institute Mater Centre, Southern Zone Oncology Service, Raymond Terrace, Brisbane, QLD, Australia. hickmenn@bigpond.net.au

BACKGROUND: After surgery for localised breast cancer, adjuvant radiotherapy improves both local control and breast cancer specific survival. In patients at risk of harbouring micro-metastatic disease, adjuvant chemotherapy improves 15-year survival. However, the best sequence of administering these two types of adjuvant therapy for early stage breast cancer is not clear. OBJECTIVES: To determine the effects of different sequencing of chemotherapy and radiotherapy for women with early breast cancer. SEARCH STRATEGY: We searched the Cochrane Breast Cancer Group Specialized Register (10 March 2005). Details of the search strategy and methods of coding are described in the Group's module in The Cochrane Library. We extracted studies that had been coded as 'early', 'chemotherapy' and 'radiotherapy'. SELECTION CRITERIA: Randomised controlled trials evaluating different sequencing of chemotherapy and radiotherapy were included. DATA COLLECTION AND ANALYSIS: We assessed the eligibility and quality of the identified studies and extracted data from the published reports of the included studies. We derived odds ratios (OR) and risk ratios from the available numerical data. Hazard ratios were extracted directly from text. Toxicity data were extracted, where reported. We used a fixed-effect model for meta-analysis and conducted analyses on the basis of the method of sequencing of the two treatments. MAIN RESULTS: Three trials reporting two different sequencing comparisons were identified. There were no significant differences between the various methods of sequencing adjuvant therapy for survival, distant metastases or local recurrence, based on 853 randomised patients in two trials. One of these two trials (647 women) provided data on toxicity. Haematological toxicity (OR 1.43, confidence interval (CI) 1.01 to 2.03) and oesophageal toxicity (OR 1.44, CI 1.03 to 2.02) were significantly increased with concurrent therapy, and nausea and vomiting were significantly decreased (OR 0.70, CI 0.50 to 0.98). Other measures of toxicity did not differ between the two types of sequencing. On the basis of one trial (244 women), radiotherapy before chemotherapy was associated with a significantly increased risk of neutropenic sepsis (OR 2.96, 95% CI 1.26 to 6.98) compared with chemotherapy before radiotherapy, but other measures of toxicity were not significantly different. AUTHORS' CONCLUSIONS: The data included in this review, from three well conducted randomised trials, suggest that different methods of sequencing chemotherapy and radiotherapy do not appear to have a major effect on survival or recurrence for women with breast cancer if radiation therapy is commenced within 7 months after surgery.

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Cochrane Database Syst Rev. 2006 Oct 18;(4):CD005001.
Exercise for women receiving adjuvant therapy for breast cancer.
Markes M, Brockow T, Resch KL.
Rehabilitation Research Institute, Lindenstr. 5, Bad Elster, GERMANY. martina.markes@fbk.sms.sachsen.de

BACKGROUND: A huge clinical research database on adjuvant cancer treatment has verified improvements in breast cancer outcomes such as recurrence and mortality rates. On the other hand, adjuvant therapy with agents such as hormone therapy, chemotherapy and radiotherapy impacts on quality of life due to substantial short- and long-term side effects. OBJECTIVES: To assess the effect of aerobic or resistance exercise interventions during adjuvant treatment for breast cancer on treatment-related side effects such as physical deterioration, fatigue, psychosocial distress and physiological, morphological and biological changes. SEARCH STRATEGY: We searched the Cochrane Breast Cancer Specialised Register (16 July 2004) and the following electronic databases: MEDLINE (1966 to 2006), EMBASE (1988 to 2004), CINAHL (1982 to 2004), SPORTDiscus (1975 to 2004), PsycINFO (1872 to 2003), SIGLE (1880 to 2004), ProQuest Digital Dissertations (1861 to 2004) and Conference Papers Index (1973 to 2004). Furthermore, we screened references in relevant reviews and clinical trials and handsearched relevant journals. SELECTION CRITERIA: We included randomised and non-randomised controlled trials that examined aerobic or resistance exercise, or both, in women undergoing adjuvant treatment for breast cancer. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed methodological quality and adequacy of the training stimulus following a set of standardised criteria. Meta-analyses were performed for physical fitness, fatigue and weight gain using a random-effects model. MAIN RESULTS: Nine trials involving 452 women met the inclusion criteria. Meta-analysis for cardiorespiratory fitness (involving 207 participants) suggested that exercise improves cardiorespiratory fitness (SMD 0.66, 95% CI 0.20 to 1.12). Meta-analysis for fatigue (317 participants) found statistically non-significant improvements for participants in the exercise intervention groups compared to control (non-exercising) groups (SMD -0.12, 95% CI -0.37 to 0.13); the same applied for the meta-analysis of weight gain (147 participants) (SMD -1.11, 95% CI -2.44 to 0.22). Evidence for other outcomes remains limited. Adverse effects (lymphedema and shoulder tendonitis) were observed in two trials. The results from non-randomised controlled trials are similar to those of randomised controlled trials and do not appear to produce any bias. This review is based on a small number of trials with a considerable degree of clinical heterogeneity regarding adjuvant cancer treatments and exercise interventions. AUTHORS' CONCLUSIONS: Exercise during adjuvant treatment for breast cancer can be regarded as a supportive self-care intervention which results in improved physical fitness and thus the capacity for performing activities of daily life, which may otherwise be impaired due to inactivity during treatment. Improvements in fatigue were ambiguous and there was a lack of evidence for improvement with exercise for other treatment-related side effects. Since exercise interventions (for sedentary participants) require behaviour change, strategies for behaviour change should underpin these interventions. Furthermore, long-term evaluation is required due to possible long-term side effects.

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Ann Surg. 2006 Aug;244(2):282-288.
New Trends in Breast Cancer Management: Is the Era of Immediate Breast Reconstruction Changing?
Pomahac B, Recht A, May JW, Hergrueter CA, Slavin SA.
>From the Harvard Medical School, Brigham and Women's Hospital, and Beth Israel Deaconess Medical Center, Boston, MA.

OBJECTIVE:: Review of available literature on the topic of breast reconstruction and radiation is presented. Factors influencing the decision-making process in breast reconstruction are analyzed. New trends of immediate breast reconstruction are presented. SUMMARY BACKGROUND DATA:: New indications for postmastectomy radiation have caused a dramatic increase in the number of radiated patients presenting for breast reconstruction. The major studies and their impact on breast cancer management practice are analyzed. Unsatisfactory results of conventional immediate reconstruction techniques followed by radiotherapy led to a new treatment algorithm for these patients. If the need for postoperative radiation therapy is known, a delayed reconstruction should be considered. When an immediate reconstruction is still desired despite the certainty of postoperative radiotherapy, reconstructive options should be based on tissue characteristics and blood supply. Autologous tissue reconstruction options should be given a priority in an order reflecting superiority of vascularity and resistance to radiation: latissimus dorsi flap, free TRAM or pedicled TRAM without any contralateral components of tissue, pedicled TRAM/midabdominal TRAM, and perforator flap. CONCLUSIONS:: When the indications for postoperative radiotherapy are unknown, premastectomy sentinel node biopsy, delayed-immediate reconstruction, or delayed reconstruction is preferable.

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Am J Ther. 2006 Jul-Aug;13(4):337-48.
Chemoprevention of breast cancer: tamoxifen, raloxifene, and beyond.
Bao T, Prowell T, Stearns V.
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Breast cancer is the most common cancer and the second most common cause of cancer death among women in the United States. While nonrandomized studies have reported that prophylactic mastectomy or oophorectomy can significantly reduce the risk of breast cancer, these approaches are unacceptable to the majority of women. Chemoprevention, which is defined as the prevention of cancer by pharmacological agents that inhibit or reverse the process of carcinogenesis, has thus increasingly become the focus of breast cancer prevention efforts. The first-generation selective estrogen receptor modulator (SERM) tamoxifen is the only US Food and Drug Administration- approved drug for breast cancer prevention and reduces the risk of breast cancer by as much as 50% in high-risk women. Raloxifene, a second-generation SERM, also has demonstrated efficacy for breast cancer prevention and is being compared with tamoxifen in a large randomized trial that has recently completed accrual. The aromatase inhibitors (AIs) decrease the incidence of contralateral breast cancer when used in the adjuvant setting and are being evaluated in ongoing primary prevention studies. In addition, a number of novel agents, including antiinflammatory drugs and retinoid derivatives, which appear to be of promise based on preclinical and epidemiological data, are under investigation. Several important challenges remain, including determination of the appropriate dose and duration of treatment when used in the primary prevention setting and development of new research models using surrogate end points for breast cancer incidence and mortality to permit more rapid clinical application of promising new agents.

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Psychooncology. 2006 Jul 24; [Epub ahead of print]
Long-term telephone therapy outcomes for breast cancer patients.
Sandgren AK, McCaul KD.
MeritCare Roger Maris Cancer Center, USA.

We present the results of a breast cancer clinical trial that tested two therapy interventions delivered by telephone. Women (N=218) with Stages I, II, or III breast cancer were randomly assigned to breast cancer health education or emotional expression interventions, or to a standard care control condition. Outcome and process measures were obtained at baseline, 6-month and 13-month follow-ups. Oncology certified nurses conducted the therapies in six, 30-minute individual phone sessions. Women in the health education condition reported significantly better knowledge and less perceived stress compared to women in the emotional expression and control conditions. No treatment effects, however, were obtained for quality of life or mood, and all women generally improved on these measures over time. Secondary analyses showed that younger women and women with a more advanced stage of breast cancer reported significantly greater avoidant coping. The data show that telephone therapy is a viable delivery modality and that distress improves with time for most women. Overall, this study showed that neither of the two telephone interventions tested had a meaningful effect on quality of life or mood. Copyright (c) 2006 John Wiley & Sons, Ltd.

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Radiat Oncol. 2006 Jul 20;1(1):22 [Epub ahead of print]
Radiation therapy planning with photons and protons for early and advanced breast cancer: an overview.
Weber DC, Ares C, Lomax AJ, Kurtz JM.

ABSTRACT: Postoperative radiation therapy substantially decreases local relapse and moderately reduces breast cancer mortality, but can be associated with increased late mortality due to cardiovascular morbidity and secondary malignancies. Sophistication of breast irradiation techniques, including conformal radiotherapy and intensity modulated radiation therapy, has been shown to markedly reduce cardiac and lung irradiation. The delivery of more conformal treatment can also be achieved with particle beam therapy using protons. Protons have superior dose distributional qualities compared to photons, as dose deposition occurs in a modulated narrow zone, called the Bragg peak. As a result, further dose optimization in breast cancer treatment can be reasonably expected with protons. In this review, we outline the potential indications and benefits of breast cancer radiotherapy with protons. Comparative planning studies and preliminary clinical data are detailed and future developments are considered.

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Cancer. 2006 Jul 21; [Epub ahead of print]
The safety of breast-conserving surgery in patients who achieve a complete pathologic response after neoadjuvant chemotherapy.
Peintinger F, Symmans WF, Gonzalez-Angulo AM, Boughey JC, Buzdar AU, Yu TK, Hunt KK, Singletary SE, Babiera GV, Lucci A, Meric-Bernstam F, Kuerer HM.
Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.

BACKGROUND.: The objectives of this study were to determine the locoregional recurrence (LRR) rate and to evaluate the correlation between surgical resection volume (RV) and LRR in patients with breast cancer who underwent segmental mastectomy after achieving a pathologic complete response (pCR) on neoadjuvant chemotherapy. METHODS.: The authors reviewed the outcomes of all 109 patients who underwent segmental mastectomy after the complete eradication of invasive disease by neoadjuvant chemotherapy at their institution between 1987 and 2002. LRRs were recorded, and RVs after segmental mastectomy were calculated and categorized as small, medium, or large. RESULTS.: At a median follow-up of 6.6 years, 3 patients (2.7%) developed LRR. In 2 of those patients, the recurrence was located in the ipsilateral breast; in the other patient, the recurrence was located in the supraclavicular lymph nodes with synchronous distant metastases. The median RV was 73.12 cm(3) (range, 2.82-451.51 cm(3)). Large RVs (>125 cm(3)) were less common than small RVs (up to 70 cm(3)) or medium RVs (between 70 cm(3) and 125 cm(3); P = .009 and P<.0001, respectively). One patient with a small RV had an LRR at 4 years, and 2 patients with medium RVs had LLRs at 2.3 years and 6 years, respectively. The 5-year and 10-year LRR-free survival rates were 98.1% and 96.5%, respectively, and the corresponding overall survival rates were 96% and 92%, respectively. CONCLUSIONS.: Segmental mastectomy was associated with excellent locoregional control in patients who achieved a pCR after neoadjuvant chemotherapy. Prospective studies are needed to examine whether decreasing the RVs in this patient population leads to an increased LRR rate. Cancer 2006;107:000-000. (c) 2006 American Cancer Society.

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Cochrane Database Syst Rev. 2006 Jul 19;3:CD003368.
Addition of drug/s to a chemotherapy regimen for metastatic breast cancer.
Jones D, Ghersi D, Wilcken N.

BACKGROUND: The addition of a chemotherapy drug or drugs to an established regimen is one method used to increase the dose and intensity of treatment for metastatic breast cancer. OBJECTIVES: To identify and review the randomised trial evidence in the first line management of women with metastatic breast cancer that evaluates the addition of one or more chemotherapy drugs to an established regimen. SEARCH STRATEGY: We searched the specialised register maintained by the Editorial Base of the Cochrane Breast Cancer Group on 3rd August 2004 (updated search on 2nd August 2005) using the codes for "advanced breast cancer" and "chemotherapy". Details of the search strategy applied by the Group to create the register, and the procedure used to code references, are described in the Group's module on the Cochrane Library. SELECTION CRITERIA: Randomised trials that evaluated a first line regimen of at least two chemotherapy drugs, and compared it to that same regimen plus the addition of one or more chemotherapy drugs in women with metastatic breast cancer. DATA COLLECTION AND ANALYSIS: We collected data from published trials and assessed studies for eligibility and quality. Two reviewers extracted data independently. We derived hazard ratios (HR) from time-to-event outcomes where possible, and a fixed effect model was used for meta-analysis. We analysed response rates as dichotomous variables and extracted toxicity data where available. MAIN RESULTS: We identified 17 trials reporting on 22 treatment comparisons (2674 patients randomised). Fifteen trials (20 treatment comparisons) reported results for tumour response and 11 trials (14 treatment comparisons) published time-to-event data for overall survival. There were 1532 deaths in 2116 women randomised to trials of the addition of a drug to the regimen and control (the regimen alone). There was no detectable difference in overall survival between these patients, with an overall HR of 0.96 (95% CI 0.87 to 1.07, P = 0.47) and no statistically significant heterogeneity. We found no difference in time to progression between these regimens, with an overall HR of 0.93 (95% CI 0.81 to 1.07, P = 0.31) and no statistically significant heterogeneity. Addition of a drug to the regimen was favourably associated with overall tumour response rates (OR 1.21, 95% CI 1.01 to 1.44, P = 0.04) although we observed statistically significant heterogeneity for this outcome across the trials. Where measured, acute toxicities such as alopecia, nausea and vomiting and leukopenia were more common with the addition of a drug. AUTHORS' CONCLUSIONS: The addition of one or more drugs to the regimen shows a statistically significant advantage for tumour response in women with metastatic breast cancer but the results suggest no difference in survival time or time to progression. The positive effect on tumour response observed with addition of a drug to the regimen was also associated with increased toxicity.

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Breast Cancer Res Treat. 2006 Jul 19; [Epub ahead of print]
Randomized Phase II Trial of weekly paclitaxel alone versus trastuzumab plus weekly paclitaxel as first-line therapy of patients with Her-2 positive advanced breast cancer.
Gasparini G, Gion M, Mariani L, Papaldo P, Crivellari D, Filippelli G, Morabito A, Silingardi V, Torino F, Spada A, Zancan M, De Sio L, Caputo A, Cognetti F, Lambiase A, Amadori D.
Medical Oncology Division, "San Filippo Neri" Hospital, Unita Operativa Complessa di Oncologia Medica, Azienda Complesso Ospedaliero di Rilevanza Nazionale "S. Filippo Neri ", Via G. Martinotti, 20-00135, Rome, Italy, gasparini.oncology@tiscalinet.it.

BACKGROUND: A randomized Phase II study evaluated the activity of weekly paclitaxel versus its combination with trastuzumab for treatment of patients with advanced breast cancer overexpressing HER-2. PATIENTS AND METHODS: Among 124 patients randomized, 123 are assessable for toxicity and 118 for response. Patients received weekly paclitaxel single agent (80 mg/m(2)) or combined with trastuzumab (4 mg/kg loading dose, then weekly 2 mg/kg). HER-2 overexpression was determined by immunohistochemistry (IHC). Patients with 2+/3+ IHC scores were eligible. IHC was compared with HER-2 serum extracellular domain (ECD). RESULTS: Patient characteristics were similar in the two arms. Both treatments were feasible and well tolerated with no grade 4 hematologic toxicity. No patient developed cardiac toxicity. The combined treatment was statistically significant superior for overall response rate (ORR) (75% vs. 56.9%; P = 0.037), particularly in the subset of IHC 3+ patients (84.5% vs. 47.5%; P = 0.00050). A statistically significant better median time to progression was seen in the subgroup with IHC 3+ (369 vs. 272 days; P = 0.030) and visceral disease (301 vs. 183 days; P = 0.0080) treated with combination. Multivariable analysis of predictive factors showed that only IHC score retained statistically significant value for ORR (P = 0.0035). CONCLUSION: Weekly paclitaxel plus trastuzumab is highly active and safe and it is superior to paclitaxel alone in patients with IHC score of 3+.

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Int J Radiat Oncol Biol Phys. 2006 Mar 15;64(4):1072-80.
A phase III randomized trial comparing adjuvant concomitant chemoradiotherapy versus standard adjuvant chemotherapy followed by radiotherapy in operable node-positive breast cancer: Final results.
Rouesse J, de la Lande B, Bertheault-Cvitkovic F, Serin D, Graic Y, Combe M, Leduc B, Lucas V, Demange L, Nguyen TD, Castera D, Krzisch C, Villet R, Mouret-Fourme E, Garbay JR, Nogues C; The Centre Rene Huguenin Breast Cancer Group.
Centre Rene Huguenin, Saint-Cloud, France.

Purpose: To compare concomitant and sequential adjuvant chemoradiotherapy regimens in node-positive, operable breast cancer patients. Methods and Materials: This was a randomized, French, multicenter, phase III trial enrolling 638 eligible women with prior breast surgery and positive axillary dissection. Patients in Arm A received 500 mg/m(2) 5-fluorouracil, 12 mg/m(2) mitoxantrone, and 500 mg/m(2) cyclophosphamide, with concomitant radiotherapy (50 Gy +/- 10-20-Gy boost). Patients in Arm B received 500 mg/m(2) 5-fluorouracil, 60 mg/m(2) epirubicin, and 500 mg/m(2) cyclophosphamide, with subsequent radiotherapy. Chemotherapy was administered on Day 1 every 21 days for 4 cycles. Results: Median treatment durations were 64 and 126 days (Arms A and B, respectively), with no significant difference in overall or disease-free survival. Five-year locoregional relapse-free survival favored patients with conservative surgery (two thirds of the population), with less local and/or regional recurrence in Arm A than in Arm B (3% vs. 9%; p = 0.01). Multivariate analysis in this subgroup showed a 2.8-fold increased risk of locoregional recurrence with sequential chemoradiotherapy, independent of other prognostic factors (p = 0.027). Febrile neutropenia and Grade 3-4 leukopenia were significantly more frequent in Arm A. Subclinical left ventricular ejection fraction events at 1 year were more frequent with concomitant radiotherapy (p = 0.02). Conclusions: Concomitant radiotherapy with adjuvant fluorouracil, mitoxantrone, and cyclophosphamide has significantly better locoregional control in node-positive breast cancer after conservative surgery and 50% shorter treatment, albeit with slightly more acute toxicity. With mitoxantrone no longer available for adjuvant breast cancer treatment, alternative concomitant chemoradiotherapy studies are needed.

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Expert Rev Anticancer Ther. 2006 Mar;6(3):427-36.
Drug treatments for adjuvant chemotherapy in breast cancer: recent trials and future directions.
Dang CT.
Clinical Assistant Physician, Solid Tumor Division, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. dangc@mskcc.org.

Adjuvant chemotherapy with anthracycline-based regimens has been proven to decrease the risk of relapse and cancer-related mortality in women with early-stage breast cancer. The taxanes, paclitaxel and docetaxel, have been incorporated into several adjuvant chemotherapy regimens in recent studies. Some of these trials have matured and demonstrated a definitive benefit with the use of taxanes. The available studies reveal that the addition of a taxane after an anthracycline or the substitution of a taxane into a three-drug regimen, such as docetaxel, doxorubicin and cyclophosphamide, clearly demonstrate a benefit for taxanes in the adjuvant treatment of breast cancer. The toxicities of the taxanes are generally acceptable. Targeted therapy, such as with trastuzumab, has demonstrated a large benefit that previously has never been seen in adjuvant chemotherapy trials, and thus, should now be part of the standard in the treatment of HER-2/neu positive breast cancer. Newer agents are on the horizon.

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Expert Opin Investig Drugs. 2006 Mar;15(3):317-26.
Arzoxifene: the development and clinical outcome of an ideal SERM.
Munster PN.
Director of Breast Cancer Research, H. Lee Moffitt Cancer Center, Interdisciplinary Oncology Program, SRB 2. Room 22033, 12902 Magnolia Drive, Tampa, FL 33612, USA. Munstepn@moffitt.usf.edu.

Hormone-sensitive tumours are among the most common cancers in women. Specific inhibition of the estrogen receptor by selective estrogen receptor downregulators or selective estrogen receptor modulators (SERMs) is effective for the treatment of breast and endometrial cancers and may be used for the prevention of breast cancer. Due to differential recruitment of co-activators and corepressors, SERMs are tissue specific and may have antiestrogenic effects in some tissues, with estrogen agonist activity in others. The ideal SERM would have antiestrogenic effects on the breast and endometrium, but pro-estrogenic effects on bone and lipids. The SERM, arzoxifene (LY-353381.HCl) meets all of these criteria. This review summarises the development, preclinical studies and the clinical outcome of arzoxifene and places it in context with other modalities in the treatment of hormone receptor-positive tumours.

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Int J Radiat Oncol Biol Phys. 2006 Feb 23; [Epub ahead of print]
Phase II trial of brachytherapy alone after lumpectomy for select breast cancer: Toxicity analysis of RTOG 95-17.
Kuske RR, Winter K, Arthur DW, Bolton J, Rabinovitch R, White J, Hanson W, Wilenzick RM.
Arizona Oncology Services and Foundation for Cancer Research and Education, Phoenix, AZ.

PURPOSE: Accelerated partial breast irradiation (APBI) can be delivered with brachytherapy within 4-5 days compared with 5-6 weeks for conventional whole breast external beam radiotherapy. Radiation Therapy Oncology Group 95-17 is the first prospective phase I-II cooperative group trial of APBI alone after lumpectomy in select patients with breast cancer. The toxicity rates are reported for low-dose-rate (LDR) and high-dose-rate (HDR) APBI on this trial. METHODS AND MATERIALS: The inclusion criteria for this study included invasive nonlobular tumors </=3 cm after lumpectomy with negative surgical margins and axillary dissection with zero to three positive axillary nodes without extracapsular extension. The patients were treated with either LDR APBI (45 Gy in 3.5-5 days) or HDR APBI (34 Gy in 10 twice-daily fractions within 5 days). Chemotherapy (>/=2 weeks after APBI) and/or tamoxifen could be given at the discretion of the treating physicians. RESULTS: Between August 1997 and March 2000, 100 women were enrolled in this study, and 99 were evaluated. Of the 99 women, 33 were treated with LDR and 66 with HDR APBI. The median follow-up for all patients was 2.7 years (range, 0.6-4.4 years) and was 2.9 years for LDR and 2.7 years for HDR patients. Toxicities attributed to APBI included erythema, edema, tenderness, pain, and infection. Of the 66 patients treated with HDR APBI, 2 (3%) had Grade 3 or 4 toxicity. Of the 33 patients treated with LDR, 3 (9%) had Grade 3 or 4 toxicity during brachytherapy. Late toxicities included skin thickening, fibrosis, breast tenderness, and telangiectasias. No patient experienced late Grade 4 toxicity; the rate of Grade 3 toxicity was 18% for the LDR and 4% for the HDR groups. CONCLUSION: Acute and late toxicity for this invasive breast radiation technique was modest and acceptable. Patients receiving chemotherapy, a nonprotocol therapy, had a greater rate of Grade 3 toxicity. The study design did not allow for this to be tested statistically.

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Ann Oncol. 2006 Feb 23; [Epub ahead of print]
Innovative schedule of oral idarubicin in elderly patients with metastatic breast cancer: comprehensive results of a phase II multi-institutional study with pharmacokinetic drug monitoring.
Crivellari D, Lombardi D, Corona G, Massacesi C, Talamini R, Sorio R, Magri MD, Lestuzzi C, Lucenti A, Veronesi A, Toffoli G.
Division of Medical Oncology C, Centro di Riferimento Oncologico, Aviano, Italy.

BACKGROUND: To determine if protracted low-dose oral idarubicin (IDA), feasible in a previous dose-finding study, would result in similar activity and a better toxicity profile in patients with metastatic breast cancer. PATIENTS AND METHODS: Elderly women (>/=65 years) with metastatic breast carcinoma were treated with 7.5 mg/day for 21 consecutive days, every 4 weeks. After the first fourteen patients, due to excessive toxicity, the protocol was amended to 5 mg/day. IDA and Idarubicinol (IDOL) plasma concentrations (C(trough)) were investigated in all patients. RESULTS: Between April 1999 and June 2004, 47 elderly patients were accrued in this two-part study (14 and 33 patients respectively). The median age was 74 and 75 years respectively. Visceral involvement was present in most patients. A partial response was noted in 7/31 patients (22%; 95% CI, 9.6-41.1%). Eleven patients had stable disease (33%). At the dose of 5 mg/day the treatment was well tolerated. Neutropenia grade 4 was present in only 6% of patients; alopecia > grade 1 and cardiotoxicity did not occur. The median time to progression was 3 months and the median overall survival was 17 months. IDA C(trough) and IDOL C(trough) levels were significantly associated with haematologic toxicity. CONCLUSION: This study shows that idarubicin at the dose of 5 mg/day for 21 consecutive days is feasible and effective in elderly breast cancer patients but do not demonstrate an improvement in efficacy. A determination of the IDA and IDOL plasma levels (C(trough)) is predictive for toxicity.

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J Clin Oncol. 2006 Feb 27; [Epub ahead of print]
Tamoxifen After Adjuvant Chemotherapy for Premenopausal Women With Lymph Node-Positive Breast Cancer: International Breast Cancer Study Group Trial 13-93.
[No authors listed]

PURPOSE: The value of adjuvant tamoxifen after chemotherapy for premenopausal women with breast cancer has not been adequately assessed. PATIENTS AND METHODS: Between 1993 and 1999, International Breast Cancer Study Group Trial 13-93 enrolled 1,246 assessable premenopausal women with axillary node-positive, operable breast cancer. All patients received chemotherapy (cyclophosphamide plus either doxorubicin or epirubicin for four courses followed by immediate or delayed classical cyclophosphamide, methotrexate, and fluorouracil for three courses), which was followed by either tamoxifen (20 mg daily) for 5 years or no further treatment. The primary end point was disease-free survival (DFS). Tumors were classified as estrogen receptor (ER) -positive (n = 735, 59%) if immunohistochemical (IHC) or ligand-binding assays (LBA) were clearly positive. The ER-negative group included all other tumors (n = 511, 41%). A subset of the ER-negative group was defined as ER absent (n = 108, 9%) if IHC staining was none or if the LBA result was 0 fmol/mg cytosol protein. The median follow-up time was 7 years. RESULTS: Tamoxifen improved DFS in the ER-positive cohort (hazard ratio [HR] for tamoxifen v no tamoxifen = 0.59; 95% CI, 0.46 to 0.75; P < .0001) but not in the ER-negative cohort (HR = 1.02; 95% CI, 0.77 to 1.35; P = .89). Tamoxifen had a detrimental effect on patients with ER-absent tumors compared with no tamoxifen in an unplanned exploratory analysis (HR = 2.10; 95% CI, 1.03 to 4.29; P = .04). Patients with ER-positive tumors who achieved chemotherapy-induced amenorrhea had a significantly improved outcome (HR for amenorrhea v no amenorrhea = 0.61; 95% CI, 0.44 to 0.86; P = .004), whether or not they received tamoxifen. CONCLUSION: Tamoxifen after adjuvant chemotherapy significantly improved treatment outcome in premenopausal patients with endocrine-responsive disease, but its use as adjuvant therapy for patients with ER-negative tumors is not recommended.

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BMC Cancer. 2006 Feb 21;6(1):39 [Epub ahead of print]
The use of complementary and alternative medicines among patients with locally advanced breast cancer - a descriptive study.
Helyer LK, Chin S, Chui BK, Fitzgerald B, Verma S, Rakovitch E, Dranitsaris G, Clemons M.

ABSTRACT: BACKGROUND: Complementary and alternative medicine (CAM) use is common among cancer patients. This paper reviews the use of CAM in a series of patients with locally advanced breast cancer (LABC). METHODS: Women with LABC attending a specialist clinic at a single Canadian cancer centre were identified and approached . Participants completed a self-administered survey regarding CAM usage, beliefs associated with CAM usage, views of their risks of developing recurrent cancer and of dying of breast cancer. Responses were scored and compared between CAM users and non-users. RESULTS: Thirty-six patients were approached, 32 completed the questionnaire (response rate 89%). Forty-seven percent of LABC patients were identified as CAM users. CAM users were more likely to be younger, married, in a higher socioeconomic class and of Asian ethnicity than non-users. CAM users were likely to use multiple modalities simultaneously (median 4) with vitamins being the most popular (60%). Motivation for CAM therapy was described as, "assisting their body to heal" (75%), to 'boost the immune system' (56%) and to "give a feeling of control with respect to their treatment" (56%). CAM therapy was used concurrently with conventional treatment in 88% of cases, however, 12% of patients felt that CAM could replace their conventional therapy. Psychological evaluation suggests CAM users perceived their risk of dying of breast cancer was similar to that of the non-Cam group (67% vs.65%), however the CAM group had less severe anxiety and depression. CONCLUSIONS: The motivation, objectives and benefits of CAM therapy in a selected population of women with LABC are similar to those reported for women diagnosed with early stage breast cancer. Psychological benefits can be demonstrated as CAM users display less anxiety and depression and are less likely to believe they will die of their breast cancer. However the actual benefit to overall and disease free survival has yet to be demonstrated, as well as the possible interactions with conventional therapy. Consequently more research is needed in this ever-growing field.

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N Engl J Med. 2006 Feb 23;354(8):809-20. Comment in: N Engl J Med. 2006 Feb 23;354(8):789-90.
Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer.
Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkio S, Flander M, Helle L, Ingalsuo S, Johansson K, Jaaskelainen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators.
Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland.

BACKGROUND: We compared docetaxel with vinorelbine for the adjuvant treatment of early breast cancer. Women with tumors that overexpressed HER2/neu were also assigned to receive concomitant treatment with trastuzumab or no such treatment. METHODS: We randomly assigned 1010 women with axillary-node-positive or high-risk node-negative cancer to receive three cycles of docetaxel or vinorelbine, followed by (in both groups) three cycles of fluorouracil, epirubicin, and cyclophosphamide. The 232 women whose tumors had an amplified HER2/neu gene were further assigned to receive or not to receive nine weekly trastuzumab infusions. The primary end point was recurrence-free survival. RESULTS: Recurrence-free survival at three years was better with docetaxel than with vinorelbine (91 percent vs. 86 percent; hazard ratio for recurrence or death, 0.58; 95 percent confidence interval, 0.40 to 0.85; P=0.005), but overall survival did not differ between the groups (P=0.15). Within the subgroup of patients who had HER2/neu-positive cancer, those who received trastuzumab had better three-year recurrence-free survival than those who did not receive the antibody (89 percent vs. 78 percent; hazard ratio for recurrence or death, 0.42; 95 percent confidence interval, 0.21 to 0.83; P=0.01). Docetaxel was associated with more adverse effects than was vinorelbine. Trastuzumab was not associated with decreased left ventricular ejection fraction or cardiac failure. CONCLUSIONS: Adjuvant treatment with docetaxel, as compared with vinorelbine, improves recurrence-free survival in women with early breast cancer. A short course of trastuzumab administered concomitantly with docetaxel or vinorelbine is effective in women with breast cancer who have an amplified HER2/neu gene. (International Standard Randomised Controlled Trial number, ISRCTN76560285.). Copyright 2006 Massachusetts Medical Society.

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Curr Opin Obstet Gynecol. 2006 Feb;18(1):47-52.
Locally advanced breast cancer.
Barni S, Mandala M.
Division of Medical Oncology, Treviglio Hospital, Treviglio, Italy.

PURPOSE OF REVIEW: The management of locally advanced breast cancer requires a combined-modality treatment approach involving surgery, radiotherapy and systemic therapy. In this paper, we review clinical and experimental studies in order to evaluate how basic and clinical research in locally advanced breast cancer has progressed in the past year. We focus on four distinct issues: general strategies and natural history; the role of taxanes; trastuzumab in locally advanced breast cancer; and prognostic and predictive factors. RECENT FINDINGS: This disease requires an aggressive, multimodality approach incorporating chemotherapy and mastectomy; loco-regional radiation is warranted. This should be followed by hormonal intervention for those with oestrogen-receptor-positive disease. In addition, patients with a poor response to primary chemotherapy should receive a non-cross-resistant regimen, but this issue should be further investigated in clinical trials. The addition of a taxane improves the clinical and pathological response compared with an anthracycline-based regimen. The long-term data for disease-free and overall survival are, however, still being collected. The results of ongoing studies will suggest the best schedule, dose and timing of taxanes. Trastuzumab works well as a monotherapy or in combination with chemotherapy. SUMMARY: We are entering an exciting era in which new technologies, target therapy and classical approaches may improve operability, safety and possibly the disease-free and overall survival of patients with locally advanced breast cancer.

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Curr Opin Obstet Gynecol. 2006 Feb;18(1):41-46.
Update on aromatase inhibitors in breast cancer.
Gould RE, Garcia AA.
aDivision of Hematology and Oncology, Cedars Sinai Medical Center, Los Angeles, USA bWomen's Cancer Research Institute, Cedars Sinai Medical Center, Los Angeles, USA.

PURPOSE OF REVIEW: Hormonal treatment is one of the cornerstones of management for breast cancer. For many years, tamoxifen represented the gold standard. The development of aromatase inhibitors has, however, challenged the primary role of tamoxifen. Randomized studies evaluating the role of aromatase inhibitors in both the metastatic and adjuvant settings, in postmenopausal women, have been conducted. This article describes the most recent available data for these trials. RECENT FINDINGS: The efficacy of aromatase inhibitors for metastatic disease is well established and has not changed recently. Multiple adjuvant aromatase inhibitor trials have been completed and published or presented. These trials vary in the timing of aromatase inhibitor administration, but all show statistically significant reductions in breast-cancer recurrence. An improvement in overall survival has not been observed to date. Tolerability is improved with aromatase inhibitors, the major concern with the use of aromatase inhibitors being the development of osteoporosis and bone fractures. SUMMARY: Aromatase inhibitors are consistently showing improved efficacy and tolerability to tamoxifen for both early and advanced breast cancer. Optimal therapy for postmenopausal women should include an aromatase inhibitor. The optimal sequence of aromatase inhibitors and tamoxifen for adjuvant therapy is still, however, under investigation.

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Breast Cancer Res Treat. 2005 Nov 3;:1-9 [Epub ahead of print]
High prognostic significance of residual disease after neoadjuvant chemotherapy: a retrospective study in 710 patients with operable breast cancer.
Abrial SC, Penault-Llorca F, Delva R, Bougnoux P, Leduc B, Mouret-Reynier MA, Mery-Mignard D, Bleuse JP, Dauplat J, Cure H, Chollet P.
Centre Jean Perrin, 58 Rue Montalembert, BP 392, , 63011, Clermont-Ferrand Cedex 1, France.

Prognostic factors are used to help clinical decision-making in selecting the appropriate treatment for individual patients. The purpose of this retrospective study was to identify one or more factors associated with overall survival (OS) and disease-free survival (DFS), in 710 patients with operable breast cancer, subjected to neoadjuvant chemotherapy followed by surgery, radiotherapy and adjuvant treatments. At a median follow-up of 7.6 years, univariate analysis showed that pathological complete response (pCR) was significantly related to survival (p < 0.003), as well as accepted prognostic factors, as SBR and MSBR grades, hormonal receptors or node involvement at surgery, who remained significant in our study (p < 0.001). The revised Nottingham prognostic index (NPI) and related indices (BGI, MNPI and MBGI) were also significantly associated to survival (p < 0.003). In multivariate analysis, node involvement and MSBR grade remained prognostic factors for OS and DFS (p < 0.0003 and p < 0.02, respectively). The MNPI and pCR were significantly related with OS (p = 0.04) and pts with hormonal receptor-positive tumours had a better DFS than others (p = 0.004). Among all clinical and pathological parameters, axillary dissection after neoadjuvant chemotherapy is still important to determine node involvement, a major prognostic factor. Moreover, MSBR grade seemed to be more accurate and predictive of long-term outcome than the standard SBR grade. It is concluded that, outside any other 'biological' factor, residual disease in breast and nodes must be strongly considered after an induction chemotherapy so as to choose adjuvant treatment for the individual patient.

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Breast Cancer Res Treat. 2005 Nov 3;:1-9 [Epub ahead of print]
Multicenter phase II study of trastuzumab in combination with epirubicin and docetaxel as first-line treatment for HER2-overexpressing metastatic breast cancer.
Venturini M, Bighin C, Monfardini S, Cappuzzo F, Olmeo N, Durando A, Puglisi F, Nicoletto O, Lambiase A, Del Mastro L.
Division of Medical Oncology, Istituto Nazionale per la Ricerca sul Cancro, Largo R. Benzi 10, I-16132, Genova, Italy, marco.venturini@istge.it.

The primary objective of study is to evaluate cardiac safety of trastuzumab in combination with epirubicin and docetaxel. HER2-overexpressing metastatic breast cancer patients were enrolled in a two-stage, multicenter phase II trial with weekly trastuzumab (4 and then 2 mg/kg) with epirubicin and docetaxel (either 75 mg/m(2)) on day 1 every 3 weeks. After eight courses of chemotherapy, trastuzumab was continued as a single agent. To assess cardiotoxicity, patients were evaluated for left ventricular ejection fraction (LVEF) at baseline, every two cycles during chemotherapy and trastuzumab, and every 3 months during trastuzumab alone. Cardiotoxicity was defined as signs and/or symptoms of congestive heart failure (CHF) and/or an absolute decrease in LVEF of >/=20 units or a decline to </=45%. In the first stage of the study, three episodes of cardiotoxicity were observed (two asymptomatic declines of LVEF and one CHF) in 29 patients, and recruitment continued. During follow-up of patients who continued trastuzumab after chemotherapy, seven further cardiologic events occurred (three asymptomatic decline of LVEF and four CHF). Therefore, recruitment was interrupted after the 45th patient. The majority of cardiac events occurred late during trastuzumab alone, half were asymptomatic and all cases of CHF were resolved using cardiac therapy. Complete and partial responses were 20 and 47%, respectively, and the median time to progression was 15.7 months (95% CI, 11.6-19.0 months). In light of the cardiotoxicity experienced during this study, we currently recommend that this combination be used only in controlled clinical trials under vigilant cardiac monitoring.

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Lancet Oncol. 2005 Nov;6(11):886-98.
Selection of adjuvant chemotherapy for treatment of node-positive breast cancer.
Trudeau M, Charbonneau F, Gelmon K, Laing K, Latreille J, Mackey J, McLeod D, Pritchard K, Provencher L, Verma S.
Division of Medical Oncology and Haematology, Toronto Sunnybrook Regional Cancer Centre, University of Toronto, Ontario, Canada.

Over the past two decades, several studies have suggested that regimens that contain anthracyclines are more effective than those that do not. A meta-analysis by the 2005 Early Breast Cancer Trialists' Collaborative Group confirmed that about 6 months of anthracycline-based polychemotherapy in the adjuvant setting reduced the yearly death rate from breast cancer by about 38% for women younger than 50 years and by 20% for women aged 50-69 years. Although this meta-analysis found that survival was better with regimens that contain anthracycline than with regimens based on cyclophosphamide, methotrexate, and fluorouracil, the best use of anthracycline-based regimens remains unclear. Adjuvant regimens in use can be categorised into three groups: standard-dose anthracycline; escalated-dose epirubicin; and anthracyclines and taxanes. The duration of treatment and combination of dose and drugs varies between these three categories. We reviewed the three types of regimen to establish which provide a better outcome in terms of safety, efficacy, cost, and convenience to patients. We found that both escalated-dose epirubicin and anthracycline-taxane regimens were most effective in terms of disease-free survival and overall survival. Of the specific anthracycline-based regimens, the docetaxel, doxorubicin, and cyclophosphamide regimen (TAC); the fluorouracil, 100 mg epirubicin, and cyclophosphamide regimen (FEC100); and the cyclophosphamide, epirubicin, and fluorouracil regimen (CEF) produced the greatest proportional decreases in 5-year death rate.

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Ann Oncol. 2005 Oct 26; [Epub ahead of print]
Fulvestrant, a new treatment option for advanced breast cancer: tolerability versus existing agents.
Vergote I, Abram P.
University Hospitals, Leuven, Belgium.

Owing to its favourable tolerability profile versus cytotoxic chemotherapy, endocrine therapy is the treatment of choice for postmenopausal women with hormone receptor-positive advanced breast cancer (ABC). However, tolerability concerns associated with some endocrine treatments and the potential for cross-resistance has helped to drive the need for new, effective and better-tolerated agents. Fulvestrant is a new type of oestrogen receptor antagonist with no agonist effects. In phase III trials, fulvestrant has been shown to be at least as effective as the third-generation aromatase inhibitor (AI) anastrozole in the treatment of postmenopausal women with ABC progressing on prior tamoxifen therapy. Fulvestrant is administered as a once-monthly 250 mg intramuscular injection into the gluteus muscle. Here we review the tolerability of fulvestrant in the treatment of postmenopausal women with hormone-sensitive ABC and compare it with that of the four most frequently prescribed endocrine treatments for advanced disease (tamoxifen, anastrozole, letrozole and exemestane). Compared with these agents, fulvestrant is well tolerated and is associated with a lower incidence of joint disorders compared with the non-steroidal AIs and none of the potential androgenic side-effects that are sometimes seen with steroidal AIs. It is also associated with hot flushes compared with tamoxifen. Fulvestrant therefore provides clinicians and patients with a useful, well-tolerated option for the treatment of hormone-sensitive ABC. Integration of such agents into the endocrine treatment sequence may extend the opportunity for using well-tolerated therapies before chemotherapy needs to be considered and thus may improve quality of life for patients with ABC. The overall safety profiles of newer agents such as fulvestrant will become increasingly clear with their ongoing use.

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Breast Cancer Res Treat. 2005 Oct 28;:1-11 [Epub ahead of print]
Complementary and alternative therapeutic approaches in patients with early breast cancer: a systematic review.
Gerber B, Scholz C, Reimer T, Briese V, Janni W.
Department of Obstetrics and Gynecology , University of Rostock, Rostock, Germany.

Complementary and alternative medicine (CAM) is becoming increasingly popular, particularly among patients with breast cancer. We have done a systematic review of studies published between 1995 and February 2005, identified through a comprehensive search. CAM encompasses a wide range of treatment modalities, including dietary and vitamin supplements, mind-body approaches, acupuncture, and herbal medicines. The objectives of CAM treatments are diverse: reduction of therapy-associated toxicity, improvement of cancer-related symptoms, fostering of the immune system and even direct anticancer effects. Clinical trials have generated few or no data on the efficacy of CAM, whether regarding disease recurrence, survival, overall quality of life or safety. Some CAM methods may even have adverse effects or reduce the efficacy of conventional treatment. The primary justification for CAM is based on empirical evidence, case studies, and hypothetical physiological effects. We conclude that available data on CAM modalities in the treatment of early-stage breast cancer does not support their application.

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Cancer Treat Rev. 2005 Oct 30; [Epub ahead of print]
Taxanes in the treatment of early breast cancer.
Ring AE, Ellis PA.
Department of Medical Oncology, Thomas Guy House, Guy's Hospital, London SE1 9RT, UK.

The taxanes docetaxel and paclitaxel have established roles as two of the most active agents in the treatment of metastatic breast cancer. These two drugs are now being incorporated into the management of early breast cancer. A first generation of trials has explored whether the addition of taxanes either sequentially or in combination with adjuvant anthracycline-based chemotherapy improves outcome for patients with early breast cancer. A second generation of trials are now underway which are based on the assumption that taxanes are beneficial in the adjuvant setting, and are comparing the different taxanes, dosing regimens and the addition of further agents. Trials in the neoadjuvant setting have recently demonstrated improved response rates with the addition of taxanes into existing anthracycline-based regimes. This review critically appraises these trials and provides an overview of ongoing research in the area.

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Breast Cancer Res Treat. 2005 Oct 28;:1-6 [Epub ahead of print]
Clinical response to neoadjuvant docetaxel predicts improved outcome in patients with large locally advanced breast cancers.
Tham YL, Gomez LF, Mohsin S, Gutierrez MC, Weiss H, Hilsenbeck SG, Elledge RM, Chamness GC, Osborne CK, Allred DC, Chang JC.
Breast Center and the Departments of Medicine, Pathology, and Molecular and Cellular Biology, Baylor College of Medicine and the Methodist Hospital, Houston, TX, 77030 , USA.

PURPOSE: In the adjuvant setting, taxanes modestly improve clinical outcome and survival. The goal of the present study was to define the efficacy of neoadjuvant docetaxel in treatment-naive large, locally advanced breast cancers and to better understand docetaxel's mechanism of action by evaluating biomarker modulation in response to treatment. PATIENTS AND METHODS: Fifty-one patients were enrolled. Patients received four cycles of docetaxel (100 mg/m(2) q3weeks) followed by surgery and four cycles of doxorubicin and cyclophosphamide (60/600 mg/m(2) q3weeks). Radiation and hormonal therapy were given if clinically indicated. Clinical responses were assessed at completion of neoadjuvant docetaxel. Pathological responses were considered complete (pCR) if no tumor cells were identified in the surgical specimen or near complete (npCR) if only occasional scattered tumor cells were seen. Proliferation (Ki-67) and apoptosis (cleaved caspase-3) were measured by IHC in tissue obtained at baseline and at surgery. RESULTS: The median tumor size was 9 cm (range 4-30 cm). Objective response rate was 75% with clinical complete response in 27%, partial response in 48%, and stable disease in 25% of the patients. pCR/npCR was reported in 20% of patients. With a median follow up of 28 months, 98 and 78% of the patients were alive at 12 and 24 months, respectively. Overall survival at 24 months was significantly better in patients who achieved a clinical response, 85 versus 51%, p=0.008, but pCR/npCR was not a significant predictor of outcome. Apoptosis was induced in clinical responders (p=0.002), while the proliferation index did not change significantly. In patients who had no clinical response to docetaxel, neither apoptosis nor proliferation changed significantly. CONCLUSION: Neoadjuvant single agent docetaxel is effective in treating patients with large locally advanced breast cancer and clinical response is associated with improved survival. Docetaxel acts therapeutically by inducing apoptosis and this can be used as a marker of response.

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J Clin Oncol. 2005 Oct 31; [Epub ahead of print]
Use of Statins and Breast Cancer: A Meta-Analysis of Seven Randomized Clinical Trials and Nine Observational Studies.
Bonovas S, Filioussi K, Tsavaris N, Sitaras NM.
Departments of Pharmacology and Pathophysiology, School of Medicine, University of Athens; and Department of Epidemiological Surveillance and Intervention, Hellenic Center for Infectious Disease Control, Athens, Greece.

PURPOSE: A growing body of evidence suggests that statins may have chemopreventive potential against breast cancer. Laboratory studies demonstrate that statins induce apoptosis and reduce cell invasiveness in various cell lines, including breast carcinoma cells. However, the clinical relevance of these data remains unclear. The nonconclusive nature of the epidemiologic data prompted us to conduct a detailed meta-analysis of the studies published on the subject in peer-reviewed literature. PATIENTS AND METHODS: A comprehensive search for articles published up until 2005 was performed; reviews of each study were conducted; and data were abstracted. Before meta-analysis, the studies were evaluated for publication bias and heterogeneity. Pooled relative risk (RR) estimates and 95% CIs were calculated using the random and the fixed-effects models. Subgroup and sensitivity analyses were also performed. RESULTS: Seven large randomized trials and nine observational studies (five case-control and four cohort studies) contributed to the analysis. We found no evidence of publication bias or heterogeneity among the studies. Statin use did not significantly affect breast cancer risk (fixed effects model: RR = 1.03; 95% CI, 0.93 to 1.14; random effects model: RR = 1.02; 95% CI, 0.89 to 1.18). When the analyses were stratified into subgroups, there was no evidence that study design substantially influenced the estimate of effects. Furthermore, the sensitivity analysis confirmed the stability of our results. CONCLUSION: Our meta-analysis findings do not support a protective effect of statins against breast cancer. However, this conclusion is limited by the relatively short follow-up times of the studies analyzed. Further studies are required to investigate the potential decrease in breast cancer risk among long-term statin users.

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Breast Cancer Res Treat. 2005 Oct 25; [Epub ahead of print]
Conservative Treatment of Breast Cancer: Its Evolution.
Luini A, Gatti G, Galimberti V, Zurrida S, Intra M, Gentilini O, Paganelli G, Viale G, Orecchia R, Veronesi P, Veronesi U.
Division of Breast Surgery, European Institute of Oncology, Milan, Italy.

Background. Over recent decades, breast carcinoma surgery has witnessed a considerable evolution. The extent of surgery undertaken has progressively reduced, leading to less disfigurement and a significant improvement in quality of life, thereby offering women considerable motivation to seek early diagnosis. From an oncological perspective, outcome was found to be equally effective, and this key observation provided us with significant impetus to investigate the effects of reducing the radiotherapy field.Patients and methods. We present the achievements made so far in the conservative treatment of breast carcinoma, based on experiences at the European Institute of Oncology in Milan and, prior to 1994, at the Milan Cancer Institute.Results and discussion. Conservative surgery of breast carcinoma, both in the breast and in the axillary nodes, has yielded very good results in terms of overall survival and impact on quality of life. The reduction of the radiation field, conducted in our Institute by means of electron intraoperative radiotherapy (ELIOT), is currently the subject of evaluation via a randomised trial.

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Onkologie. 2005 Oct;28(11):558-64.
Safety and Efficacy of Trastuzumab Every 3 Weeks Combined with Cytotoxic Chemotherapy in Patients with HER2-Positive Recurrent Breast Cancer: Findings from a Case Series.
Ardavanis A, Tryfonopoulos D, Orfanos G, Karamouzis M, Scorilas A, Alexopoulos A, Rigatos G.
First Department of Medical Oncology, St. Savas Anticancer Hospital, Athens, Greece.

Background: Trastuzumab has been repeatedly shown to result in significant clinical benefits and was subsequently accepted as the treatment of choice for HER2-positive advanced breast cancer - particularly as first-line treatment in combination with taxanes and as monotherapy in the second-line or third-line setting. Trastuzumab is currently licensed as a weekly treatment, although a 3-weekly schedule could be used conveniently in combination with other cytotoxic agents that are administered on a 3-weekly basis in metastatic breast cancer. Patients and Methods: We determined the safety of i.v. trastuzumab (8 mg/kg followed by 6 mg/kg) every 3 weeks in combination with chemotherapeutic agents administered in 3-weekly courses (docetaxel, vinorelbine and capecitabine) in 31 patients with HER2-positive recurrent locoregional and/or metastatic breast cancer. Results: 3-weekly trastuzumab appeared to be as well tolerated as the standard once-weekly schedule. All myelosuppressive adverse events and the majority of non-hematological adverse events were typical and characteristic of the individual concomitant cytotoxic agents. Transient trastuzumab-related infusion reactions occurred in 5 patients and 1 patient developed cardiac dysfunction, which recovered after discontinuation of trastuzumab. Efficacy appeared favourable: 18 clinical responses (3 complete and 15 partial) and 8 disease stabilizations gave an overall response rate of 58% (70% in the 20 patients receiving first-line therapy). Median progression-free and overall survival times were 9.9 months (95% CI: 6.3-13.5) and 23.1 months (95% CI: 19.2-27.0), respectively. Conclusions: These findings will likely encourage further evaluation of this more convenient 3-weekly trastuzumab regimen in patients with HER2-positive metastatic breast cancer.

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Fetal Diagn Ther. 2005 Sep-Oct;20(5):442-4.
Infiltrative breast cancer during pregnancy and conservative surgery.
Annane K, Bellocq JP, Brettes JP, Mathelin C.
Service de Gynecologie-Obstetrique, Hopitaux Universitaires de Strasbourg, Strasbourg, France.

Mastectomy is considered as the standard therapy for gestational breast cancer. Since radiation therapy is harmful for the fetus, conservative surgery is rarely used during pregnancy. Among 16 patients with gestational breast cancer, 10 and 6 were treated with conservative surgery and mastectomy, respectively. No local recurrences occurred with a median follow-up time of 87 months. Among the 10 patients treated with conservative surgery, 3 chose therapeutic abortion and 7 opted to continue their pregnancy. Concerning these 7 fetuses, there were no congenital anomalies, nor growth restriction. All children were normal physically and neurologically. We concluded that conservative breast surgery may be an alternative to mastectomy in the treatment of gestational breast cancer and is safe for the fetus. Copyright (c) 2005 S. Karger AG, Basel.

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Hell J Nucl Med. 2005 May-Aug;8(2):103-108.
Monoclonal antibodies: old and new trends in breast cancer imaging and therapeutic approach.
Stipsanelli E, Valsamaki P.
Department of Nuclear Medicine, "Alexandra" University Hospital, 80, Vas. Sophia's ave. and 2, K. Lourou str., 115 28 Athens, Greece. bats@germanos.net.gr Greece.

Over the last two decades, various research protocols were applied for scintigraphic imaging, prognosis and treatment of breast cancer, using monoclonal antibodies. Monoclonal antibodies approved by the United States Food and Drug Administration (FDA) include the anti-carcinoembryonic antigen (CEA), and B72.3, prepared against the tumour-associated glycoprotein, TAG-72. The recombinant humanized "cold" anti-HER(2) monoclonal antibody (trastuzumab), which targets oncogene receptor HER(2)has hitherto been the only monoclonal antibody widely used for the treatment of breast cancer in the USA, with or without chemotherapy. Trastuzumab is constructed against the HER2 oncogene receptor (also known as neu or c-erb-B(2)), which is overexpressed in 25%-30% of breast cancer cell lines and is associated with poor prognosis. Immuno-lymphoscintigraphy is also applied to guide and monitor the effect of treatment regimes. Radiolabelled, "hot" monoclonal antibodies are currently being applied for the treatment of primary or metastatic breast cancer, in experimental, pre-clinical, or clinical trials, in combination with traditional external beam radiotherapy and/or chemotherapy. Radioimmunotherapy comprises systemically administered monoclonal antibodies, linked to high-energy, beta-emitting radionuclides. Radioactive antibodies, in the form of yttrium-90 ((90)Y)-BetarE-3, (90)Y- m170 and (131)I- or (90)Y- labelled L6 antibody, are applied with adjuvant autologous peripheral blood stem cells transfusion, to prevent myelotoxicity. Partial omicronr rarely complete responses to "hot" antibody treatment, of breast cancer have been reported. Innovative strategies using this combined-modality treatment hold promise for better disease-free and survival rates.

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Clin Breast Cancer. 2005 Aug;6(3):223-32.
Current and future roles of neoadjuvant chemotherapy in operable breast cancer.
Kim R, Osaki A, Toge T.
Department of Surgical Oncology, Hiroshima University, Japan ; e-mail: rkim@hiroshima-u.ac.jp.

Neoadjuvant chemotherapy was initially used only as treatment for locally advanced breast cancer. However, because breast cancer is considered to be a systemic disease in which distant micrometastases are already present at the time of the initial diagnosis, primary systemic therapy may be beneficial in the eradication of these micrometastatic lesions. Despite the fact that no survival benefit of neoadjuvant chemotherapy over adjuvant chemotherapy has yet been demonstrated, the clinical indication for neoadjuvant chemotherapy is being extended not only to stage T3/4 tumors but also to some stage T1/2 operable breast cancers. The current clinical benefits of the use of neoadjuvant chemotherapy are that (1) the safety of neoadjuvant chemotherapy is comparable with that of adjuvant chemotherapy, (2) neoadjuvant chemotherapy increases the possibility of the use of breast-conserving surgery, and (3) pathologic complete response may be a predictive indicator of better survival. Importantly, the response to neoadjuvant chemotherapy in vivo could provide a useful prediction of prognosis and help define strategies for an individual patient's future treatment with alternative chemotherapy regimens or molecular-targeting agents. Furthermore, the discovery of predictive markers for tumor response to neoadjuvant chemotherapy through the analysis of complementary DNA microarrays and proteomics may also help facilitate individualized chemotherapy, particularly by improving survival in patients with breast cancer with a poor prognosis. Herein we review the current status and future role of neoadjuvant chemotherapy in operable breast cancer in terms of its survival benefit and the potential for the individualization of adjuvant therapy for these patients.

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Clin Breast Cancer. 2005 Aug;6(3):206-15.
The evolving role of aromatase inhibitors in adjuvant breast cancer therapy.
Henderson IC, Piccart-Gebhart MJ.
Carol Franc Buck Breast Care Center, University of California San Francisco Comprehensive Cancer Center; e-mail: chenderson@keryx.com.

The development of third-generation aromatase inhibitors (AIs) has brought about a major change in the therapeutic approach to patients with hormone-sensitive breast cancer. In randomized clinical trials, each of the third-generation AIs has demonstrated efficacy in the adjuvant treatment of postmenopausal women with receptor-positive tumors. Anastrozole has been shown to improve disease-free survival when compared with standard first-line tamoxifen, letrozole has been shown to further reduce the rate of breast cancer events when given as extended adjuvant therapy in women completing between 4.5 and 6 years of tamoxifen, and exemestane has been shown to improve disease-free survival when substituted for tamoxifen after an initial 2-3 years of adjuvant therapy. Although long-term follow-up for safety and overall survival continues in each of these trials, currently available data suggest that an AI should now be included as part of adjuvant endocrine therapy for the great majority of receptor-positive postmenopausal patients. To address these rapidly evolving issues related to the endocrine adjuvant treatment of postmenopausal women, an expert panel met in March 2004 in Hamburg, Germany, the site of the Fourth European Breast Cancer Conference. The panel's overview of recent endocrine data is presented along with updated results where available. In addition, case-based discussions are included to provide direction on how to integrate recent endocrine adjuvant clinical trial findings into everyday practice.

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Br J Cancer. 2005 Aug 30; [Epub ahead of print]
Does timing of adjuvant chemotherapy influence the prognosis after early breast cancer? Results of the Danish Breast Cancer Cooperative Group (DBCG).
Cold S, During M, Ewertz M, Knoop A, Moller S.
1Oncology Department R, Odense University Hospital, Sdr. Boulevard 29, DK-5000 Odense C, Denmark.

The purpose of this study was to examine the effect on survival of delaying the start of adjuvant chemotherapy for early breast cancer for up to 3 months after surgery. In the nation-wide clinical trials of the Danish Breast Cancer Cooperative Group, 7501 breast cancer patients received chemotherapy within 3 months of surgery between 1977 and 1999: 352 with classical cyclofosfamide, metotrexate and 5-fluorouracil (CMF); 6065 with CMF i.v. and 1084 with cyclofosfamide, epirubicin and 5-fluorouracil. For the analysis, the time between surgery and the start of chemotherapy was divided into four strata (1-3, 4, 5 and 6-13 weeks). The results show that within the three groups of chemotherapy, there was an even distribution of known prognostic factors across the four strata of initiation of chemotherapy. There was no pattern indicating a benefit from early start of chemotherapy. No significant interactions were found for subgroups of patients with a poorer prognosis (many involved lymph nodes, high-grade malignancies or hormone receptor negative disease). In conclusion, we have found no evidence for a survival benefit due to early initiation of adjuvant chemotherapy within the first 2-3 months after surgery.British Journal of Cancer advance online publication, 30 August 2005; doi:10.1038/sj.bjc.6602734 www.bjcancer.com.

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Cancer Chemother Pharmacol. 2005 Aug 23;:1-5 [Epub ahead of print]
Oral vinorelbine alone or in combination with trastuzumab in advanced breast cancer: results from a pilot trial.
Bartsch R, Wenzel C, Pluschnig U, Hussian D, Sevelda U, Locker GJ, Mader R, Zielinski CC, Steger GG.
Department of Internal Medicine I, Division of Oncology, Medical University of Vienna, 18-20 Waehringer Guertel, Vienna, Austria, guenther.steger@meduniwien.ac.at.

Introduction: We evaluated the efficacy of oral vinorelbine (OV) (Navelbine oral((R)) Boeringer-Ingelheim Austria) in patients with advanced breast cancer as first-line therapy or after progressing under earlier line chemotherapies alone or in combination with trastuzumab (T). Patients and methods: Seventy-eight patients [median age: 63.5 years (y), range (r): 38-84 years] were included into this trial. Patients with her-2/neu positive tumours received a combination of OV and T. Treatment effect was evaluated every three cycles and treatment continued until progression. OV was administered in a dose of 60 mg/m(2) on day 1 and 8, q = 21 days, and no dose escalation to 80 mg/m(2) was performed. Results: We observed a complete response in 5.9% of patients, partial remission in 22.1%, stable disease (SD) > 6 months in 33.8%, SD < 6 months in 2.9%, and progression despite treatment in 35.3%, respectively. Time to progression was 6 months (range 1-23+). The main toxicities consisted of nausea/vomiting (N/V) and neutropenia. Grade IV neutropenia was found in 5 patients (6.4%), grade III in 6 patients (7.7%) and grade I and II in 11.5%. We did not find any grade IV N/V in our patients, however, grade III N/V was observed in 3.8%. No other grade III and IV toxicities were reported. Conclusion: OV appears to be effective in the treatment of advanced breast cancer at the dose and schedule chosen. It is well tolerated, effective, and the oral formulation is an advantage for the patients as well as for the nursing staff.

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Ann Oncol. 2005 Aug 26; [Epub ahead of print]
Patients' preferences for adjuvant chemotherapy in early breast cancer: what makes AC and CMF worthwhile now?
Duric VM, Stockler MR, Heritier S, Boyle F, Beith J, Sullivan A, Wilcken N, Coates AS, Simes RJ.
NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia.

BACKGROUND: Studies of women who had adjuvant chemotherapy for early breast cancer 10-20 years ago showed that many judged small benefits sufficient to make it worthwhile. Indications, regimens and supportive care have changed. We sought the preferences of contemporary women who received similar chemotherapy. PATIENTS AND METHODS: Ninety-seven consecutive consenting women who completed adjuvant chemotherapy for early breast cancer 3-34 months previously were interviewed. Preferences were elicited with a structured, scripted interview using the trade-off method. Women were presented with four hypothetical scenarios based on known life expectancies (5 and 15 years) and survival rates (65% and 85% at 5 years) without adjuvant chemotherapy. RESULTS: Improvements of an additional year in life expectancy or 3% in survival rates were judged sufficient to make adjuvant chemotherapy worthwhile by 68-84% of women. Half the women judged 1 day or 0.1% sufficient to make adjuvant chemotherapy worthwhile. Recollections of better well-being during adjuvant chemotherapy, having dependants and having a friend or relative who died from cancer were independently associated with judging smaller benefits sufficient to make adjuvant chemotherapy worthwhile (all P < 0.05). CONCLUSIONS: Preferences were highly variable, but the benefits judged sufficient to make adjuvant chemotherapy worthwhile were even smaller than those found in previous studies. Preferences were influenced by factors other than direct benefits and harms of chemotherapy.

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Gan To Kagaku Ryoho. 2005 Aug;32(8):1135-8.
[Experience with capecitabine in patients with anthracycline and/or taxane-resistant recurrent breast cancer]
[Article in Japanese]
Tagaya N, Nakagawa A, Mori S, Tachibana M, Kakihara Y, Hamada K, Suzuki N, Kubota K.
Dept of Surgery II, Dokkyo University School of Medicine.

We evaluated the safety and efficacy of capecitabine in 12 patients with anthracycline and/or taxane-resistant metastatic breast cancer on an outpatient basis. Their mean age was 57 years, and they previously received chemotherapy consisting of anthracycline in 7 cases, taxane in 12 and doxifluridine in 8. Their mean disease-free interval was 28.5 months, HER 2/neu and ER and/or PgR-positive was shown in 2 and 8 cases, respectively. The recurrent sites were lymph node in 9 cases, lung in 6, skin in 5, pleural effusion in 4, liver, bone and pleura in 3, brain and CBS in 2, and thyroid, ascites and pericardial effusion in one, respectively. The administration dose was 2,400 mg/day in 11 cases and 3,000 mg/day in one. Capecitabine was administered orally for 21 consecutive days followed by a one-week rest. The mean follow-up period was 6.5 months. The overall response rate was 18.2% in 11 cases, including 2 partial responses, 4 stable diseases and 5 progressive diseases. Clinical benefit was 36.4% including two long stable diseases. The mean time to treatment failure was 6.5 months. Adverse events included Hand-Foot Syndrome in 5 cases, nausea in 3, diarrhea, appetite loss and high fever in one, respectively. In two of them administration was discontinued due to adverse events. Capecitabine had satisfactory effects with tolerable adverse events for anthracycline- and/or taxane-resistant metastatic breast cancer.

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Oncology. 2005 Aug 23;69(2):117-121 [Epub ahead of print]
A Phase II Trial of Docetaxel and Carboplatin as First-Line Chemotherapy for Metastatic Breast Cancer: NCCTG Study N9932.
Perez EA, Suman VJ, Fitch TR, Mailliard JA, Ingle JN, Cole JT, Veeder MH, Flynn PJ, Walsh DJ, Addo FK.
Mayo Clinic and Mayo Foundation, Rochester, Minn., USA.

Objective: A phase II multi-institutional clinical trial conducted to evaluate the efficacy and tolerability of docetaxel and carboplatin as first-line therapy for women with metastatic breast cancer. Methods: Patients had histologically confirmed metastatic breast cancer with at least one measurable lesion. Prior adjuvant chemotherapy was permitted, provided that at least 12 months had elapsed between any prior taxane and platinum therapy. Patients received docetaxel 75 mg/m(2) with carboplatin AUC 6 mg/ml.min every 21 days until disease progression or prohibitive toxicity. Results: All 53 patients enrolled were evaluable for response and toxicity. Median number of cycles delivered was 6. Overall response rate was 60%, with 3 complete responses (6%) and 29 partial responses (54%). Median time to disease progression was 9.6 months. Median survival time was 20.4 months. Myelosuppression was the predominant toxicity, with grade 3 or 4 neutropenia occurring in 94% of patients and 15% of patients experiencing febrile neutropenia. The overall incidence (grades 1-3) of neurosensory toxicity was 57% and neuromotor toxicity was 25%, respectively, with grade 3 toxicity occurring in 4% of patients each. Conclusions: The combination of docetaxel and carboplatin is highly active in metastatic breast cancer. Prophylactic growth factor support is recommended in any further evaluation of this combination in the treatment of patients with breast cancer. Copyright (c) 2005 S. Karger AG, Basel.

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Clin Cancer Res. 2005 Aug 15;11(16):5671-7.
Letrozole in the extended adjuvant treatment of postmenopausal women with history of early-stage breast cancer who have completed 5 years of adjuvant tamoxifen.
Mann BS, Johnson JR, Kelly R, Sridhara R, Williams G, Pazdur R.
Division of Oncology Drug Products, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland 20857, USA. mannb@cder.fda.gov

PURPOSE: To present the basis of the decision of the Food and Drug Administration to grant accelerated approval for letrozole for extended adjuvant treatment of early-stage breast cancer in postmenopausal women after completion of adjuvant tamoxifen. EXPERIMENTAL DESIGN: The Food and Drug Administration reviewed the data from the MA17 trial, a single, multinational, randomized, double-blind, and placebo-controlled trial, submitted by the applicant to support the proposed new indication. RESULTS: MA17 consisted of a core study and Lipid and Bone Mineral Density safety substudies. It enrolled 5,187 patients. In the core study, median treatment duration was 24 months and median follow-up duration was 27.4 months. Using a conventional definition of disease-free survival, 122 events on letrozole and 193 events on placebo were observed (hazard ratio, 0.62; 95% confidence interval, 0.49-0.78; P = 0.00003). Distant disease-free survival also improved with letrozole, 55 versus 92 events (hazard ratio, 0.61; 95% confidence interval, 0.44-0.84; P = 0.003). No statistically significant improvement in overall survival was observed. Hot flushes, arthralgia/arthritis, myalgia, and new diagnosis of osteoporosis were more common on letrozole. Frequency of fractures and cardiovascular ischemic events was not significantly different. A statistically significant mean decrease in bone mineral density in the hip occurred at 24 months on letrozole. CONCLUSIONS: Letrozole administration led to a statistically significant prolongation in disease-free survival. Fractures and cardiovascular events were similar to placebo; however, new diagnoses of osteoporosis were more frequent. Short duration of treatment and follow-up precluded assessment of long-term safety and efficacy. Thus, accelerated approval was granted instead of regular approval.

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Expert Rev Anticancer Ther. 2005 Aug;5(4):613-33.
Docetaxel in the treatment of breast cancer: current experience and future prospects.
Nabholtz JM, Gligorov J.
Breast Cancer Research Institute, La Prandie, 24290 Valojoulx, France. jmnabholtz@hotmail.com

It has become clear over the past 10 years that docetaxel, a semisynthetic taxoid antineoplastic agent, is among the most promising compounds to have been developed in the 1990s for the treatment of breast cancer. Data indicate that this drug became standard therapy in the treatment of patients with metastatic disease who have failed anthracycline treatment, and secondarily showed very encouraging results in the first-line metastatic setting either in monochemotherapy or when docetaxel was combined with an anthracycline. More recently, docetaxel also became one of the standard therapies in the adjuvant and neoadjuvant settings, and a promising partner for novel biologic therapies. Current research is further exploring the effect of docetaxel on outcome of early breast cancer in order to fully determine the extent that this chemotherapeutic agent will change the natural history of breast cancer.

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Expert Rev Anticancer Ther. 2005 Aug;5(4):591-604.
Use of goserelin in the treatment of breast cancer.
Rody A, Loibl S, von Minckwitz G, Kaufmann M.
Department of Obstetrics and Gynecology, JW Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany. achim.rody@em.uni-frankfurt.de

Gonadotropin-releasing hormone analogs are, alongside tamoxifen, one of the most commonly used drugs in the treatment of pre-/perimenopausal endocrine-responsive breast cancer. Goserelin, as a principal agent of this class of drugs, is mainly investigated in clinical trials. The indirect comparison of goserelin with tamoxifen as a single drug in the adjuvant setting showed similar efficacy. Furthermore, goserelin is as effective as cyclophosphamide, methotrexate and 5-fluorouracil chemotherapy, and total endocrine blockade as a combination of gonadotropin-releasing hormone analog and tamoxifen showed a comparable benefit with anthracycline-containing adjuvant chemotherapy. Goserelin administered after cessation of chemotherapy leads to a further improvement and may be equieffective as tamoxifen or a combination of both. Data concerning taxane-based and dose-dense chemotherapy as well as combination of gonadotropin-releasing hormone analogs with third-generation aromatase inhibitors are still lacking (ongoing suppression of ovarian function, tamoxifen and exemestane, and premenopausal endocrine-responsive chemotherapy trials). Moreover, duration of therapy with gonadotropin-releasing hormone analogs (2-3 years or longer) is still a matter of debate. Palliative endocrine treatment is standard in the first-line therapy of patients without life-threatening disease and endocrine-responsive breast cancer. Treatment decisions depend upon adjuvant endocrine pretreatment. Clinical data regarding ovarian protection by synchronous use of gonadotropin-releasing hormone in young breast cancer patients receiving chemotherapy are incoherent.

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Br J Cancer. 2005 Jun 7; [Epub ahead of print]
Soybean products and reduction of breast cancer risk: a case-control study in Japan.
Hirose K, Imaeda N, Tokudome Y, Goto C, Wakai K, Matsuo K, Ito H, Toyama T, Iwata H, Tokudome S, Tajima K.
1Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, 1-1 Kanokoden Chikusa-ku, Nagoya 464-8681, Japan.

Components of the Japanese diet, which might contribute to the relatively low breast cancer incidence rates in Japan, have not been clarified in detail. Since soybean products are widely consumed in Japan, a case-control study taking account of the menopausal status was conducted using data from the hospital-based epidemiologic research program at Aichi Cancer Center (HERPACC). In total, 167 breast cancer cases were included and 854 women confirmed as free of cancer were recruited as the control group. Odds ratios (OR) and 95% confidence intervals (95% CI) were determined by multiple logistic regression analysis. There were reductions in risk of breast cancer associated with high intake of soybean products among premenopausal women. Compared with women in the lowest tertile, the adjusted ORs for top tertile intake of tofu (soybean curd) was 0.49 (95% CI, 0.25-0.95). A significant decrease in premenopausal breast cancer risk was also observed for increasing consumption of isoflavones (OR=0.44; 95% CI, 0.22-0.89 for highest vs lowest tertile; P for trend=0.02). The present study found a statistically inverse association between tofu or isoflavone intake and risk of breast cancer in Japanese premenopausal women, while no statistically significant association was evident with the risk among postmenopausal women.British Journal of Cancer advance online publication, 7 June 2005; doi:10.1038/sj.bjc.6602659 www.bjcancer.com.

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J Steroid Biochem Mol Biol. 2005 Jun 3; [Epub ahead of print]
Aromatase inhibitors for therapy of advanced breast cancer.
Ingle JN, Suman VJ.
Division of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.

In postmenopausal women with advanced breast cancer, numerous phase III trials have been performed comparing the third-generation non-steroidal aromatase inhibitors (NS-AIs) anastrozole and letrozole and the steroidal AI (S-AI) exemestane in the "first-line" setting against tamoxifen and in the "second-line" setting against megestrol acetate. In both settings, the AIs were at least as efficacious or superior in some endpoints with a preferable toxicity profile including a lower incidence of thrombotic events. Relatively small differences in potency between the three AIs have been identified and it has not been demonstrated that these differences have clinical implications. The recent establishment of the value of AIs in the adjuvant setting for postmenopausal women will impact on their utilization in advanced disease. In premenopausal women the third-generation AIs have not been studied as monotherapy and there is a paucity of data in combination with ovarian function suppression in the advanced disease setting. The main area of future investigations for the AIs in premenopausal women will be in the adjuvant therapy setting in combination with suppression of ovarian function.

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N Engl J Med. 2005 Jun 2;352(22):2302-13.
Adjuvant docetaxel for node-positive breast cancer.
Martin M, Pienkowski T, Mackey J, Pawlicki M, Guastalla JP, Weaver C, Tomiak E, Al-Tweigeri T, Chap L, Juhos E, Guevin R, Howell A, Fornander T, Hainsworth J, Coleman R, Vinholes J, Modiano M, Pinter T, Tang SC, Colwell B, Prady C, Provencher L, Walde D, Rodriguez-Lescure A, Hugh J, Loret C, Rupin M, Blitz S, Jacobs P, Murawsky M, Riva A, Vogel C; Breast Cancer International Research Group 001 Investigators.
Hospital Universitario San Carlos, Madrid, Spain. mmartin@geicam.org

BACKGROUND: We compared docetaxel plus doxorubicin and cyclophosphamide (TAC) with fluorouracil plus doxorubicin and cyclophosphamide (FAC) as adjuvant chemotherapy for operable node-positive breast cancer. METHODS: We randomly assigned 1491 women with axillary node-positive breast cancer to six cycles of treatment with either TAC or FAC as adjuvant chemotherapy after surgery. The primary end point was disease-free survival. RESULTS: At a median follow-up of 55 months, the estimated rates of disease-free survival at five years were 75 percent among the 745 patients randomly assigned to receive TAC and 68 percent among the 746 randomly assigned to receive FAC, representing a 28 percent reduction in the risk of relapse (P=0.001) in the TAC group. The estimated rates of overall survival at five years were 87 percent and 81 percent, respectively. Treatment with TAC resulted in a 30 percent reduction in the risk of death (P=0.008). The incidence of grade 3 or 4 neutropenia was 65.5 percent in the TAC group and 49.3 percent in the FAC group (P<0.001); rates of febrile neutropenia were 24.7 percent and 2.5 percent, respectively (P<0.001). Grade 3 or 4 infections occurred in 3.9 percent of the patients who received TAC and 2.2 percent of those who received FAC (P=0.05); no deaths occurred as a result of infection. Two patients in each group died during treatment. Congestive heart failure and acute myeloid leukemia occurred in less than 2 percent of the patients in each group. Quality-of-life scores decreased during chemotherapy but returned to baseline levels after treatment. CONCLUSIONS: Adjuvant chemotherapy with TAC, as compared with FAC, significantly improves the rates of disease-free and overall survival among women with operable node-positive breast cancer. Copyright 2005 Massachusetts Medical Society.

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Bone Marrow Transplant. 2005 Jun 6; [Epub ahead of print]
A longitudinal prospective study of health-related quality of life in breast cancer patients following high-dose chemotherapy with autologous blood stem cell transplantation.
Conner-Spady BL, Cumming C, Nabholtz JM, Jacobs P, Stewart D.
1University of Alberta, Edmonton, Alberta, Canada.

Summary:This prospective longitudinal study examined both short- and long-term changes in health-related quality of life (HRQL) in 52 breast cancer patients with poor prognosis receiving high-dose chemotherapy (HDC) treatment with autologous blood stem cell transplantation (ASCT). HRQL was measured seven times from baseline to 2 years post enrollment with the Functional Living Index-Cancer (FLIC), the EuroQol (EQ-5D), and a quality of life visual analogue scale. The percentage of questionnaires returned at each assessment time ranged from 80 to 92%. All three measures showed a similar pattern of change, with HRQL decreasing following administration of HDC, and returning to baseline levels 8 weeks post HDC. A repeated-measures analysis of variance showed that the FLIC at 2 years was significantly better than baseline (P=<0.0001). Difficulty sleeping, headaches, and decreased sexual interest were the most common symptoms reported in the longer term. Our results have implications for early psychosocial intervention in the care of breast cancer patients with poor prognosis undergoing treatment with HDC and ASCT because such interventions can further improve the quality of their survival.Bone Marrow Transplantation advance online publication, 6 June 2005; doi:10.1038/sj.bmt.1705032.

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Ann Oncol. 2005 Jun 3; [Epub ahead of print]
A 2-month cisplatin-epirubicin-paclitaxel (PET) weekly combination as primary systemic therapy for large operable breast cancer: a phase II study.
Frasci G, D'Aiuto G, Comella P, Thomas R, Botti G, Di Bonito M, D'Aiuto M, Romano G, Rubulotta MR, Comella G.
Divisions of Medical Oncology A, Surgical, Oncology, Pathology, Radiology, National Tumor Institute, Naples, Italy.

Purpose: The present study aimed to define the antitumor activity of eight cisplatin-epirubicin-paclitaxel (PET) weekly cycles with granulocyte colony-stimulating factor (G-CSF) support in patients with large operable breast cancer. Methods: Operable breast cancer (T2-3 N0-1; T >3 cm) patients received eight preoperative weekly cycles of cisplatin 30 mg/m(2), epirubicin 50 mg/m(2) and paclitaxel 120 mg/m(2), with G-CSF (5 microg/kg, days 3-5) support. Results: Sixty-three patients (T2/T3=30/33; N0/N+=8/55) were enrolled. Thirty-one clinical complete (49%) and 30 partial (48%) responses were recorded, giving a 97% response rate (95% confidence interval 89% to 100%). Breast-sparing surgery was performed in 32/63 (51%) patients. At pathological assessment, 28 patients (45%) showed absence of invasive residual disease in breast and 34 (55%) had negative axilla. In 20 women (32%) both breast and axilla were found to be disease-free. At a 23-month median follow-up (range 4-63), only eight relapses and two deaths had occurred, with the 4-year projected relapse-free and overall survival being 59% and 95%, respectively. Grade 3-4 neutropenia and anemia occurred in 24% and 5% of patients, respectively. Emesis, diarrhea and mucositis were the main non-hematological toxicities; however, only nine (14%) patients experienced one or more episodes of severe non-hematological toxicity. Peripheral neuropathy was frequent, but never severe. Conclusions: A 2-month weekly treatment with PET represents a well tolerated and highly effective approach in large operable breast cancer patients. In spite of the short duration of chemotherapy, one-third of patients achieved a complete eradication of the tumor in both breast and axilla.

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Jpn J Clin Oncol. 2005 Jun 1; [Epub ahead of print]
Late Phase II Clinical Study of Vinorelbine Monotherapy in Advanced or Recurrent Breast Cancer Previously Treated with Anthracyclines and Taxanes.
Toi M, Saeki T, Aogi K, Sano M, Hatake K, Asaga T, Tokuda Y, Mitsuyama S, Kimura M, Kobayashi T, Tamura M, Tabei T, Shin E, Nishimura R, Ohno S, Takashima S.
Department of Clinical Trials and Research, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan.

BACKGROUND: At present, it is one of the most important issues for the treatment of breast cancer to develop the standard therapy for patients previously treated with anthracyclines and taxanes. With the objective of determining the usefulness of vinorelbine monotherapy in patients with advanced or recurrent breast cancer after standard therapy, we evaluated the efficacy and safety of vinorelbine in patients previously treated with anthracyclines and taxanes. METHODS: Vinorelbine was administered at a dose level of 25 mg/m(2) intravenously on days 1 and 8 of a 3 week cycle. Patients were given three or more cycles in the absence of tumor progression. A maximum of nine cycles were administered. RESULTS: The response rate in 50 evaluable patients was 20.0% (10 out of 50; 95% confidence interval, 10.0-33.7%). Responders plus those who had minor response (MR) or no change (NC) accounted for 58.0% [10 partial responses (PRs) + one MR + 18 NCs out of 50]. The Kaplan-Meier estimate (50% point) of time to progression (TTP) was 115.0 days. The response rate in the visceral organs was 17.3% (nine PRs out of 52). The major toxicity was myelosuppression, which was reversible and did not require discontinuation of treatment. CONCLUSION: The results of this study show that vinorelbine monotherapy is useful in patients with advanced or recurrent breast cancer previously exposed to both anthracyclines and taxanes.

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J Steroid Biochem Mol Biol. 2005 Jun 2; [Epub ahead of print]
Vascular effects of aromatase inhibitors: Data from clinical trials.
Howell A, Cuzick J.
CRUK Department of Medical Oncology, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.

Aromatase inhibitors (AIs) are becoming the endocrine treatment of first choice for postmenopausal women with hormone receptor-positive breast cancer and are under investigation for use in breast cancer prevention. AIs reduce circulating estrogen to barely detectable concentrations. It is possible that such a low concentration will be deleterious to the vascular system since estrogen receptors are known to be in the cell walls of blood vessels and estrogen is thought to be important in maintaining blood vessel integrity. Because most women who present with primary breast cancer are cured by surgery and systemic therapy and the major cause of female death is vascular disease, it is particularly important to investigate the vascular side effects of AIs in current breast cancer adjuvant and prevention trials. In order to set the vascular toxicities of AIs reported in the current adjuvant trials into context, here we compare them with the toxicities seen during treatment with hormone replacement therapy (HRT) and selective estrogen receptor modulators (SERMs). Clinical trial evidence indicates that HRT increases risk of coronary heart disease (CHD) whereas SERMs and AIs (to date) appear to be neutral. Cerebrovascular disease and venous thromboembotic events are increased by HRT and SERMs but appear to be unaffected by treatment with AIs. Cognitive function is also considered here since it may also have a vascular component and is potentially a serious potential side effect/benefit of AIs. Recent studies indicate that HRT has a small detrimental effect on cognitive function and is associated with a doubling of the incidence of dementia. A comprehensive study of the SERM, raloxifene, on cognitive function showed no significant effect. There are no definitive reported studies investigating tamoxifen and none for AIs on cognitive function, although there is one in progress in the context of the IBIS II prevention trial which compares anastrozole to placebo in women at high risk. At present concerns about deleterious vascular side effects are confined to HRT and SERMs. However, we have few long-term data using AIs for the treatment and prevention of breast cancer.

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Am J Clin Oncol. 2005 Jun;28(3):289-94.
Randomized trials of breast-conserving therapy versus mastectomy for primary breast cancer: a pooled analysis of updated results.
Jatoi I, Proschan MA.
Department of Surgery, National Naval Medical Center and The Uniformed Services University, Bethesda, Maryland, USA. ismail.jatoi@us.army.mil

We have undertaken a pooled analysis of the 6 major randomized trials comparing mastectomy (MT) and breast-conserving therapy (BCT) in the treatment of primary breast cancer. Specifically, these trials compared the 2 most widely used options in local treatment: mastectomy and axillary dissection (MT) versus breast-conserving surgery, axillary dissection, and breast radiotherapy (BCT). The early results of these 6 trials formed the basis for a 1990 National Institutes of Health Consensus statement. However, most of these trials have recently published long-term follow-up results, and this pooled analysis incorporates the updated results of these 6 trials. For each of these trials, the observed number of treatment events was compared with that expected under the null hypothesis, given the number of patients per arm and the total number of events. Approximate odds ratios were computed using the observed and expected number of events, and the variance of the observed number of events. These were then pooled across trials to give overall odds ratios for the risk of locoregional recurrence, total recurrence, and death. Four of the 6 trials show that MT significantly reduces the risk of locoregional recurrence when compared with BCT, and the pooled odds ratio also shows a significant benefit for MT (odds ratio [OR], 1.561; 95% confidence interval [CI], 1.289-1.890; P < 0.001). However, only 1 trial shows a statistically significant benefit for MT in reducing mortality, and the pooled odds ratio shows no significant difference between MT and BCT (OR, 1.070; 95% CI, 0.935-1.224; P = 0.33). This pooled analysis confirms that MT and BCT have comparable effects on mortality, even after long-term follow up. However, BCT is associated with a significantly greater risk of locoregional recurrence.

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Ann Fam Med. 2005 May-Jun;3(3):242-7.
Tamoxifen for breast cancer chemoprevention: low uptake by high-risk women after evaluation of a breast lump.
Taylor R, Taguchi K.
Division of General Surgery, University of Ottawa, Ottawa, Ontario, Canada. beccaanntaylor@hotmail.com <beccaanntaylor@hotmail.com>

PURPOSE: The Breast Cancer Prevention Trial (BCPT) published results in 1998 showing that the use of tamoxifen in high-risk women reduced the incidence of invasive breast cancer by 49%. We examined the clinical impact of the BCPT to determine whether high-risk women informed of these results would use tamoxifen for chemoprophylaxis and to investigate the factors influencing this decision. METHODS: Of 345 women evaluated for a breast lump at a referral center, 89 were defined as high risk for but did not currently have cancer. These women were contacted about their elevated risk and informed that there exists a medication proved to reduce this risk. They were encouraged to discuss the issue with their family physician, to whom we sent copies of the 3 largest tamoxifen chemoprevention studies, including the BCPT. Follow-up was conducted by telephone to determine each woman's choice regarding tamoxifen use for chemoprevention and to ascertain her reasons for reaching this decision. RESULTS: Of the 89 high-risk women, 1 decided to take tamoxifen for breast cancer chemoprevention. Only 48 women discussed tamoxifen with their family physician; in 3 cases (3.4%) the family physician recommended that the patient start taking tamoxifen, in 8 cases (9.1%) the family physician made no recommendations, and in 37 cases (42%) the family physician advised against tamoxifen. The most frequently cited factors influencing the decision not to start tamoxifen were a fear of adverse events (46.8%), the family physician's recommendation (31.9%), and a perceived low breast cancer risk (34%). CONCLUSION: Family physicians recommended prophylactic tamoxifen to few women and even fewer women chose to take it. The major barrier appears to be concern about potential adverse effects of tamoxifen.

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ANZ J Surg. 2005 May;75(5):292-9.
Experience of sentinel node biopsy alone in early breast cancer without further axillary dissection in patients with negative sentinel node.
Soni NK, Spillane AJ.
Sydney Breast Cancer Institute, Sydney Cancer Centre, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.

Aims: The aims of surgical therapy of breast cancer are loco-regional tumour control and staging. Axillary staging is still considered the single most important prognostic indicator in breast cancer. Surgical removal of axillary nodes remains the standard way to assess their involvement in most centres. The morbidity associated with axillary dissection (AD) is well recognized. In recent years sentinel node biopsy (SNB) has evolved. Multiple studies suggest it has the same accuracy as AD in axillary staging and less morbidity in early breast cancer (EBC). SNB has become the standard of practice in EBC in many parts of the world. In Australia, the preference has been to wait for the results of the Sentinel Node versus Axillary Clearance (SNAC) trial as well as other international trials before accepting SNB as a standard of care. The experience of a single surgeon with SNB alone in EBC without further completion axillary dissection (CAD) in negative sentinel node (SLN) is described in the present paper. Methods: An audit was done of the senior author's prospective data from the Royal Australasian College of Surgeons database. Other information was added retrospectively from case notes. Results: Between December 2000 and December 2003, 154 EBC cases (153 patients) underwent SNB alone. An average of four SLN was removed. Of these cases, 31.8% had positive SLNs (excluding 2.6% cases that had isolated tumour cells), of these, 93.9% had metastases (39.1% micro- and 60.9% macro-metastases) in axillary-SLN (ASLN) and almost all of these had CAD. ASLNs were the only positive nodes in 73.9%. Extra-ASLN retrieved in 68.8% of 34% demonstrated on lymphoscintigraphy. Of these, 12.1% were positive (6.1% micro- and macro-metastases each), all internal mammary. Mean follow up was 22.1 months. There was one local-regional-systemic and one systemic recurrence over this time. Conclusion: SNB has a valid role in staging of the axilla particularly in low-risk patients. After adequate self audit, SNB offers a minimal morbidity and reliable method of axillary staging. Patients choosing SNB alone must understand that the long-term results of the randomized controlled trial are still pending for level I evidence of long-term efficacy.

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J Exp Clin Cancer Res. 2005 Mar;24(1):43-8.
Low dose-intensity docetaxel in the treatment of pre-treated elderly patients with metastatic breast cancer.
Massacesi C, Marcucci F, Boccetti T, Battelli N, Pilone A, Rocchi MB, Bonsignori M.
Dept. of Oncology and Radiotherapy, Ospedali Riuniti Umberto I-Salesi-Lancisi, Polo Ospedale-Universita, Ancona. c.massacesi@ao-umbertoprimo.marche.it

We evaluated the efficacy and toxicity profile of single-agent docetaxel administered in daily clinical practice at low-dose regimen in 37 pre-treated elderly patients with metastatic breast cancer previously exposed to chemotherapy. Docetaxel was employed by physician's preference according to a weekly (8 patients, 25-30 mg/m2 every 7 days), bi-weekly (19 patients, 40-50 mg/m2 every 14 days), or tri-weekly (10 patients, 75-100 mg/m2 every 21-28 days) schedule. The median age of patients was 70 yrs, and most of them (84%) had a good PS; visceral metastases were found in 26 patients. Twenty-five patients were pre-treated by two or more chemotherapy lines. Anthracycline or anthracycline/paclitaxel therapy was previously employed in 25 patients (67%). Median delivered dose-intensity of docetaxel was 21 mg/m2/week (range 11-32), without significant differences between the regimens used. Thirty-three patients were evaluable for response. Eight (24%) patients had objective responses (2 complete and 6 partial) to docetaxel, with a median duration of response of 18 months; 14 (42%) patients had stable disease lasting more than 6 months (median 10 months). Median overall time to progression was 6 months. Median overall survival was 16 months, with 1- and 2-year survival rates of 64% and 34%, respectively. Grade 3/4 toxicities were rare: leucopenia in 18% of patients, neutropenia in 13%, emesis in 8%, diarrhea in 5%, and mucositis in 5%. Severe fatigue was recorded in 4 patients. In conclusion, docetaxel, even when administered at low dose-intensity, demonstrated good disease control and toxicity profile. This approach provides an excellent alternative for pre-treated elderly patients with advanced breast cancer.

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Breast. 2005 Apr;14(2):136-41.
First-line chemotherapy with docetaxel and cisplatin in metastatic breast cancer.
Vassilomanolakis M, Koumakis G, Barbounis V, Demiri M, Panopoulos C, Chrissohoou M, Apostolikas N, Efremidis AP.
2nd Medical Oncology Department, "St. Savas" Regional Oncology Hospital, Athens.

The purpose of this study was to evaluate the efficacy and tolerance of combined treatment with docetaxel-cisplatin as first-line chemotherapy in patients with metastatic breast cancer (MBC). Consecutive eligible chemonaive patients received docetaxel 75mg/m(2) on day 1 and cisplatin 75mg/m(2) on day 2 every 3 weeks for 6 cycles, with prophylactic recombinant human granulocyte colony-stimulating factor (rHuG-CSF) on days 4-11. Thirty-two patients (64%) had received prior adjuvant chemotherapy; these included 16 (32%) who had received anthracyclines. In 50 evaluable patients with a median age (range) of 56 (31-72) years, the overall response rate was 68% (95% CI, 55-81%), with 7 (14%) complete and 27 (54%) partial responses. Stable and progressive disease was observed in 10 (20%), and 6 (12%) patients, respectively. The median duration of response was 10 months, and the median time to progression was 39 weeks. Grade 3/4 hematological toxicity included-neutropenia in 9 patients (18%), anemia in 2 (4%) and thrombocytopenia in 1 (2%). One patient (2%) with febrile neutropenia required hospitalization. Grade 3/4 nonhematological toxicities included nausea/vomiting in 18%, nephrotoxicity in 14%, asthenia (4%), and neurotoxicity (2%). Toxicity was common in older patients (>56 years). There were no treatment-related deaths. A combination of docetaxel-cisplatin with rHuG-CSF support is well tolerated and effective as first-line chemotherapy in MBC.

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Breast Cancer Res Treat. 2005 Mar;90(1):85-91.
Long-term outcomes of breast cancer patients after endoscopic axillary lymph node dissection: a prospective analysis of 52 patients.
Langer I, Kocher T, Guller U, Torhorst J, Oertli D, Harder F, Zuber M.
Department of Surgery, University Hospital Basel, Spitalstrasse 21, CH-4031, Basel, Switzerland, ilanger@uhbs.ch.

Background. Reports on long-term outcomes after endoscopic axillary lymph node dissection (ALND) of breast cancer patients are still lacking in the medical literature. The objective of this prospective study was to assess the oncological and functional outcomes in breast cancer patients after endoscopic ALND. Methods. Fifty-five breast cancer patients were prospectively enrolled, of whom 52 were available for follow-up with a median of 71.9 months (range 11-96). The following oncological and functional endpoints were evaluated during follow-up at several time points: occurrence of local, axillary and distant metastases, seroma or infection, shoulder mobility (range of motion), numbness, pain, presence of lymphoedema as well as restriction in activities of daily living. Results. In 52 patients endoscopic ALND of level I and II was successfully performed. Two port-site metastases (2/52, 4%) occurred, one of which in a patient with negative axillary lymph nodes. The same patient suffered from the only axillary recurrence (1/52, 2%). Three patients (3/52, 6%) developed lymphoedema. No other functional adverse events (shoulder mobility, pain, numbness, hypertrophic scar) were noticed at the end of the observation period. Conclusion. The present investigation with long-term follow-up after endoscopic ALND - the first one in the literature - reveals minor morbidity, good functional and cosmetic results. In contrary to conventional surgery, the endoscopic procedure is associated with the occurrence of port-site metastases, not seen in the open approach. Axillary recurrences do not appear more frequently when compared with results after conventional ALND. In the meantime the less invasive sentinel lymph node (SLN) biopsy is the established standard technique in evaluating the axillary lymph node status.

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Arch Intern Med. 2005 Mar 14;165(5):516-20.
A population-based study of bilateral prophylactic mastectomy efficacy in women at elevated risk for breast cancer
in community practices.
Geiger AM, Yu O, Herrinton LJ, Barlow WE, Harris EL, Rolnick S, Barton MB, Elmore JG, Fletcher SW.
Research and Evaluation Department, Southern California Permanente Medical Group, Pasadena.

BACKGROUND: Findings from several studies suggest that bilateral prophylactic mastectomy reduces breast cancer incidence by 90% or more, but the studies used highly selected patients from referral centers, and the comparison groups were not population based. We studied the efficacy of bilateral prophylactic mastectomy in women with elevated breast cancer risk cared for in community practices. METHODS: We conducted a retrospective case-cohort study of women aged 18 to 80 years with 1 or more breast cancer risk factors (family history of breast cancer, history of atypical hyperplasia, or >/=1 breast biopsies with benign findings). Using computerized data and medical records, we identified 276 women with bilateral prophylactic mastectomy and a stratified random sample of 196 women representing an underlying cohort of 666 800 women with elevated breast cancer risk without prophylactic mastectomy, and then we determined who developed breast cancer. RESULTS: Breast cancer developed in 1 woman (0.4%) after bilateral prophylactic mastectomy vs 26 800 women (4.0%) without prophylactic mastectomy. Stratifying by birth year, the hazard ratio for breast cancer occurrence after bilateral prophylactic mastectomy was 0.005 (95% confidence interval, 0.001-0.044). No woman with bilateral prophylactic mastectomy died of breast cancer vs a calculated 0.2% of women without prophylactic mastectomy. CONCLUSIONS: Bilateral prophylactic mastectomy reduced breast cancer incidence in women at elevated risk for breast cancer cared for in community-based practices. However, the absolute risk of breast cancer incidence and death in women who did not undergo the procedure in these settings was relatively low.

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Br J Cancer. 2005 Mar 15; [Epub ahead of print]
Phase II study of weekly vinorelbine and 24-h infusion of high-dose 5-fluorouracil plus leucovorin as first-line treatment of advanced breast cancer.
Yeh KH, Lu YS, Hsu CH, Lin JF, Chao HJ, Huang TC, Chung CY, Chang CS, Yang CH, Cheng AL.
[1] 1National Taiwan University Hospital, Taiwan [2] 2National Taiwan University College of Medicine, Taiwan [3] 3Far Eastern Memorial Hospital, Taiwan.

We prospectively investigated the efficacy and safety of combining weekly vinorelbine (VNB) with weekly 24-h infusion of high-dose 5-fluorouracil (5-FU) and leucovorin (LV) in the treatment of patients with advanced breast cancer (ABC). Vinorelbine 25 mg m(-2) 30-min intravenous infusion, and high-dose 5-FU 2600 mg m(-2) plus LV 300 mg m(-2) 24-h intravenous infusion (HDFL regimen) were given on days 1 and 8 every 3 weeks. Between June 1999 and April 2003, 40 patients with histologically confirmed recurrent or metastatic breast cancer were enrolled with a median age of 49 years (range: 36-68). A total of 25 patients had recurrent ABC, and 15 patients had primary metastatic diseases. The overall response rate for the intent-to-treat group was 70.0% (95% CI: 54-84%) with eight complete responses and 20 partial responses. All 40 patients were evaluated for survival and toxicities. Among a total of 316 cycles of VNB-HDFL given (average: 7.9: range: 4-14 cycles per patient), the main toxicity was Gr3/4 leucopenia and Gr3/4 neutropenia in 57 (18.0%) and 120 (38.0%) cycles, respectively. Gr1/2 infection and Gr1/2 stomatitis were noted in five (1.6%) and 59 (18.7%) cycles, respectively. None of the patients developed Gr3/4 stomatitis or Gr3/4 infection. Gr2/3 and Gr1 hand-foot syndrome was noted in two (5.0%) and 23 (57.5%) patients, respectively. Gr1 sensory neuropathy developed in three patients. The median time to progression was 8.0 months (range: 3-25.5 months), and the median overall survival was 25.0 months with a follow-up of 5.5 to 45+ months. This VNB-HDFL regimen is a highly active yet well-tolerated first-line treatment for ABC.British Journal of Cancer advance online publication, 15 March 2005; doi:10.1038/sj.bjc.6602469.

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Int J Hyperthermia. 2005 Mar;21(2):159-67.
Thermoradiotherapy of the chest wall in locally advanced or recurrent breast cancer with marginal resection.
Welz S, Hehr T, Lamprecht U, Scheithauer H, Budach W, Bamberg M.
Department of Radiation Oncology Eberhard-Karls-Universitat Tubingen Hoppe-Seyler-Str. 3 72076 Tubingen Germany.

Background and purpose: Evaluation of the efficacy of combined hyperthermia and radiotherapy (TRT) in high-risk breast cancer patients with microscopic involved margins (R1) after mastectomy or with resected locoregional, early recurrence with close margins or R1-resection. Main endpoint was local tumour control (LC); secondary endpoints were overall survival (OS), disease free survival (DFS) and acute toxicity. Material and methods: Between 1997-2001, 50 patients were treated with TRT. Thirteen patients (group 1) received a post-operative TRT in a high-risk situation (free margin <1 cm or R1, N+), 37 patients (group 2) received TRT after close/R1 resection of a locoregional recurrence. Thirteen out of 37 patients in group 2 already had had two-to-seven recurrences prior to TRT. Median radiation dose was 60 Gy (range: 44-66.4 Gy), the additional local hyperthermia (>41 degrees C, 60 min) was given twice a week. Median follow-up for patients at risk was 28 months. All statistical tests were done using Statistica(R) software. Results: Actuarial OS for all patients at 3 years accounted for 89%, DFS for 68% and LC for 80%. Actuarial OS was 90% for group 1 and 89% for group 2, with four patients having died so far. DFS at 3 years was 64% in group 1 and 69% in group 2, actuarial 3 year LC was 75% and 81%, respectively. For patients with recurrent chest wall disease, there was no difference concerning local control between patients who underwent TRT with or without prior radiation. No prognostic factors could be detected due to the small number of patients investigated. The combined modality treatment was well tolerated. Grade IV toxicity, according to the Common Toxicity Criteria, did not occur. Conclusion: The results concerning local tumour control and overall survival in these high-risk patients are promising, especially for TRT for the treatment of local recurrences. A longer follow-up is needed to estimate late toxicity.

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Oncol Nurs Forum. 2005 Mar 5;32(2):343-53.
Aromatase inhibitor agents in breast cancer: evolving practices in hormonal therapy treatment.
Viale PH.
Santa Clara Valley Medical Center, San Jose, CA, USA. pamela.viale@hhs.co.santa-clara.ca.us.

PURPOSE/OBJECTIVES: To review the role of aromatase inhibitor agents with regard to current treatment strategies with hormonal therapy for women with breast cancer. DATA SOURCES: Published articles and books. DATA SYNTHESIS: Hormonal therapy is an essential component of the treatment of most women with breast cancer. Aromatase inhibitor agents are becoming an integral part of treatment for women with metastatic breast cancer and recently have become much more prominent in the treatment of women with early-stage breast cancer. The exact role of these agents in adjuvant therapy of breast cancer, either sequentially with the "gold standard" tamoxifen or for the duration of therapy, has yet to be determined. CONCLUSIONS: Recent studies with aromatase inhibitor agents are intriguing and suggest an improved side-effect profile and efficacy. The approval of these agents for the adjuvant treatment of breast cancer has led to a significant change in practice. IMPLICATIONS FOR NURSING: Breast cancer is an extremely common cancer in women, and oncology nurses take care of large numbers of patients with this disease. Oncology nurses need the most recent information so they can discuss aromatase inhibitor agents and therapy with their patients.

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Breast Cancer Res Treat. 2005 Jan;89 Suppl 1:S9-S15.
Optimizing the treatment of metastatic breast cancer.
Gralow JR.
Department of Medicine, Division of Oncology, University of Washington School of Medicine, WA, USA, pink@u.washington.edu.

There is currently no standard care for metastatic breast cancer; consequently, individual patient and tumor characteristics are among several factors considered in treatment decisions. Clinical studies continue to clarify the roles of endocrine therapy, chemotherapy, and biologic therapy, and results have been promising. For patients with hormone receptor-positive disease, several endocrine agents are currently available including selective estrogen receptor (ER) modulators (tamoxifen and toremifene), aromatase inhibitors (anastrozole, exemestane, and letrozole), as well as the selective ER down-regulator, fulvestrant. Effective first- and second-line, single-agent chemotherapeutic treatments include the taxanes, anthracyclines, vinorelbine, capecitabine, and gemcitabine. The benefits of sequential, single-agent versus combination chemotherapy are also being evaluated. Although combination chemotherapy generally results in a greater objective response, it is associated with similar survival and usually greater toxicity compared with sequential, single-agent chemotherapy. Research involving biologic therapy continues to provide encouraging results for patients with metastatic breast cancer. Chemotherapy plus trastuzumab has been shown to result in greater overall survival versus chemotherapy alone in human epidermal growth factor 2 (HER-2)-positive patients. Trastuzumab has been associated with cardiotoxicity when administered with conventional anthracyclines. Newer formulations of anthracyclines have been developed (e.g., liposomal anthracyclines) to decrease the incidence of cardiotoxicity, and these provide additional treatment options for patients with metastatic breast cancer. The potential effect of all of these endocrine, chemotherapeutic, and biologic treatments on quality of life is an important consideration. Additionally, integrating patient concerns into treatment decisions and collaborating with cross-disciplinary healthcare providers can help to manage the disease more effectively.

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Breast Cancer Res Treat. 2005 Jan;89 Suppl 1:S1-7.
Evolving treatment approaches for early breast cancer.
Campos SM.
Harvard Medical School, Dana Farber Cancer Institute, Boston, MA, USA, Susana.Campos@dfci.harvard.edu.

Treatment approaches for early breast cancer continue to evolve as key trials involving adjuvant chemotherapy and hormonal therapy provide results that can inform clinical practice. The administration of a taxane, either in combination with or following doxorubicin and cyclophosphamide, has been shown to significantly improve disease-free survival (DFS) and overall survival (OS). In addition, a dose-dense treatment approach (reducing the inter-treatment interval) was found to be more effective than conventionally scheduled treatment in terms of DFS and OS. As treatment schemes evolve, supportive care becomes increasingly important to manage the toxicities of chemotherapy, such as anemia and impaired cognition. In addition to chemotherapy, the use of hormonal therapy continues to evolve, with studies demonstrating the benefit of the aromatase inhibitors and serum estrogen receptor down-regulation.

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ANZ J Surg. 2004 Dec;74(12):1043-8.
Prospective trial of intraoperative radiation treatment for breast cancer.
Joseph DJ, Bydder S, Jackson LR, Corica T, Hastrich DJ, Oliver DJ, Minchin DE, Haworth A, Saunders CM.
Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, Australia.

Background: A new device, Intrabeam, is available for intraoperative radiotherapy. We have prospectively examined its feasibility and tolerability in delivering adjuvant breast cancer treatment. Methods: Thirty-five patients undergoing breast-conserving surgery received targeted tumour bed irradiation consisting of 5 Gy (at 10 mm) in a single fraction. This single intraoperative treatment was used to replace the external beam radiotherapy 'boost' that would usually be given in 10 daily treatments following 5 weeks of whole breast irradiation. Patients later completed external beam radiotherapy as usual. Potential toxicities were prospectively assessed fortnightly prior to external beam radiotherapy, weekly during it, and 3 monthly subsequently. Results: The intraoperative radiotherapy was able to be delivered without difficulty, either at time of initial cancer surgery or as a second procedure. When performed as a separate procedure the median operating time was 56 min. The treatment was well tolerated, with only one patient experiencing any grade 3 or 4 toxicities - this was acute grade three itch. There was an overall early breast infection rate of 17%. No unexpected toxicities were seen. Conclusions: This simple and well-tolerated treatment delivers a useful radiation dose to the area of highest risk of tumour recurrence. The early infection rate is similar to that reported in the literature, for treatments without intraoperative radiotherapy. Whether such a treatment may adequately replace the entire adjuvant radiation therapy treatment for low-risk patients is now being studied in a randomized trial.

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J Natl Cancer Inst. 2004 Dec 1;96(23):1751-61.
Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene.
Martino S, Cauley JA, Barrett-Connor E, Powles TJ, Mershon J, Disch D, Secrest RJ, Cummings SR; CORE Investigators.
Cancer Institute Medical Group, 2001 Santa Monica Blvd., Ste. 560W, Santa Monica, CA 90404, USA. smartino@cimg.org

BACKGROUND: The randomized, double-blind Multiple Outcomes of Raloxifene Evaluation (MORE) trial found that 4 years of raloxifene therapy decreased the incidence of invasive breast cancer among postmenopausal women with osteoporosis by 72% compared with placebo. We conducted the Continuing Outcomes Relevant to Evista (CORE) trial to examine the effect of 4 additional years of raloxifene therapy on the incidence of invasive breast cancer in women in MORE who agreed to continue in CORE. METHODS: Women who had been randomly assigned to receive raloxifene (either 60 or 120 mg/day) in MORE were assigned to receive raloxifene (60 mg/day) in CORE (n = 3510), and women who had been assigned to receive placebo in MORE continued on placebo in CORE (n = 1703). Breast cancer incidence was analyzed by a log-rank test, and a Cox proportional hazards model was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. RESULTS: During the CORE trial, the 4-year incidences of invasive breast cancer and estrogen receptor (ER)-positive invasive breast cancer were reduced by 59% (HR = 0.41; 95% CI = 0.24 to 0.71) and 66% (HR = 0.34; 95% CI = 0.18 to 0.66), respectively, in the raloxifene group compared with the placebo group. There was no difference between the two groups in incidence of ER-negative invasive breast cancer during CORE (P = .86). Over the 8 years of both trials, the incidences of invasive breast cancer and ER-positive invasive breast cancer were reduced by 66% (HR = 0.34; 95% CI = 0.22 to 0.50) and 76% (HR = 0.24; 95% CI = 0.15 to 0.40), respectively, in the raloxifene group compared with the placebo group. During the CORE trial, the relative risk of thromboembolism in the raloxifene group compared with that in the placebo group was 2.17 (95% CI = 0.83 to 5.70). This increased risk, also observed in the MORE trial, persisted over the 8 years of both trials. CONCLUSIONS: The reduction in invasive breast cancer incidence continues beyond 4 years of raloxifene treatment in postmenopausal women with osteoporosis. No new safety concerns related to raloxifene therapy were identified during CORE.

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Am J Clin Oncol. 2004 Dec;27(6):555-64.
Local-regional radiation therapy after breast reconstruction: what is the appropriate target volume?: a case-control study of patients treated with electron arc radiotherapy and review of the literature.
Hazard L, Miercort C, Gaffney D, Leavitt D, Stewart JR.
From the Department of Radiation Oncology, University of Utah Medical Center, Salt Lake City, Utah.

The oncologic safety and cosmetic outcome of immediate breast reconstruction in breast cancer patients requiring radiation therapy remains ill-defined. Between 1980 and 1998, 18 patients were treated at the University of Utah Medical Center with mastectomy, immediate breast reconstruction, and adjuvant radiation therapy delivered via an electron arc technique. A case-control study was performed matching reconstructed patients in a 1:2 ratio with patients undergoing mastectomy without reconstruction, using number of lymph nodes and tumor size. Median follow-up was 61 months for the reconstructed group. Five-year local-regional control, disease-free survival, and overall survival rates were 87%, 58%, and 74% respectively in the reconstructed group, versus 88%, 57%, and 67% respectively in the matched control group. Cosmesis was good/excellent in 11 of 13 living patients (85%). Significant capsular contraction occurred in 18% of prosthetic reconstruction patients, and revisional surgery was required in 24% of prosthetic reconstruction patients. Utilizing the electron arc technique, the median radiation dose to the chest wall at the midlevel of the ribs was 20% of the prescribed dose, and no patient failed deep to the implant. These results suggest that in appropriately selected patients, structures deep to the reconstruction are not at high risk for local-regional recurrence, and immediate breast reconstruction yields comparable local-regional control, disease-free survival, and overall survival rates to nonreconstructed patients, with acceptable cosmetic results.

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Expert Opin Pharmacother. 2004 Dec;5(12):2549-58.
Fulvestrant - a new treatment for postmenopausal women with hormone-sensitive advanced breast cancer.
Possinger K.
Universitatsmedizin, Department of Oncology and Haematology, Charite Campus Mitte, Berlin, Germany. kurt.possinger@charite.de.

Approximately 75% of breast tumours in postmenopausal women are positive for the oestrogen receptor (ER) and/or the progesterone receptor (PgR) and are, therefore, potential candidates for endocrine treatment. Fulvestrant is a new type of ER antagonist with no agonist effects and a novel mode of action; it binds, blocks and degrades the ER, leading to a reduction in cellular ER and, consequently, in PgR levels. This novel mode of action results in a lack of cross-resistance with other commonly used endocrine treatments. In Phase III trials in postmenopausal women with advanced breast cancer progressing on prior anti-oestrogen therapy, fulvestrant was at least as effective as the third-generation aromatase inhibitor, anastrozole, in terms of time to progression and objective response, and was associated with similar overall survival. In the first-line setting, fulvestrant showed similar efficacy to tamoxifen in patients with ER-positive and/or PgR-positive disease. Efficacy in more heavily pretreated patients has also been demonstrated in the fulvestrant compassionate use programme. Fulvestrant is well tolerated, being associated with a significantly lower incidence of joint disorders compared with anastrozole, and a lower incidence of hot flushes compared with tamoxifen. Fulvestrant, therefore, provides clinicians with a useful additional treatment for hormone-sensitive advanced breast cancer in postmenopausal women. Ongoing trials will help to clarify the optimal position of fulvestrant in the endocrine treatment sequence for these patients.

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J Clin Oncol. 2004 Dec 1;22(23):4639-47.
Postmastectomy radiation improves local-regional control and survival for selected patients with locally advanced breast cancer treated with neoadjuvant chemotherapy and mastectomy.
Huang EH, Tucker SL, Strom EA, McNeese MD, Kuerer HM, Buzdar AU, Valero V, Perkins GH, Schechter NR, Hunt KK, Sahin AA, Hortobagyi GN, Buchholz TA.
Department of Radiation Oncology, Box 97, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: tbuchhol@mdanderson.org.

PURPOSE To evaluate the efficacy of radiation in patients treated with neoadjuvant chemotherapy and mastectomy. PATIENTS AND METHODS We retrospectively analyzed the outcomes of 542 patients treated on six consecutive institutional prospective trials with neoadjuvant chemotherapy, mastectomy, and radiation. These data were compared to those of 134 patients who received similar treatment in these same trials but without radiation. Results Irradiated patients had a lower rate of local-regional recurrence (LRR) (10-year rates: 11% v 22%, P = .0001). Radiation reduced LRR for patients with clinical T3 or T4 tumors, stage >/= IIB disease (AJCC 1988), pathological tumor size >2 cm, or four or more positive nodes (P </= .002 for all comparisons). Patients who presented with clinically advanced stage III or IV disease but subsequently achieved a pathological complete response to neoadjuvant chemotherapy still had a high rate of LRR, which was significantly reduced with radiation (10-year rates: 33% v 3%, P = .006). Radiation improved cause-specific survival (CSS) in the following subsets: stage >/= IIIB disease, clinical T4 tumors, and four or more positive nodes (P </= .007 for all comparisons). On multivariate analyses of LRR and CSS, the hazard ratios for lack of radiation were 4.7 (95% CI, 2.7 to 8.1; P < .0001) and 2.0 (95% CI, 1.4 to 2.9; P < .0001), respectively. CONCLUSION After neoadjuvant chemotherapy and mastectomy, comprehensive radiation was found to benefit both local control and survival for patients presenting with clinical T3 tumors or stage III-IV (ipsilateral supraclavicular nodal) disease and for patients with four or more positive nodes. Radiation should be considered for these patients regardless of their response to initial chemotherapy.

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J Clin Oncol. 2004 Dec 1;22(23):4631-8.
Randomized Phase III Trial of Marimastat Versus Placebo in Patients With Metastatic Breast Cancer Who Have Responding or Stable Disease After First-Line Chemotherapy: Eastern Cooperative Oncology Group Trial E2196.
Sparano JA, Bernardo P, Stephenson P, Gradishar WJ, Ingle JN, Zucker S, Davidson NE.
Albert Einstein Cancer Center, Montefiore Medical Center, Weiler Division, 1825 Eastchester Rd, 2 South, Rm 47-48, Bronx, NY 10461; e-mail: Sparano@jimmy.harvard.edu.

PURPOSE To determine whether a matrix metalloproteinase inhibitor improves progression-free survival (PFS) in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy. PATIENTS AND METHODS One hundred seventy-nine eligible patients were randomly assigned to receive oral marimastat (10 mg bid; n = 114) or a placebo (n = 65) within 3 to 6 weeks of completing six to eight cycles of first-line doxorubicin- and/or taxane-containing chemotherapy for metastatic disease. Patients were evaluated every 3 months until disease progression. Results When comparing placebo with marimastat, there was no significant difference in PFS (median, 3.1 months v 4.7 months, respectively; hazard ratio, 1.26; 95% CI, 0.91 to 1.74; P = .16) or overall survival (median, 26.6 months v 24.7 months, respectively; hazard ratio, 1.03; 95% CI, 0.73 to 1.46; P = .86). Patients treated with marimastat were more likely to develop grade 2 or 3 musculoskeletal toxicity (MST), a known complication of the drug indicative of achieving a biologic effect, compared with patients administered placebo (63% v 22%, respectively; P < .0001). Patients with grade 2 or 3 MST had significantly inferior survival compared with patients who had grade 0 or 1 MST (median, 22.5 months v 28.2 months; P = .04). In addition, patients who had a marimastat plasma concentration of at least 10 ng/mL at month 1 and/or 3 were significantly more likely to have grade 2 to 3 MST (P < .0001). CONCLUSION Marimastat does not prolong PFS when used after first-line chemotherapy for metastatic breast cancer. Patients with higher marimastat levels exhibited MST, and MST was associated with inferior survival.

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Cancer Invest. 2004;22(4):555-68.
Dose density in adjuvant chemotherapy for breast cancer.
Citron ML.
Albert Einstein College of Medicine, Bronx, New York, USA. mcitron@prohealthcare.com

BACKGROUND: Dose-dense chemotherapy increases the dose intensity of the regimen by delivering standard-dose chemotherapy with shorter intervals between the cycles. This article discusses the rationale for dose-dense therapy and reviews the results with dose-dense adjuvant regimens in recent clinical trials in breast cancer. METHODS: The papers for this review covered evidence of a dose-response relation in cancer chemotherapy; the rationale for dose-intense (and specifically dose-dense) therapy; and clinical experience with dose-dense regimens in adjuvant chemotherapy for breast cancer, with particular attention to outcomes and toxicity. RESULTS: Evidence supports maintaining the dose intensity of adjuvant chemotherapy within the conventional dose range. Disease-free and overall survival with combination cyclophosphamide, methotrexate, and fluorouracil are significantly improved when patients receive within 85% of the planned dose. Moderate and high dose cyclophosphamide, doxorubicin, and fluorouracil within the standard range results in greater disease-free and overall survival than the low dose regimen. The sequential addition of paclitaxel after concurrent doxorubicin and cyclophosphamide also significantly improves survival. Disease-free and overall survival with dose-dense sequential or concurrent doxorubicin, cyclophosphamide, and paclitaxel with filgrastim (rhG-CSF; NEUPOGEN) support are significantly greater than with conventional schedules (q21d). CONCLUSIONS: The delivered dose intensity of adjuvant chemotherapy within the standard dose range is an important predictor of the clinical outcome. Prospective trials of high-dose chemotherapy have shown no improvement over standard regimens, and toxicity was greater. Dose-dense adjuvant chemotherapy improves the clinical outcomes with doxorubicin-containing regimens. Filgrastim support enables the delivery of dose-dense chemotherapy and reduces the risk of neutropenia and its complications.

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Asian J Surg. 2004 Oct;27(4):268-74.
Selective sentinel lymphadenectomy for breast cancer in the United States.
Leong SP.
Sentinel Lymph Node Program, Department of Surgery, University of California, San Francisco, U.S.A.

Lymph node status is the most reliable prognostic indicator for breast cancer patients. Sentinel lymph nodes (SLNs) are the first draining lymph nodes for metastatic breast cancer to spread from the primary site. Although the therapeutic role of selective sentinel lymphadenectomy (SSL) in breast cancer has not been determined, the practical significance is that it is being used as a staging procedure, so that a negative SLN can spare a patient more extensive axillary lymph node dissection (ALND) with its associated morbidity. If the SLN is negative, the negative predictive value of the remaining nodal basin for breast cancer exceeds 95%. SSL selects out one or a few SLNs and permits more extensive study of the nodes by the pathologist. Such extensive examination would not be practical for the many nodes yielded by a standard ALND. SSL is rapidly evolving into a standard approach for staging primary breast cancer in the United States, without the maturation of results from clinical trials.

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Asian J Surg. 2004 Oct;27(4):262-7.
Sentinel lymph node biopsy following neoadjuvant chemotherapy: review of the literature and recommendations for use in patient management.
Xing Y, Cormier JN, Kuerer HM, Hunt KK.
Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A.

Breast cancer is a significant health problem worldwide and is one of the leading causes of cancer-related mortality in women. Preoperative chemotherapy has become the standard of care for patients with locally advanced disease and is being used more frequently in patients with early-stage breast cancer. Sentinel lymph node biopsy has shown great promise in the surgical management of breast cancer patients, but its use following preoperative chemotherapy is yet to be determined. Eleven studies have been published with respect to the accuracy of sentinel lymph node biopsy following neoadjuvant chemotherapy. Ten studies showed favourable results, with the ability to identify a sentinel lymph node in 84% to 98% of cases, and reported false negative rates ranging from 0% to 20%. The accuracy of sentinel lymph node biopsy following preoperative chemotherapy for breast cancer ranges from 88% to 100%, with higher rates when specific techniques and inclusion criteria are applied. The published literature supports the use of sentinel lymph node biopsy for assessment of the axilla in patients with clinically node-negative disease following preoperative chemotherapy.

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Front Biosci. 2004 Sep 1;9:2827-47.
Tamoxifen: an emerging preventive.
Schwartz J.
Department of Physiology, School of Medicine, 540 E. Canfield, Wayne State University, Detroit, MI 48201.

Tamoxifen is well known for its actions as an antagonist of estrogen receptor-mediated signaling and is one of the most extensively used endocrine agents both in the clinic and in the research setting. Tamoxifen has emerged from recent Breast Cancer Prevention Trials, conducted to evaluate risk reduction, as an effective preventive agent. Specifically, comparing tamoxifen to placebo (for 5 years) has shown that tamoxifen: (a) significantly reduced the risk of breast cancer recurrence, in those with a history of the disease; (b) reduced or delayed breast cancer progression, from an noninvasive to invasive breast cancer; (c) prevented or substantially reduced the risk of getting breast cancer (risk of occurrence) in healthy women with risk factors. The extraordinary outcomes offer support for the use of tamoxifen in multilevel preventive approaches and predict that it will continue to be vital in facilitating mechanistic studies. Information produced by mechanistic studies is needed to understand how to prevent cancer and how to confront treatment problems such as resistance.Molecular determinants of the resistant phenotype to tamoxifen are currently being identified. The next major effort will be to link these determinants to readily detectable biological changes that could be used to indicate the development of resistance before clinical manifestations develop.

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Lancet. 2004 Sep 4;364(9437):858-68.
Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials.
Fisher PB, Jeong JH, Bryant PJ, Anderson S, Dignam J, Fisher PE, Wolmark PN.
Operations Center, National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA, USA.

Background Findings from the National Surgical Adjuvant Breast and Bowel Project B-14 and B-20 trials showed that tamoxifen benefited women with oestrogen-receptor-positive tumours and negative axillary nodes, and that chemotherapy plus tamoxifen was more effective than tamoxifen alone. We present long-term findings from those trials and relate them to age, menopausal status, and tumour oestrogen-receptor concentrations. We also discuss the extent of progress made in the treatment of such patients. Methods B-14 patients were randomly assigned to placebo (n=1453) or tamoxifen (n=1439); B-20 patients to tamoxifen (n=788) or cyclophosphamide, methotrexate, fluorouracil, and tamoxifen (CMFT, n=789). Primary endpoints were recurrence-free survival and overall survival estimated according to patients' age, menopausal status, and tumour oestrogen-receptor concentration. Smoothed recurrence rates were used to measure patterns of recurrence as a continuous function of age. Findings Compared with placebo, tamoxifen benefited women in B-14 through 15 years, irrespective of age, menopausal status, or tumour oestrogen-receptor concentration (hazard ratio [HR] for recurrence-free survival 0.58, 95% CI 0.50-0.67, p<0.0001; HR for overall survival 0.80, 0.71-0.91, p=0.0008). In B-20, the benefit from CMFT over 12 years was greater than that from tamoxifen alone (HR for recurrence-free survival 0.52, 0.39-0.68, p<0.0001; HR for overall survival 0.78, 0.60-1.01, p=0.063). When CMFT was compared with placebo, there were reductions in treatment failure of about 65% in all age-groups. Interpretation Much benefit has been achieved in treatment of women with oestrogen-receptor-positive tumours and negative nodes. When planning systemic therapy for such patients of all ages, it should be understood that some have tumours with variable concentrations of oestrogen-receptors, a surrogate for other biomarkers associated with tumour growth and response to treatment. Older women tend to have higher tumour oestrogen-receptor concentrations and are more likely to benefit from tamoxifen than from chemotherapy; in younger women, the converse is true. Consequently, the notion that use of tamoxifen or chemotherapy should be based only on age is too restrictive.

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Onkologie. 2004 Aug;27(4):385-8.
Weekly Paclitaxel combined with local hyperthermia in the therapy of breast cancer locally recurrent after mastectomy - a pilot experience.
Zoul Z, Filip S, Melichar B, Dvorak J, Odrazka K, Petera J.
Department of Oncology and Radiotherapy, Charles University Medical School Teaching Hospital, Hradec Kralove, Czech Republic.

Background: The combination of chemotherapy and hyperthermia (HT) is a promising approach in the treatment of malignant tumors. In the present report we evaluate the efficacy and toxicity of a combination of weekly paclitaxel combined with local hyperthermia in breast cancer. Patients and Methods: 7 patients were treated for inoperable local recurrence of breast cancer after mastectomy, irradiation, and chemotherapy or hormonal therapy. They weekly received paclitaxel (60-80 mg/m(2)) in 3-h infusions followed by local HT 41-44 degrees C for 45 min for 6-18 cycles. Results: Objective local response was observed in all treated patients (complete response in 4 patients and partial response in 3 patients). There were no grade 3 or 4 toxicities, neurologic toxicity or hypersensitivity reactions. Local tolerance to this regimen was also good, with only 4 patients developing mild transient erythema. Conclusion: Our experience indicates that the combination of weekly paclitaxel and HT may be effective in the treatment of locally recurrent breast cancer after mastectomy. Copyright 2004 S. Karger GmbH, Freiburg

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Clin Breast Cancer. 2004 Sep;5 Suppl 1:S18-23.
Adjuvant aromatase inhibitors following tamoxifen for early-stage breast cancer in postmenopausal women: what do we really know?
Chung CT, Carlson RW.
Division of Oncology, Stanford University, CA.

Adjuvant hormonal therapy in the treatment of women with early-stage, hormone receptor (HR)-positive breast cancer is now considered the standard of care. Adjuvant tamoxifen decreases the risk of breast cancer recurrence and death in women with early-stage breast cancer when taken for 5 years. The benefits of tamoxifen are counterbalanced by toxicities including an increased risk of endometrial cancer and thromboembolic events. The selective aromatase inhibitors (AIs)-including anastrozole, letrozole, and exemestane-are challenging the role of tamoxifen as the adjuvant hormonal therapy of choice in postmenopausal women. Results of the Arimidex and Tamoxifen Alone or in Combination trial favor the use of anastrozole over tamoxifen as initial adjuvant hormonal therapy, with improvement in disease-free survival (DFS) and a favorable toxicity profile. The results of 2 large adjuvant trials using AIs sequentially with tamoxifen in postmenopausal women with early-stage, HR-positive breast cancer have been reported. The MA-17 study randomized women to placebo or letrozole for 5 years after completion of 4.5-6 years of initial tamoxifen. The Intergroup Exemestane Study (IES) randomized women following 2-3 years of adjuvant tamoxifen to continue to receive tamoxifen or switch to exemestane for a total of 5 years of adjuvant hormonal therapy. The MA-17 and IES trials demonstrated superior DFS with the AI and corroborated the smaller GROCTA-4B and Italian Tamoxifen Arimidex trials, which studied sequential therapy with aminoglutethamide or anastrozole. There is now substantial medical evidence supporting the use of AIs in postmenopausal women with early-stage, HR-positive breast cancer.

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Clin Breast Cancer. 2004 Sep;5 Suppl 1:S6-S12.
The ATAC (Arimidex(R), Tamoxifen, Alone or in Combination) Trial: An Update.
Buzdar AU.
The University of Texas M. D. Anderson Cancer Center, Houston; e-mail: abuzdar@mdanderson.org

Until recently, tamoxifen was the only adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive, early-stage breast cancer. However, the first efficacy update from the ATAC (Arimidex(R), Tamoxifen, Alone or in Combination) trial has introduced a choice of adjuvant therapy in this setting. After a median follow-up of 47 months, these data indicated that anastrozole continued to show superior efficacy compared with tamoxifen, including significantly greater disease-free survival, a longer median time to recurrence, and a reduced incidence of contralateral breast cancer. Anastrozole also exhibited a number of important tolerability benefits compared with tamoxifen, including reduced incidences of thromboembolic events, vaginal bleeding, and endometrial cancer. Additional ATAC subprotocols included the examination of bone mineral density and its associated sequelae, endometrial abnormalities, and quality of life. The results of these studies support the primary conclusions of the main efficacy and safety analyses: the efficacy benefits of anastrozole were not at the expense of quality of life, anastrozole was associated with reduced endometrial stimulation compared with tamoxifen, and only patients receiving tamoxifen had endometrial atypical hyperplasia. Anastrozole was associated with a modest loss of bone mineral density and an initial increase of fractures compared with tamoxifen. However, the fracture rate with anastrozole stabilizes after 2 years, and indirect comparison suggests that any increased fracture risk with anastrozole is modest. This review concludes that, based on the overall risk-benefit profile from the ATAC study, anastrozole is a rational alternative to tamoxifen for the adjuvant treatment of women with hormone-sensitive early-stage breast cancer.

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Australas Radiol. 2004 Sep;48(3):376-382.
Breast-conserving therapy in young women with invasive carcinoma of the breast.
Borg M.
Department of Radiation Oncology, Royal Adelaide Hospital, Adelaide South Australia, Australia.

Summary Higher local recurrence rates have been reported in young women with invasive carcinoma of the breast treated with breast-conserving therapy (BCT). However, age itself may not be responsible for this increased risk of recurrence. To investigate this further, a computerized literature search of MEDLINE was performed using data from 1996 to May 2003. The research was limited to female patients with localized, invasive adenocarcinoma of the breast but also included patients of young age with ductal carcinoma in situ. Women of young age with breast cancer, treated with BCT are at an increased risk of recurrence ranging from 7.5 to 35%. However, the data would suggest that the increased risk is secondary to the association of young age with more aggressive tumours and a positive family history of breast cancer. Other factors that may explain the adverse prognosis in women of a young age include associated genetic abnormalities and the lack of mammographic screening programmes for women of young age. Young age is a risk factor for breast recurrence after BCT. However, management decisions should be based on tumour stage, grade and other related prognostic features rather than on young age alone.

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N Engl J Med. 2004 Sep 2;351(10):963-70.
Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer.
Fyles AW, McCready DR, Manchul LA, Trudeau ME, Merante P, Pintilie M, Weir LM, Olivotto IA.
Department of Radiation Oncology, Princess Margaret Hospital,, Toronto, ON, Canada. anthony.fyles@rmp.uhn.on.ca

BACKGROUND: We determined the effect of breast irradiation plus tamoxifen on disease-free survival and local relapse in women 50 years of age or older who had T1 or T2 node-negative breast cancer. METHODS: Between December 1992 and June 2000, 769 women with early breast cancer (tumor diameter, 5 cm or less) were randomly assigned to receive breast irradiation plus tamoxifen (386 women) or tamoxifen alone (383 women). The median follow-up was 5.6 years. RESULTS: The rate of local relapse at five years was 7.7 percent in the tamoxifen group and 0.6 percent in the group given tamoxifen plus irradiation (hazard ratio, 8.3; 95 percent confidence interval, 3.3 to 21.2; P<0.001), with corresponding five-year disease-free survival rates of 84 percent and 91 percent (P=0.004). A planned subgroup analysis of 611 women with T1, receptor-positive tumors indicated a benefit from radiotherapy (five-year rates of local relapse, 0.4 percent with tamoxifen plus radiotherapy and 5.9 percent with tamoxifen alone; P<0.001). Overall, there was a significant difference in the rate of axillary relapse at five years (2.5 percent in the tamoxifen group and 0.5 percent in the group given tamoxifen plus irradiation, P=0.049), but no significant difference in the rates of distant relapse or overall survival. CONCLUSIONS: As compared with tamoxifen alone, radiotherapy plus tamoxifen significantly reduces the risk of breast and axillary recurrence after lumpectomy in women with small, node-negative, hormone-receptor-positive breast cancers. Copyright 2004 Massachusetts Medical Society

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N Engl J Med. 2004 Sep 2;351(10):971-7.
Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer.
Hughes KS, Schnaper LA, Berry D, Cirrincione C, McCormick B, Shank B, Wheeler J, Champion LA, Smith TJ, Smith BL, Shapiro C, Muss HB, Winer E, Hudis C, Wood W, Sugarbaker D, Henderson IC, Norton L; Cancer and Leukemia Group B; Radiation Therapy Oncology Group; Eastern Cooperative Oncology Group.
Avon Comprehensive Breast Evaluation Center, Breast/Ovarian Cancer Genetics and Risk Assessment Program, Massachusetts General Hospital, Division of Surgical Oncology, Boston 02114, USA. kshughes@partners.org

BACKGROUND: In women 70 years of age or older who have early breast cancer, it is unclear whether lumpectomy plus tamoxifen is as effective as lumpectomy followed by tamoxifen plus radiation therapy. METHODS: Between July 1994 and February 1999, we randomly assigned 636 women who were 70 years of age or older and who had clinical stage I (T1N0M0 according to the tumor-node-metastasis classification), estrogen-receptor-positive breast carcinoma treated by lumpectomy to receive tamoxifen plus radiation therapy (317 women) or tamoxifen alone (319 women). Primary end points were the time to local or regional recurrence, the frequency of mastectomy for recurrence, breast-cancer-specific survival, the time to distant metastasis, and overall survival. RESULTS: The only significant difference between the two groups was in the rate of local or regional recurrence at five years (1 percent in the group given tamoxifen plus irradiation and 4 percent in the group given tamoxifen alone, P<0.001). There were no significant differences between the two groups with regard to the rates of mastectomy for local recurrence, distant metastases, or five-year rates of overall survival (87 percent in the group given tamoxifen plus irradiation and 86 percent in the tamoxifen group, P=0.94). Assessment by physicians and patients of cosmetic results and adverse events uniformly rated tamoxifen plus irradiation inferior to tamoxifen alone. CONCLUSIONS: Lumpectomy plus adjuvant therapy with tamoxifen alone is a realistic choice for the treatment of women 70 years of age or older who have early, estrogen-receptor-positive breast cancer. Copyright 2004 Massachusetts Medical Society

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Exp Biol Med (Maywood). 2004 Sep;229(8):722-31.
The consequences of exhaustive antiestrogen therapy in breast cancer: estrogen-induced tumor cell death.
Osipo C, Liu H, Meeke K, Jordan VC.
Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine, 303 East Chicago Avenue, Olson Pavilion, Room 8258, Chicago, IL 60611. vcjordan@northwestern.edu

Forty years ago, the endocrine treatment for breast cancer was a last resort at palliation before the disease overwhelmed the patient (1). Ovarian ablation was the treatment of choice for the premenopausal patient, whereas either adrenalectomy or, paradoxically, high-dose synthetic estrogen therapy were used for treatment in postmenopausal patients. A reduction or an excess of estrogen provoked objective responses in one out of three women. Unfortunately, there was no way of predicting who would respond to endocrine ablation, and because so few patients responded there was no enthusiasm for developing new endocrine agents. All hopes for a cure for breast cancer turned to appropriate combinations of cytotoxic chemotherapy.Today tamoxifen, a nonsteroidal antiestrogen (2), has proven to be effective in all stages of premenopausal and postmenopausal breast cancer, and several new endocrine strategies, including aromatase inhibitors, luteinizing-hormone releasing hormone (LHRH) superagonists, and a pure antiestrogen (fulvestrant), are now available for breast cancer treatment. Additionally, tamoxifen and raloxifene, a related compound, are used to reduce the risk of breast cancer and osteoporosis, respectively, in high-risk groups (3). Hormonal modulation and strategies to prevent the actions of estrogen in the breast are ubiquitous. However, with successful changes in treatment strategies comes the consequence of change.This minireview will describe the current strategies for the treatment and prevention of breast cancer and present emerging new concepts about the consequences of exhaustive antiestrogen treatment on therapeutic resistance.

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Int J Radiat Oncol Biol Phys. 2004 Sep 1;60(1):71-6.
Breast-conserving therapy for stage I-II breast cancer in elderly women.
Cutuli B, Aristei C, Martin C, Perrucci E, Latini P, Quetin P.
Department of Radiation Oncology, Polyclinique de Courlancy, Reims, France.

PURPOSE: To assess breast-conserving therapy results in elderly patients with early-stage breast cancer (clinical Stage I-II). METHODS AND MATERIALS: Between 1979 and 1998, 196 women (200 treated breasts) aged >/=70 years (median age, 72.5 years) were treated with breast-conserving therapy (lumpectomy or quadrantectomy with axillary lymph node dissection and radiotherapy). Pathologic axillary node involvement was found in 51 patients (28%). Two-thirds of patients received tamoxifen, and 16% received chemotherapy. RESULTS: At a median follow-up of 59 months, 3 patients (1.5%) had developed local recurrence and 20 (10.2%) distant metastases. The overall survival rate was 81% and 62% at 5 and 10 years, respectively. The corresponding disease-specific survival rates were 92% and 88%. Axillary nodal involvement was the only statistically significant risk factor for the development of metastases (p = 0.0035). Arm mobility impairment and arm lymphedema each occurred in 5 patients. In another 5 patients, a thromboembolic event occurred during tamoxifen treatment. CONCLUSION: Elderly women tolerate breast-conserving therapy, including radiotherapy, well and have excellent rates of locoregional control and disease-specific survival.

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J Formos Med Assoc. 2004 Aug;103(8):579-98.
Recent advances in the management of primary breast cancers.
Lu YS, Kuo SH, Huang CS.
Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.

The current concept of breast cancer treatment arises from Fisher's theory that operable breast cancer has distant micrometastasis at its very early stages. Since it is the presence of systemic diseases or micrometastasis that determines the final outcome, variation in local treatment would not affect survival. Fisher's theory led to a change in local treatment, from Halsted's radical mastectomy to breast-conserving therapy (BCT), and the introduction of adjuvant systemic treatment. As part of the job of surgery is replaced by radiation therapy in local control, the efficacy and side effects of radiation should be carefully monitored. The recently published results of 20-year follow-up in 2 important studies confirm that BCT achieves equal survival compared to mastectomy in women with early breast cancers, even after all causes of mortality have been considered. The introduction of sentinel lymph node biopsy has further decreased the adverse impact of breast cancer treatment on women. As variation in local control does not affect survival, more efforts are being put into developing adjuvant systemic treatment with curative intent. Adjuvant chemotherapy has been demonstrated to substantially affect the survival of women with early breast cancers. It is now apparent from numerous studies that adjuvant therapy improves survival in all subgroups of women with early breast cancer, although the absolute benefit varies depending on axillary lymph node status, tumor size, and other prognostic factors. This article reviews recent advances in the management of primary breast cancer, including: long-term follow-up after BCT; side effects of radiation therapy in BCT; post-mastectomy radiotherapy; sentinel node biopsy; adjuvant hormone therapy; and chemotherapy, including new strategies such as the incorporation of taxanes, dose-dense chemotherapy schedules, and the use of aromatase inhibitors in place of, or in addition to, tamoxifen.

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Cancer Chemother Pharmacol. 2004 Aug 17
Docetaxel and high-dose epirubicin as neoadjuvant chemotherapy in locally advanced breast cancer.
Espinosa E, Morales S, Borrega P, Casas A, Madronal C, Machengs I, Illarramendi JA, Lizon J, Moreno JA, Belon J, Janariz J, De La Puente M, Checa T, Mel JR, Gonzalez Baron M.
Oncopaz Cooperative Group, Madrid, Spain.

PURPOSE. Epirubicin and docetaxel are two of the most active drugs against breast carcinoma. As the achievement of a pathological complete response (pCR) is important for survival of patients with locally advanced disease, we used both drugs as neoadjuvant chemotherapy. PATIENTS AND METHODS. Women with locally advanced or inflammatory breast cancer received epirubicin 120 mg/m(2) followed by docetaxel 75 mg/m(2), both on day 1, every 21 days for four cycles. Lenograstim was administered for 10 days in all cycles. RESULTS. Of 51 patients included, 50 received a total of 188 cycles, with a median of 4 per patient. The median age was 47 years, tumour stage was IIIA in 14 patients and IIIB in 36. Oestrogen receptors were positive in 65% of tumours. There were 10 clinical complete responses (20%) and 29 partial responses (58%). Surgery consisted of mastectomy in 40 patients and tumorectomy in 6. After surgery, 9 pCR were recorded (18%). One patient progressed and died soon after the end of chemotherapy. After a median follow-up of 22 months, the median disease-free survival was 33.7 months. Grade 3/4 neutropenia was observed in 32% of patients, anaemia in 6%, and thrombocytopenia in 4%. Five patients had febrile neutropenia. There were no toxic deaths or grade 4 nonhaematological toxicities. CONCLUSIONS. Docetaxel plus high-dose epirubicin showed promising activity in patients with locally advanced and inflammatory breast cancer, at the cost of moderate toxicity.

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Ann Surg Oncol. 2004 May;11(5):542-9.
Cryoablation of Early-Stage Breast Cancer: Work-in-Progress Report of a Multi-Institutional Trial.
Sabel MS, Kaufman CS, Whitworth P, Chang H, Stocks LH, Simmons R, Schultz M.
University of Michigan, 3304 Cancer Center, 1500 East Medical Center, Ann Arbor, MI 48109-0932. msabel@umich.edu.

BACKGROUND: With recent improvements in breast imaging, our ability to identify small breast tumors has markedly improved, prompting significant interest in the use of ablation without surgical excision to treat early-stage breast cancer. We conducted a multi-institutional pilot safety study of cryoablation in the treatment of primary breast carcinomas. METHODS: Twenty-nine patients with ultrasound-visible primary invasive breast cancer </=2.0 cm were enrolled. Twenty-seven (93%) successfully underwent ultrasound-guided cryoablation with a tabletop argon gas-based cryoablation system with a double freeze/thaw cycle. Standard surgical resection was performed 1 to 4 weeks after cryoablation. Patients were monitored for complications, and pathology data were used to assess efficacy. RESULTS: Cryoablation was successfully performed in an office-based setting with only local anesthesia. There were no complications to the procedure or postprocedural pain requiring narcotic pain medications. Cryoablation successfully destroyed 100% of cancers <1.0 cm. For tumors between 1.0 and 1.5 cm, this success rate was achieved only in patients with invasive ductal carcinoma without a significant ductal carcinoma-in-situ (DCIS) component. For unselected tumors >1.5 cm, cryoablation was not reliable with this technique. Patients with noncalcified DCIS were the cause of most cryoablation failures. CONCLUSIONS: Cryoablation is a safe and well-tolerated office-based procedure for the ablation of early-stage breast cancer. At this time, cryoablation should be limited to patients with invasive ductal carcinoma </=1.5 cm and with <25% DCIS in the core biopsy. A multicenter phase II clinical trial is planned.

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J Clin Oncol. 2004 May 1;22(9):1621-9.
Phase II Trial of Trastuzumab Followed by Weekly Paclitaxel/Carboplatin As First-Line Treatment for Patients With Metastatic Breast Cancer.
Burris H 3rd, Yardley D, Jones S, Houston G, Broome C, Thompson D, Greco FA, White M, Hainsworth J.
The Sarah Cannon Cancer Center, 250 25th Avenue N, Suite 110, Nashville, TN 37203; e-mail: hburris@tnonc.com

PURPOSE To determine the response rate of trastuzumab as first-line therapy in patients with HER-2 overexpressing metastatic breast cancer. To assess the feasibility and toxicity of weekly paclitaxel/carboplatin with or without trastuzumab following initial treatment with trastuzumab. PATIENTS AND METHODS Sixty-one patients received trastuzumab (8 mg/kg followed by 4 mg/kg/wk) for 8 weeks. Responding patients received 8 additional weeks of trastuzumab (4 mg/kg/wk), and then proceeded to receive trastuzumab (2 mg/kg) in combination with paclitaxel 70 mg/m(2) and carboplatin (area under the curve, 2) weekly for 6 weeks followed by 2 weeks rest. Stable patients after the initial 8 weeks of trastuzumab proceeded to treatment with trastuzumab, paclitaxel, and carboplatin. Patients with disease progression during the initial 8 weeks had the trastuzumab discontinued and were treated with weekly paclitaxel/carboplatin. Results Weekly paclitaxel/carboplatin with or without trastuzumab was well tolerated. Fifty-two patients were assessable for response and all 61 patients were assessable for survival. Seventeen (33%) of 52 patients experienced a minor/partial response to single-agent trastuzumab and received 8 additional weeks of single-agent trastuzumab. Fifteen (29%) of 52 patients had stable disease and proceeded to receive paclitaxel/carboplatin/trastuzumab. Thirty-one patients with measurable disease were assessable for response after initial single-agent trastuzumab followed by paclitaxel/carboplatin/trastuzumab. An overall response rate of 84% (eight complete responses/18 partial responses), median time to progression of 14.2 months, and median overall survival of 32.2 months was reported with the triplet combination. In the patients treated with paclitaxel/carboplatin alone after disease progression on initial single-agent trastuzumab, an overall response rate of 69% (one complete response/10 partial responses), median time to progression of 8.3 months, and median overall survival of 22.2 months was reported. Median time to progression for all 61 patients is 10 months and the median overall survival is 26.7 months. CONCLUSION This trial confirms the activity and tolerability of weekly paclitaxel/carboplatin alone or in combination with trastuzumab in women with HER-2 overexpressing metastatic breast cancer.

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J Clin Oncol. 2004 May 1;22(9):1605-13.
Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: a multinational, double-blind, randomized trial.
Howell A, Robertson JF, Abram P, Lichinitser MR, Elledge R, Bajetta E, Watanabe T, Morris C, Webster A, Dimery I, Osborne CK.
Christie Hospital National Health Service Trust, Wilmslow Rd, Manchester M20 9BX, UK; e-mail: maria.parker@christie-tr.nwest.nhs.uk

PURPOSE To evaluate the efficacy and tolerability of fulvestrant (Faslodex; AstraZeneca Pharmaceuticals LP, Wilmington, DE), a new estrogen receptor (ER) antagonist that downregulates ER and has no agonist effects, versus tamoxifen, an antiestrogen with agonist and antagonist effects, for the treatment of advanced breast cancer in postmenopausal women. PATIENTS AND METHODS In this multicenter, double-blind, randomized trial, patients with metastatic/locally advanced breast cancer previously untreated for advanced disease were randomly assigned to receive either fulvestrant (250 mg, via intramuscular injection, once monthly; n = 313) or tamoxifen (20 mg, orally, once daily; n = 274). Patients' tumors were positive for ER (ER+) and/or progesterone receptor (PgR+), or had an unknown receptor status. Results At a median follow-up of 14.5 months, there was no significant difference between fulvestrant and tamoxifen for the primary end point of time to progression (TTP; median TTP, 6.8 months and 8.3 months, respectively; hazard ratio, 1.18; 95% CI, 0.98 to 1.44; P =.088). In a prospectively planned subset analysis of patients with known ER+ and/or PgR+ tumors ( approximately 78%), median TTP was 8.2 months for fulvestrant and 8.3 months for tamoxifen (hazard ratio, 1.10; 95% CI, 0.89 to 1.36; P =.39). The objective response rate for the overall population was 31.6% with fulvestrant and 33.9% with tamoxifen, and 33.2% and 31.1%, respectively, in the known hormone receptor-positive subgroup. Both treatments were well tolerated. CONCLUSION In the overall population, between-group differences in efficacy end points favored tamoxifen, and statistical noninferiority of fulvestrant could not be demonstrated. However, in patients with hormone receptor-positive tumors, fulvestrant had similar efficacy to tamoxifen and was well tolerated.

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Am J Obstet Gynecol. 2004 Apr;190(4):1141-67.
A comparative review of the risks and benefits of hormone replacement therapy regimens.
Warren MP.
Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, New York, NY USA.

The Women's Health Initiative (a large, randomized, placebo-controlled trial) investigated the effect of conjugated equine estrogens combined with medroxyprogesterone acetate on specific potential long-term benefits and risks. A review of the clinical studies that have investigated different types and regimens of estrogens combined with progestins was conducted to assess how applicable the results of the Women's Health Initiative are to hormone replacement therapy regimens in general. The studies that were reviewed were limited to randomized clinical trials and observational studies that have been published over the last 15 years (1987-2002) and to meta-analyses and reviews that may have included the literature before 1987. The increased risks for venous thromboembolism, stroke, coronary heart disease, and breast cancer that were identified in the Women's Health Initiative trial have also been reported with postmenopausal hormone therapies that contain a variety of estrogen and progestin products. The beneficial effects that were noted in the Women's Health Initiative, with respect to reductions in fractures and colorectal cancer, have not been evaluated in large, randomized controlled trials that use different estrogen/progestin combinations; however, observational trials that used a variety of estrogen or hormone replacement therapy products and randomized clinical studies that evaluated bone mineral density (an excellent predictor of fracture risk) with different estrogen/hormone replacement therapy regimens would suggest that results would be similar to those found in the Women's Health Initiative. Although the relief of menopausal symptoms, the primary reason women seek treatment, was not included in the overall benefit/risk analysis of the Women's Health Initiative, numerous trials suggest that all therapies are effective. Overall, these data indicate that the benefit/risk analysis that was reported in the Women's Health Initiative can be generalized to all postmenopausal hormone replacement therapy products.

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N Engl J Med. 2004 Mar 11;350(11):1081-92.
A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer.
Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, Jones SE, Alvarez I, Bertelli G, Ortmann O, Coates AS, Bajetta E, Dodwell D, Coleman RE, Fallowfield LJ, Mickiewicz E, Andersen J, Lonning PE, Cocconi G, Stewart A, Stuart N, Snowdon CF, Carpentieri M, Massimini G, Bliss JM; Intergroup Exemestane Study.
Department of Cancer Medicine, Imperial College and Charing Cross Hospital, London, United Kingdom.

BACKGROUND: Tamoxifen, taken for five years, is the standard adjuvant treatment for postmenopausal women with primary, estrogen-receptor-positive breast cancer. Despite this treatment, however, some patients have a relapse. METHODS: We conducted a double-blind, randomized trial to test whether, after two to three years of tamoxifen therapy, switching to exemestane was more effective than continuing tamoxifen therapy for the remainder of the five years of treatment. The primary end point was disease-free survival. RESULTS: Of the 4742 patients enrolled, 2362 were randomly assigned to switch to exemestane, and 2380 to continue to receive tamoxifen. After a median follow-up of 30.6 months, 449 first events (local or metastatic recurrence, contralateral breast cancer, or death) were reported--183 in the exemestane group and 266 in the tamoxifen group. The unadjusted hazard ratio in the exemestane group as compared with the tamoxifen group was 0.68 (95 percent confidence interval, 0.56 to 0.82; P<0.001 by the log-rank test), representing a 32 percent reduction in risk and corresponding to an absolute benefit in terms of disease-free survival of 4.7 percent (95 percent confidence interval, 2.6 to 6.8) at three years after randomization. Overall survival was not significantly different in the two groups, with 93 deaths occurring in the exemestane group and 106 in the tamoxifen group. Severe toxic effects of exemestane were rare. Contralateral breast cancer occurred in 20 patients in the tamoxifen group and 9 in the exemestane group (P=0.04). CONCLUSIONS: Exemestane therapy after two to three years of tamoxifen therapy significantly improved disease-free survival as compared with the standard five years of tamoxifen treatment. Copyright 2004 Massachusetts Medical Society

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Cancer. 2004 Feb 1;100(3):490-8.
Potential applicability of balloon catheter-based accelerated partial breast irradiation after conservative surgery for breast carcinoma.
Pawlik TM, Perry A, Strom EA, Babiera GV, Buchholz TA, Singletary E, Perkins GH, Ross MI, Schecter NR, Meric-Bernstam F, Ames FC, Hunt KK, Kuerer HM.
Department of Surgical Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.

BACKGROUND: Balloon catheter-based accelerated partial breast irradiation (APBI) is an alternative to whole-breast external-beam irradiation during breast-conserving therapy (BCT) for breast carcinoma, but it is limited by the size of the segmental mastectomy cavity. There are scant data on the average or optimal volume of resection (VR) in BCT. The objective of the current study was to evaluate the percentage of patients who would be eligible for balloon catheter-based APBI based on the selection criteria of the American Society of Breast Surgeons and the surgical VR. METHODS: The authors reviewed the medical records of 443 patients with ductal carcinoma in situ (DCIS) or invasive carcinoma treated with BCT. Patient treatment and pathologic data were analyzed to assess VR and eligibility for APBI. RESULTS: BCT was performed for 178 patients with DCIS and 267 patients with invasive breast carcinoma. The majority of invasive carcinomas (63.3%) were infiltrating ductal carcinomas. The median overall lumpectomy volume was 67.61 cm3, with no significant difference between DCIS and invasive carcinoma (P>0.05). Although the majority (62.9-82.0%) of patients met the individual selection criteria for APBI, only 27.4% of the cohort was found to be eligible for any type of APBI when the selection criteria were considered together. Based on VR, only approximately one-half of the patients initially eligible for APBI would be candidates for immediate balloon catheter-based APBI using the 70 cm3 balloon device (13.3%). However, with the new, larger 125 cm3 balloon device, approximately three-fourths of patients initially eligible for APBI would be eligible for balloon catheter-based APBI at the time of the initial surgical procedure (20.7%). Although not evaluated in the current study, shrinkage of the lumpectomy cavity with time may increase the number of patients eligible based strictly on VR criteria. Patients with a very large VR (> or =125 cm3) were more likely to have invasive carcinoma (P=0.02; hazard ratio [HR], 7.4) and tumors > or =5 cm on final pathology (P<0.01; HR, 22.0). CONCLUSIONS: Approximately one-fifth to one-fourth of patients presenting for BCT may be eligible for balloon catheter-based APBI according to accepted national guidelines and VR. VR must be considered when selecting patients for balloon catheter-based APBI, because a minority of patients will have a lumpectomy cavity that exceeds the size limit of the current balloon device. Copyright 2003 American Cancer Society.

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Eur J Cancer. 2004 Feb;40(3):352-7.
Weekly paclitaxel as first-line chemotherapy for elderly patients with metastatic breast cancer. A multicentre phase II trial.
ten Tije AJ, Smorenburg CH, Seynaeve C, Sparreboom A, Schothorst KL, Kerkhofs LG, van Reisen LG, Stoter G, Bontenbal M, Verweij J.
Department of Medical Oncology, Erasmus MC (Rotterdam Cancer Institute)m Groene Hilledijk 301, 3075 EA, Rotterdam, The Netherlands. a.tentije@erasmusmc.nl

Paclitaxel is a cytotoxic agent with proven antitumour activity in metastatic breast cancer. Weekly administration of paclitaxel has demonstrated sustained efficacy together with a more favourable toxicity profile (e.g. less myelotoxicity) than the 3-weekly administration. This study evaluates the activity and toxicity of weekly paclitaxel (Taxol(R)) as first-line chemotherapy in elderly patients (>70 years of age) with hormone-refractory metastatic breast cancer. Patients with metastatic breast cancer received 80 mg/m(2) paclitaxel administered weekly on days 1, 8 and 15 of a 28-day cycle. Additional cycles were given until disease progression, or unacceptable toxicity. A dose increase to 90 mg/m(2) was allowed in the absence of toxicity. 26 Patients received a total of 101 cycles (median 4, range 1-11). 22 patients completed at least two cycles (six administrations). In 23 patients who were evaluable for response, there were 10 partial responses (38%), 9 patients with stable disease (35%), while 4 patients had disease progression (15%). The median duration of response was 194 days (>6 months). Overall treatment was relatively well tolerated, but 8 patients (32%) had to prematurely discontinue treatment because of fatigue. Neuropathy >grade 1 was noted only after five or more cycles in 4 patients. Weekly paclitaxel at this dose and schedule is an effective treatment regimen in the elderly patient with metastatic breast cancer, and is feasible, but yields relevant fatigue in a subset of patients.

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Cancer. 2004 Feb 15;100(4):688-93.
Effect of breast-conserving therapy versus radical mastectomy on prognosis for young women with
breast carcinoma.
Kroman N, Holtveg H, Wohlfahrt J, Jensen MB, Mouridsen HT, Blichert-Toft M, Melbye M.
Department of Epidemiology Research, Danish Epidemiology Science Center, Statens Serum Institut, Copenhagen, Denmark.

BACKGROUND: Among middle-aged and older women with early breast carcinoma, breast-conserving therapy (BCT) has been shown to have an effect on survival that is similar to that of modified radical mastectomy (RM). Nonetheless, it remains to be established whether BCT also is the optimal treatment option for early breast carcinoma in young women, because these women generally have more aggressive disease and a higher frequency of local recurrence compared with older women. METHODS: We investigated a cohort of 9285 premenopausal women with primary breast carcinoma who were age < 50 years at diagnosis. These women were identified from a population-based Danish breast carcinoma database containing detailed information on patient and tumor characteristics, predetermined treatment regimens, and survival. RESULTS: In total, 7165 patients (77.2%) were treated with RM, and 2120 patients (22.8%) were treated with BCT. We calculated the relative risk of death within the first 10 years after diagnosis according to surgical treatment and age, both before and after adjustment for known prognostic factors. No increased risk of death was observed among women who received BCT compared with women who underwent RM, regardless of age at diagnosis (< 35 years, 35-39 years, 40-44 years, or 45-49 years), despite the increased risk of local recurrence among young women. Restricting the analysis to women with small tumors (size < 2 cm) yielded similar results. CONCLUSIONS: Despite having a higher rate of local recurrence, young women with breast carcinoma who receive BCT are similar to young women treated with RM in terms of survival. Copyright 2003 American Cancer Society.

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Arch Surg. 2004 Feb;139(2):148-50.
Nipple-sparing mastectomy: technique and results of 54 procedures.
Crowe JP Jr, Kim JA, Yetman R, Banbury J, Patrick RJ, Baynes D.
Departments of General Surgery and Plastic Surgery, The Cleveland Clinic Breast Center, The Cleveland Clinic Foundation, Cleveland, Ohio, USA. crowej@ccf.org

HYPOTHESIS: The rationale for removal of the nipple-areolar complex (NAC) during total mastectomy centers on long-standing concerns about possible neoplastic involvement of the NAC and its postoperative viability. Nipple-sparing mastectomy (NSM) combines a skin-sparing mastectomy with preservation of the NAC, intraoperative pathological assessment of the nipple tissue core, and immediate reconstruction, thereby permitting better cosmesis for patients undergoing total mastectomy. Neoplastic involvement of the NAC can be predicted before surgery and assessed during the operation, and sustained postoperative viability of the NAC is likely with appropriate surgical technique. RESULTS: Fifty-four NSMs with immediate reconstruction were attempted among 44 patients. Six NAC core specimens revealed neoplastic involvement on frozen section analysis, resulting in conversion to total mastectomies. Forty-five of the 48 completed NSMs maintained postoperative viability of the NAC; 3 NACs had partial loss. CONCLUSION: Nipple-sparing mastectomy is a reasonable option for carefully screened patients.

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Cancer Treat Rev. 2004 Feb;30(1):53-81.
Platinum-based chemotherapy in metastatic breast cancer: current status.
Decatris MP, Sundar S, O'Byrne KJ.
University Department of Oncology, The Osborne Building, Leicester Royal Infirmary, Leicester LE1 5WW, UK. marios.decatris@uhl-tr.nhs.uk

Cisplatin and carboplatin are active in previously untreated patients with metastatic breast cancer (MBC) with mean response rates (RRs) of 50 and 32%, respectively. In pretreated patients the RR to cisplatin/carboplatin monotherapy declines markedly to <10%. Cisplatin and carboplatin have been combined with many other cytotoxics. In first-line setting high activity has been observed in combination with taxanes or vinorelbine (RRs consistently approximately 60%). It appears that these newer combinations are superior to older regimens with etoposide (RRs 30 to 50%) or 5-fluorouracil (RRs 40 to 60%). Cisplatin-/carboplatin-based regimens with infusional 5-FU and epirubicin/paclitaxel/vinorelbine achieve high RRs of around 60 to 80%. However these regimens are difficult to administer in all patients because they require central venous access for continuous 5-FU infusion. In pretreated MBC the combinations of cisplatin-taxane/vinorelbine/gemcitabine or carboplatin-docetaxel/vinorelbine yield RRs of 40 to 50%, which are higher than those achieved with platinum-etoposide/5-FU. In locally advanced disease cisplatin-based regimens achieve very high RRs (>80%). This would suggest that in chemotherapy-naive patients platinum-based therapy might have an important role to play. Additionally the synergy demonstrated between platinum compounds, taxanes and herceptin, in preclinical and clinical studies is of immense importance and the results of the two ongoing Breast Cancer International Research Group randomized phase III studies are eagerly awaited. These studies may help clarify the role of platinum compounds in the treatment of metastatic and possibly early breast cancer.

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Crit Rev Oncol Hematol. 2004 Feb;49(2):109-17.
Progress in chemoprevention of breast cancer.
Serrano D, Perego E, Costa A, Decensi A.
Division of Chemoprevention, European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy.

Primary prevention trials have shown that tamoxifen lowers breast cancer incidence by 30-40%. Because of the endometrial risk of tamoxifen and the pro-thrombotic effects of tamoxifen and raloxifene, different strategies are being pursued to improve the risk:benefit ratio of breast cancer chemoprevention. Thus, raloxifene is being compared with tamoxifen in a phase III trial, while the minimal active dose of tamoxifen is being assessed in phase I-II trials. Also, the combination of hormone replacement therapy (HRT) and tamoxifen may reduce the risks while retaining the benefits of either agent. Anastrozole holds promise as a preventive agent based on preliminary results on contralateral breast cancer. The identification of women at increased risk for estrogen receptor (ER)-positive breast cancer due to hormonal and reproductive factors may maximize the therapeutic index of hormonal agents. Finally, new targets that interfere with ER-negative breast carcinogenesis are being sought as one-third of breast cancers will not be preventable by hormonal interventions.

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Crit Rev Oncol Hematol. 2004 Feb;49(2):91-107.
Antiangiogenic strategies, compounds, and early clinical results in breast cancer.
Morabito A, Sarmiento R, Bonginelli P, Gasparini G.
Division of Medical Oncology, Azienda Complesso Ospedaliero "San Filippo Neri", Via Martinotti 20, Rome 00135, Italy.

Angiogenesis is a multi-step process leading to the formation of new blood vessels from pre-existing vasculature and it is necessary for primary tumor growth, invasiveness and development of metastasis. Experimental and clinical data demonstrated that breast cancer is an angiogenesis-dependent disease and that the vascular endothelial growth factor (VEGF) family plays a key role it being a highly expressed and selective endothelial cell growth factor. Preclinical studies have shown that the angiogenic switch occurs early in the multistage process of breast cancer development. Targeting the molecular pathways involved in tumor progression by biologically-designed treatments is a new therapeutic paradigm aimed to reach cancer growth control. A number of possible therapeutic targets for antiangiogenic agents have been identified. Here we discuss the therapeutic approach based on inhibition of angiogenesis in the context of breast cancer with a focus on the early clinical studies on antiangiogenic agents in advanced disease.

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Altern Ther Health Med. 2004 Jan-Feb;10(1):52-7.
Complementary and alternative medicine use by women after completion of allopathic treatment for breast cancer.
Henderson JW, Donatelle RJ.
Health Division, Western Oregon University, USA.

CONTEXT: A growing number of women are being diagnosed and successfully treated for breast cancer. Therefore, many women are living with a history of breast cancer. The use of complementary and alternative therapies within this patient population has increased. OBJECTIVE: To determine post breast cancer treatment health behaviors with regard to use of complementary and alternative therapies. DESIGN: Survey participants were asked about their use of 15 complementary and alternative medicine (CAM) therapies. In order to determine the relative importance of the hypothesized predictor variables, standard logistic regression was performed with CAM use as the dependent variable. PARTICIPANTS: 551 women who had been diagnosed with breast cancer and were post treatment. INTERVENTION: Telephone Survey. RESULTS: Telephone interviews were conducted with 551 females in the Portland, Oregon, metropolitan area who had been diagnosed with breast cancer an average of 3.5 years earlier. Two-thirds (66%) of the women used at least one CAM therapy during the previous 12 months, and the majority of them perceived that their CAM use was without the recommendation of their doctor. Relaxation/meditation, herbs, spiritual healing, and megavitamins were used most often. Significant predictors of CAM use included younger age, higher education, and private insurance. The majority of the CAM therapies were perceived by their users to be at least "moderately important" in remaining free of cancer. The reasons given for using CAM were to enhance overall quality of life, to feel more in control, to strengthen the immune system, and to reduce stress. CONCLUSIONS: Two-thirds of women in this study followed conventional treatment for breast cancer with one or more CAM therapies, which, they believed, could prevent cancer recurrence and/or improve their quality of life. CAM use did not reflect negative attitudes towards conventional medical care, but rather an orientation to self-care in the optimization of their health and well being.

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Br J Surg. 2004 Jan;91(1):54-60.
Randomized clinical trial investigating the use of drains and fibrin sealant following surgery for
breast cancer.
Jain PK, Sowdi R, Anderson AD, MacFie J.
Department of Surgery, Scarborough General Hospital, Woodland Drive, Scarborough YO12 6QL, UK.

BACKGROUND: Despite limited evidence, closed suction drainage is often used to reduce the risk of seroma formation after breast cancer surgery. The aim of this study was to evaluate the effect of drains and fibrin sealant on the incidence of seroma formation. METHODS: A total of 116 patients undergoing surgery for breast cancer were randomized to receive suction drainage (group 1; n = 58), or to receive no drain (n = 58). Patients allocated to receive no drain were further randomized to have fibrin sealant applied to the dissected area (group 2; n = 29), or to no intervention (group 3; n = 29). Outcome measures were incidence and volume of postoperative seroma, length of hospital stay and postoperative pain scores. RESULTS: There was no significant difference in the incidence of seroma between group 1 (15 of 58) and either group with no drains (ten of 29 in group 2; 12 of 29 in group 3). There was a significant reduction in hospital stay and postoperative pain scores in patients who did not have a drain. Following mastectomy without a drain, the use of fibrin sealant was associated with a significant reduction in the incidence and total volume of seroma (190 versus 395 ml; P = 0.012). CONCLUSION: Drains did not prevent seroma formation, and were associated with a longer postoperative stay and higher pain scores after surgery for breast cancer. In patients who had mastectomy the use of fibrin sealant reduced the rate of seroma formation. Copyright 2004 British Journal of Surgery Society Ltd.

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J Natl Cancer Inst. 2004 Jan 21;96(2):115-21.
Breast-conserving surgery with or without radiotherapy: pooled-analysis for risks of ipsilateral breast tumor recurrence and mortality.
Vinh-Hung V, Verschraegen C.
Oncology Center, Academic Hospital, Vrije Universiteit Brussel, Jette, Belgium. conrvhgv@az.vub.ac.be

BACKGROUND: The objective of the study was to investigate whether radiotherapy or its omission after breast-conserving surgery has measurable consequences on local tumor growth and patient survival. METHODS: We conducted a pooled analysis of published randomized clinical trials that compared radiotherapy versus no radiotherapy after breast-conserving surgery. The outcomes studied were ipsilateral breast tumor recurrence and patient death from any cause. The pooled relative risks (RRs) were estimated with a random-effects model. Heterogeneity was assessed using the Cochran Q test. RESULTS: A search of the literature identified 15 trials with a pooled total of 9422 patients available for analysis. The relative risk of ipsilateral breast tumor recurrence after breast-conserving surgery, comparing patients treated with no radiotherapy or radiotherapy, was 3.00 (95% confidence interval [CI] = 2.65 to 3.40). Mortality data were available for 13 trials with a pooled total of 8206 patients. The relative risk of mortality was 1.086 (95% CI = 1.003 to 1.175), corresponding to an estimated 8.6% (95% CI = 0.3% to 17.5%) relative excess mortality if radiotherapy was omitted. CONCLUSION: Omission of radiotherapy is associated with a large increase in risk of ipsilateral breast tumor recurrence and with a small increase in the risk of patient mortality.

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Bull Cancer. 2004 Jan;91(1):55-62.
[Neoadjuvant endocrine therapy for breast cancer: an overview]
[Article in French]
Domont J, Namer M, Khayat D, Spano JP.
Institut Curie, Departement de radiotherapie, Paris, France.

The clinical benefits of endocrine therapy for patients with hormonosensitive breast cancer remains perfectly established. For instance, tamoxifen, the gold standard of the adjuvant treatment, has largely contributed of the effectiveness of such a therapy. The recent development of new endocrine agents (the third-generation aromatase inhibitors, selective estrogen receptors modulators), provides to physicians the opportunity of a more effective and tolerable therapeutic approach, in the metastatic disease setting or likely in adjuvant setting for breast cancer patients. Preoperative therapy has been widely used for the treatment of initially inoperable locally advanced breast cancers with the main objective of breast-conserving surgery. The benefits of neoadjuvant chemotherapy has widely been demonstrated; however, the success of neoadjuvant endocrine therapy is much recent. The clinical and pharmacological data of the main published studies using neoadjuvant hormonotherapy are presented herein this review. Therefore, clinical and histologic assessments of response brings essential informations about the breast cancer hormonal sensitivity, but may also be predictor of the future (adjuvant or metastatic) treatment responsiveness.

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Breast Cancer. 2004;11(1):10-4.
Current status of antibody therapy for breast cancer.
Toi M, Takada M, Bando H, Toyama K, Yamashiro H, Horiguchi S, Saji S.
Department of Surgery, Tokyo Metropolitan Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan. maktoi77@wa2.so-net.ne.jp

Antibody therapy with trastuzumab has greatly impacted breast cancer treatment. Combination treatment with trastuzumab is regarded currently as a first-line therapy for metastatic breast cancers that overexpress Her-2. It has become routine practice to examine the status of Her-2 expression in primary tumors. The impact of this therapy might be as great as that of endocrine therapy from a historical point of view. A number of new approaches using trastuzumab for seeking individualized treatment are being tested in current clinical trials. We reviewed recent advances in trastuzumab treatment and discuss the future of antibody therapy for breast cancer.

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Vopr Onkol. 2003;49(6):748-51.
[Experience with turbulent magnetic field as a component of breast cancer therapy]
[Article in Russian]
Letiagin VP, Protchenko NV, Rybakov IuL, Dobrynin IaV.
N.N. Blokhin Center for Oncology Research, Russian Academy of Medical Sciences, Zdorovje Research Center, Moscow.

No adverse side-effects were reported in an investigation of the antitumor effect of turbulent magnetic field (TMF) carried out as a component of preoperative chemoradiotherapy for breast cancer at the Center's Clinic. The study group included 114 patients with locally advanced tumors(T3, N1-N3, M0). According to the clinical, roentgenological and histological evidence on the end-results, the procedure was highly effective. Also, it was followed by shorter and less extensive postoperative lymphorrhea.

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J Surg Oncol. 2003 Dec;84(4):192-7.
Randomized trial comparing neo-adjuvant versus adjuvant chemotherapy in operable locally advanced breast cancer (T4b N0-2 M0).
Deo SV, Bhutani M, Shukla NK, Raina V, Rath GK, Purkayasth J.
Department of Surgical Oncology, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India. svsdeo@yahoo.co.in

BACKGROUND AND OBJECTIVES: Locally advanced breast cancer (LABC) remains a major problem in developing countries. While trials utilizing neo-adjuvant chemotherapy demonstrate superior survival rates compared to historic controls, randomized studies evaluating the precise role of neo-adjuvant chemotherapy in LABC are lacking. In the present trial, neo-adjuvant chemotherapy was compared against adjuvant chemotherapy to assess survival advantage in operable T4b N0-2 M0 breast cancer. METHODS: A total of 101 women with operable LABC (T4b N0-2 M0) were randomized. In arm A, 50 patients received 3 cycles of CEF chemotherapy before and 3 cycles following surgery. In arm B, 51 patients had primary surgery followed by 6 cycles of CEF chemotherapy. In both arms, loco-regional radiotherapy was given after completion of CEF. RESULTS: The response of primary tumor to neo-adjuvant chemotherapy was 66%, complete response (CR) 14% and partial response (PR) 52%. Clinical nodal response occurred in 95% of node positive patients. Only two (4%) patients had pathologic CR both in tumor and axilla. There was a significant (P = 0.02) increase in incidence of pathologically negative nodes in arm A. At a median follow up of 25 months, there was no significant difference in overall and disease free survival (DFS) in both arms (P = 0.42 and 0.18). Patients showing a response to neo-adjuvant chemotherapy had better DFS (P = 0.04) compared to those who had no response. CONCLUSIONS: Early results of the study indicate no survival benefit with the inclusion of neo-adjuvant chemotherapy in LABC (T4b N0-2 M0). Neo-adjuvant chemotherapy resulted in significant down staging; good responders had a better DFS compared to those who did not respond.

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Clin Breast Cancer. 2003 Dec;4(5):348-53.
Neoadjuvant trastuzumab and docetaxel in breast cancer: preliminary results.
Van Pelt AE, Mohsin S, Elledge RM, Hilsenbeck SG, Gutierrez MC, Lucci A Jr, Kalidas M, Granchi T, Scott BG, Allred DC, Chang JC.
Department of Surgery, Methodist Hospital, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.

Trastuzumab/chemotherapy combinations have already shown superior results in metastatic breast cancer patients. The purpose of this study is to determine the clinical efficacy of neoadjuvant trastuzumab and docetaxel in women with locally advanced breast cancer, with or without metastatic disease. Treatment-naive women with HER2-overexpressing locally advanced breast cancer, with or without metastatic disease, were included. Patients received trastuzumab 4 mg/kg loading dose intravenously then 2 mg/kg weekly. On day 22, docetaxel 100 mg/m2 every 3 weeks for 4 cycles was added to weekly trastuzumab. Patients then underwent surgery and subsequent 4 cycles of AC (doxorubicin/cyclophosphamide; 60/600 mg/m2) without trastuzumab. Weekly trastuzumab was resumed 1 month after completion of AC and continued for a year. Preliminary results from the first 22 patients with median follow-up of 15.5 months (range, 2-38 months) are reported. Of these, 9 patients (40.9%) had inflammatory breast cancer, and 6 patients (27.3%) had stage IV breast cancer. Seventeen of 22 patients (77.3%) had objective clinical response, with a clinical complete response in 9 patients (40.9%). Two patients (9.1%) had decline in cardiac function and 7 patients (31.8%) experienced neutropenia, with 2 deaths (9.1%) from neutropenic sepsis. Eight patients (36.4%) have relapsed, 3 with local skin recurrence (13.6%) and 5 with distant recurrence, of whom 1 had liver metastasis (4.5%) and 4 had brain metastasis (18.2%). Combined neoadjuvant trastuzumab and docetaxel induced high clinical response rates for HER2-overexpressing breast cancer, in particular for inflammatory breast cancer. A high rate of brain metastasis was noted, particularly in patients with baseline metastatic disease.

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J Am Coll Surg. 2003 Nov;197(5):726-9.
Breast conservation in patients with multiple ipsilateral synchronous cancers.
Kaplan J, Giron G, Tartter PI, Bleiweiss IJ, Estabrook A, Smith SR.
Department of Surgery, St Luke's-Roosevelt Hospital Center, New York, NY, USA.

BACKGROUND: Because breast cancer survival after breast conservation has proved comparable to mastectomy, contraindications to mastectomy are increasingly being challenged. We treated the majority of our patients with multiple synchronous ipsilateral cancers with breast conservation and we compared them with patients who underwent mastectomy for comparable disease during the same interval. STUDY DESIGN: Patients with multiple ipsilateral synchronous breast cancers between 1989 and 2002 were identified from prospective databases maintained by us. A comparison was made between 36 patients treated with lumpectomy and 19 patients treated with mastectomy. RESULTS: There were no significant (all p values >0.2) differences between mastectomy and breast conservation patients in age, racial distribution, size of cancers, pathology, tumor differentiation, nodal involvement, or hormone receptor positivity. The majority of patients treated with breast conservation underwent at least one reexcision to obtain clear pathologic margins, and they were more likely to receive postoperative radiotherapy than patients treated with mastectomy. There were no significant differences in the local (97% versus 100%, p = 0.54) or distant (97% versus 95%, p = 0.20) 5-year disease- free survival between the group treated with breast conservation and the group treated with mastectomy. One patient in each group developed distant metastases. One patient in the breast conservation group developed local recurrence at both primary sites simultaneously 39 months after lumpectomies. She is free of disease 78 months after mastectomy. The remaining 52 patients are alive and free of disease. CONCLUSIONS: Breast conservation is an effective treatment for patients with synchronous ipsilateral breast cancers.

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Cancer. 2003 Nov 15;98(10):2144-51.
Prognosis after regional lymph node recurrence in patients with stage I-II breast carcinoma treated with breast conservation therapy.
Harris EE, Hwang WT, Seyednejad F, Solin LJ.
Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. harris@xrt.upenn.edu

BACKGROUND: The authors evaluated the risk factors for regional lymph node recurrence and the prognosis of patients with regional nodal recurrence after breast conservation therapy for Stage I-II breast carcinoma. METHODS: Between 1977 and 1995, 1293 women with pathologic Stage I and II (T1-2, N0-1) breast carcinoma were treated with breast-conserving therapy including lumpectomy, axillary lymph node dissection, and definitive breast irradiation. A total of 39 women (3%) had any regional lymph node recurrence. The median follow-up was 8.5 years (range, 1.5-24 years). RESULTS: Among 39 patients with a regional lymph node recurrence, 10 women had regional recurrence only, 16 had simultaneous locoregional recurrence, and 13 had simultaneous regional and distant recurrence. Regional recurrence occurred in the axillary lymph nodes only (n = 21; 51%), supraclavicular lymph nodes only (n = 8; 23%), internal mammary lymph nodes only (n = 3; 8%), infraclavicular lymph nodes only (n = 3; 8%), or multiple lymph node sites (n = 4; 10%). The median time to regional lymph node recurrence was 3.1 years (range, 0.2-20.9 years). Overall survival after regional-only disease recurrence was 44%, locoregional disease recurrence was 26%, and regional with distant disease recurrence was 12%. Cause-specific survival rates at 10 years for the 3 groups were 44%, 40%, and 12%, respectively. For patients who presented with simultaneous regional and distant metastases, the median survival period was 1.1 years, compared with 5.2 years for women who developed distant disease subsequent to regional recurrence. CONCLUSIONS: Regional lymph node recurrence after breast conservation therapy may be salvaged, but is associated with a high rate of either simultaneous or subsequent distant metastatic dissemination and poor overall prognosis. Copyright 2003 American Cancer Society.

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Cancer. 2003 Nov 1;98(9):1802-10.
Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses.
Baum M, Buzdar A, Cuzick J, Forbes J, Houghton J, Howell A, Sahmoud T; The ATAC (Arimidex, Tamoxifen Alone or in Combination) Trialists' Group.
University College London, London, United Kingdom.

BACKGROUND: The first analysis of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial (median follow-up, 33 months) demonstrated that in adjuvant endocrine therapy for postmenopausal patients with early-stage breast cancer, anastrozole was superior to tamoxifen in terms of disease-free survival (DFS), time to recurrence (TTR), and incidence of contralateral breast cancer (CLBC). In the current article, the results of the first efficacy update, based on a median follow-up period of 47 months, are reported along with the results of an updated safety analysis, performed 7 months after the first analysis (median duration of treatment, 36.9 months). METHODS: DFS, TTR, CLBC incidence, and safety were assessed in the same patient group as in the first analysis of the ATAC trial. RESULTS: DFS estimates at 4 years remained significantly more favorable (86.9% vs. 84.5%, respectively) for patients receiving anastrozole compared with those receiving tamoxifen (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.76-0.99; P = 0.03). The benefit generated by anastrozole in terms of DFS was even greater in patients with hormone receptor-positive tumors (HR, 0.82; 95% CI, 0.70-0.96; P = 0.014). The HR for TTR also indicated a significant benefit for patients receiving anastrozole compared with those receiving tamoxifen (HR, 0.83; 95% CI, 0.71-0.96; P = 0.015), with additional benefit for patients with hormone receptor-positive tumors (HR, 0.78; 95% CI, 0.65-0.93; P = 0.007). CLBC incidence data also continued to favor anastrozole (odds ratio [OR], 0.62; 95% CI, 0.38-1.02; P = 0.062), and statistical significance was achieved in the hormone receptor-positive subgroup (OR, 0.56; 95% CI, 0.32-0.98; P = 0.042). The updated safety analysis also confirmed the findings of the first analysis, in that endometrial cancer (P = 0.007), vaginal bleeding and discharge (P < 0.001 for both), cerebrovascular events (P < 0.001), venous thromboembolic events (P < 0.001), and hot flashes (P < 0.001) all occurred less frequently in the anastrozole group, whereas musculoskeletal disorders and fractures (P < 0.001 for both) continued to occur less frequently in the tamoxifen group. These results indicated that the safety profile of anastrozole remained consistent. CONCLUSIONS: After an additional follow-up period, anastrozole continues to show superior efficacy, which is most apparent in the clinically relevant hormone receptor-positive population. Furthermore, anastrozole has numerous noteworthy advantages in terms of tolerability compared with tamoxifen. These findings suggest that the benefits of anastrozole are likely to be maintained in the long term and provide further support for the status of anastrozole as a valid treatment option for postmenopausal women with hormone-sensitive early-stage breast cancer. Copyright 2003 American Cancer Society.

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Eur J Cancer. 2003 Nov;39(16):2318-27.
An open randomised trial of second-line endocrine therapy in advanced breast cancer. comparison of the aromatase inhibitors letrozole and anastrozole.
Rose C, Vtoraya O, Pluzanska A, Davidson N, Gershanovich M, Thomas R, Johnson S, Caicedo JJ, Gervasio H, Manikhas G, Ben Ayed F, Burdette-Radoux S, Chaudri-Ross HA, Lang R.
Department of Oncology, Lund University Hospital, 221 85, Lund, Sweden. carsten.rose@skane.se

It was previously shown that letrozole (Femara) was significantly more potent than anastrozole (Arimidex) in inhibiting aromatase activity in vitro and in inhibiting total body aromatisation in patients with breast cancer. The objective of this study was to compare letrozole (2.5 mg per day) and anastrozole (1 mg per day) as endocrine therapy in postmenopausal women with advanced breast cancer previously treated with an anti-oestrogen. This randomised, multicentre and multinational open-label phase IIIb/IV study enrolled 713 patients. Treatment was for advanced breast cancer that had progressed either during anti-oestrogen therapy or within 12 months of completing that therapy. Patients had tumours that were either positive for oestrogen and/or progesterone receptors (48%) or of unknown receptor status (52%). The primary efficacy endpoint was time to progression (TTP). Secondary endpoints included objective response, duration of response, rate and duration of overall clinical benefit (responses and long-term stable disease), time to treatment failure, and overall survival, as well as general safety. There was no difference between the treatment arms in TTP; median times were the same for both treatments. Letrozole was significantly superior to anastrozole in the overall response rate (ORR) (19.1% versus 12.3%, P=0.013), including in predefined subgroups (receptor status-unknown, and soft-tissue- and viscera-dominant site of disease). There were no significant differences between the treatment arms in the rate of clinical benefit, median duration of response, duration of clinical benefit, time to treatment failure or overall survival. Both agents were well tolerated and there were no significant differences in safety. These results support previous data documenting the greater aromatase-inhibiting activity of letrozole and indicate that advanced breast cancer is more responsive to letrozole than to anastrozole as second-line endocrine therapy.

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N Engl J Med. 2003 Nov 6;349(19):1793-802. Epub 2003 Oct 09.
A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer.
Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JL.
Division of Hematology-Oncology, Princess Margaret Hospital, Toronto, ON, Canada. pegoss@interlog.com

BACKGROUND: In hormone-dependent breast cancer, five years of postoperative tamoxifen therapy--but not tamoxifen therapy of longer duration--prolongs disease-free and overall survival. The aromatase inhibitor letrozole, by suppressing estrogen production, might improve the outcome after the discontinuation of tamoxifen therapy. METHODS: We conducted a double-blind, placebo-controlled trial to test the effectiveness of five years of letrozole therapy in postmenopausal women with breast cancer who have completed five years of tamoxifen therapy. The primary end point was disease-free survival. RESULTS: A total of 5187 women were enrolled (median follow-up, 2.4 years). At the first interim analysis, there were 207 local or metastatic recurrences of breast cancer or new primary cancers in the contralateral breast--75 in the letrozole group and 132 in the placebo group--with estimated four-year disease-free survival rates of 93 percent and 87 percent, respectively, in the two groups (P< or =0.001 for the comparison of disease-free survival). A total of 42 women in the placebo group and 31 women in the letrozole group died (P=0.25 for the comparison of overall survival). Low-grade hot flashes, arthritis, arthralgia, and myalgia were more frequent in the letrozole group, but vaginal bleeding was less frequent. There were new diagnoses of osteoporosis in 5.8 percent of the women in the letrozole group and 4.5 percent of the women in the placebo group (P=0.07); the rates of fracture were similar. After the first interim analysis, the independent data and safety monitoring committee recommended termination of the trial and prompt communication of the results to the participants. CONCLUSIONS: As compared with placebo, letrozole therapy after the completion of standard tamoxifen treatment significantly improves disease-free survival. Copyright 2003 Massachusetts Medical Society

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Cancer. 2003 Nov 15;98(10):2152-60.
Reoperations after prophylactic mastectomy with or without implant reconstruction.
Zion SM, Slezak JM, Sellers TA, Woods JE, Arnold PG, Petty PM, Donohue JH, Frost MH, Schaid DJ, Hartmann LC.
New York Presbyterian Hospital, Weill Cornell Medical Center, New York, New York, USA.

BACKGROUND: The authors characterized the unanticipated reoperations after prophylactic mastectomy, with or without implant reconstruction. METHODS: The surgical cohort was comprised of 1417 women with a family history of breast carcinoma. The women received a prophylactic mastectomy with (bilateral, n = 593; contralateral, n = 506) or without reconstruction (n = 318) at the Mayo Clinic (Rochester, MN) between 1960 and 1993. Reoperations and indications for reoperation were compiled from medical records and a patient survey. RESULTS: Three hundred eighteen women received a bilateral (n = 39) or contralateral (n = 279) prophylactic mastectomy without reconstruction. With a median follow-up of 15 years, 18 women (6%) required reoperation. Most of these reoperations occurred within the first year after prophylactic mastectomy. Five hundred ninety-three women had reconstruction with implants following bilateral prophylactic mastectomy. Approximately one-half of the women (52%) required at least 1 unanticipated reoperation during a median follow-up of 14 years. Approximately 39% of all reoperations occurred within 1 year of breast reconstruction and 69% within 5 years. Implant-related issues were the most common cause for reoperation. Some women with breast carcinoma elected to receive contralateral prophylactic mastectomy with therapeutic mastectomy for the affected breast. Five hundred six women received reconstruction with implants. During a median follow-up of 8.8 years, 189 women (37%) required unanticipated reoperation. The most common indication was implant-related issues. The time course of reoperations was similar to that for women in the bilateral group. CONCLUSIONS: Surgical reoperations were fairly common among women who received prophylactic mastectomy with implant reconstruction. Most of the reoperations were implant related. Reoperations were fairly uncommon after prophylactic mastectomy without reconstruction. Copyright 2003 American Cancer Society.

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J Clin Oncol. 2003 Oct 15;21(20):3792-7.
Does timing of adjuvant chemotherapy for early breast cancer influence survival?
Shannon C, Ashley S, Smith IE.
Breast Unity, Royal Marsden Hospital, United Kingdom.

PURPOSE: Theoretically, patients with early breast cancer might benefit from starting adjuvant chemotherapy soon after surgery, and this would have important clinical implications. We have addressed this question from a large, single-center database in which the majority of patients received anthracyclines. PATIENTS AND METHODS: A total of 1161 patients from a prospectively maintained database treated with adjuvant chemotherapy for early breast cancer at the Royal Marsden Hospital (London, United Kingdom), including 686 (59%) receiving anthracyclines, were retrospectively analyzed. The disease-free survival (DFS) and overall survival (OS) of the 368 patients starting chemotherapy within 21 days of surgery (group A) were compared with those of the 793 patients commencing chemotherapy >or= 21 days after surgery (group B). Median follow-up time was 39 months (range, 12 to 147 months). RESULTS: No significant difference in 5-year DFS was found between the two groups overall (70% for group A v 72% for group B; P =.4) or in any subgroup. Likewise, there was no difference in 5-year OS (82% for group A v 84% for group B; P =.2) or when the interval to the start of chemotherapy was considered as a continuous variable (P =.4). CONCLUSION: We have been unable to identify any significant survival benefit from starting adjuvant chemotherapy early after surgery, either overall or in any subset of patients.

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Cancer Invest. 2003;21(4):497-504.
Vinorelbine and cisplatin for metastatic breast cancer: a salvage regimen in patients progressing after docetaxel and anthracycline treatment.
Vassilomanolakis M, Koumakis G, Demiri M, Missitzis J, Barbounis V, Efremidis AP.
2nd Department of Medical Oncology, St. Savas Oncology Hospital, 171 Alexandra's Ave., Athens 115-22, Greece.

PURPOSE: To assess the antitumor efficacy and safety of a combination of vinorelbine (VNR) and cisplatin in patients with metastatic breast cancer previously treated with anthracyclines and docetaxel. PATIENTS AND METHODS: Thirty-six patients with assessable metastatic breast cancer previously treated with anthracyclines and docetaxel (adjuvant n = 1, palliative n = 20, both n = 15) were studied. Cisplatin was given at 75 mg/m2 on day 1 followed by 25 mg/m2 VNR on days 1 + 8 in a 5-minute i.v. infusion. Courses were repeated every 3 weeks. Treatment was continued until disease progression, excess toxicity, or patient refusal. Patients were classified according to their response to anthracyclines according to criteria published previously: 1) Anthracycline and/or docetaxel resistant were patients who progressed during treatment with anthracyclines and docetaxel or within 4 months after cessation of treatment (metastatic). In addition, adjuvant patients who progressed within 6 months after completion of chemotherapy belong to this group. 2) Anthracycline and/or docetaxel relapsed were either metastatic patients who responded initially and then progressed after 4 months of completing an anthracycline- and docetaxel-based chemotherapy or patients who progressed after 6 months from completion of anthracycline/docetaxel-based adjuvant chemotherapy. RESULTS: Two patients (5.6%) achieved a complete response (CR) and 15 patients (41.6%) achieved a partial response (PR), for an overall response rate (OR) of 47.2% (95% confidence interval, 31-63). Of 18 patients relapsed to anthracycline/docetaxel, 2 had a CR (11%) and 8 a PR (44.4%), giving an objective response of 55.5%. Stable disease (SD) was observed in one patient (5.5%); seven patients had progressive disease (PD) (39%). Among the 18 resistant patients, 7 PRs (39%) were observed (p = 0.5), one patient (5.5%) had stable disease, 10 patients (55.5%) progressed. The median time to progression (TTP) was 16 weeks and median overall survival 36 weeks. Relapsed patients had a longer TTP than resistant patients (24 vs. 8 weeks, p = 0.05) but similar survival (48 vs. 24 weeks, p = 0.173). All patients were assessed for toxicity. The main toxicity was neutropenia grade 3 and 4 in 47% of patients. Febrile neutropenia requiring hospitalization was absent. There were no treatment-related deaths. Thrombocytopenia grade 3 and 4 occurred in four patients (11%). Phlebitis, orthostatic hypotension, and asthenia, all reversible, were observed in 3% of patients, respectively. CONCLUSION: This cisplatin/VNR regimen is well tolerated and active in patients who failed anthracyclines and docetaxel treatment. The response rate, TTP, and survival data are high and indicate that cisplatin/VNR may have a place as salvage treatment in this group of patients. If these results can be verified in multi-institutional trials, this combination of drugs would merit investigation as part of a first-line therapy in breast cancer.

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Am J Surg. 2003 Oct;186(4):362-7.
Low-risk palpable breast masses removed using a vacuum-assisted hand-held device.
Fine RE, Whitworth PW, Kim JA, Harness JK, Boyd BA, Burak WE Jr.
The Breast Center, Marietta, GA, USA.

BACKGROUND: This study evaluates the safety, efficacy, and patient acceptance of a vacuum-assisted, hand-held biopsy device (Mammatome) in the percutaneous removal of breast masses using ultrasound guidance. METHODS: A multicenter, nonrandomized study evaluated 216 women with low-risk palpable lesions. Lesions 1.5 to 3.0 cm in size were removed using an 8-gauge probe. Those lesions <1.5 cm were removed with the 11-gauge probe. Follow-up evaluation was performed at 10 days and 6 months after biopsy. RESULTS: A total of 127 patients had biopsies using the 8-gauge probe, and 89 patients had biopsies using the 11-gauge probe. At 6-month follow-up, 98% of the lesions remained nonpalpable, 73% with no ultrasonographically visible evidence of the original lesion. Most complications were mild and anticipated. Most patients (98%) were satisfied with incision appearance, and 92% of patients would recommend the procedure to others. CONCLUSIONS: Percutaneous removal of palpable benign breast masses using the Mammotome system is feasible and safe, and yields high patient satisfaction. The results at 6 months after biopsy demonstrated the effectiveness of benign lesion removal, with correlative clinical data demonstrating lack of palpability and no need for additional procedures. Continuing evaluation of long-term efficacy is ongoing.

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Gan To Kagaku Ryoho. 2003 Oct;30(10):1441-5.
[Retrospective study on utility of irinotecan hydrochloride in patients with advanced and
recurrent breast cancer]
[Article in Japanese]
Okubo S, Kurebayashi J, Sonoo H, Hirono M, Nomura N, Udagawa K, Yamamoto Y, Ikeda M, Nakashima K, Tanaka K.
Dept. of Breast and Thyroid Surgery, Kawasaki Medical School.

Irinotecan hydrochloride has been administered to patients with breast cancer resistant to anthracyclines and/or taxanes in our department. A retrospective analysis of the efficacy and toxicity of irinotecan therapy was conducted to clarify its clinical usefulness. A total of 35 consecutive patients with advanced or recurrent breast cancer were treated with irinotecan between June 1996 and March 2002. The patients ranged in age from 37 to 66 years old (median, 52). The most frequent metastatic lesion was in the liver. The number of previous chemotherapy was 2 to 7 regimens (median, 3). Ninety-one percent and 97% of the tumors were anthracycline- and taxane-resistant, respectively. The weekly dose of irinotecan was 40-160 mg/body (median, 100), and the total dose was 40-6, 110 mg/body (median, 840). An objective response rate of 6% and a clinical benefit rate of 23% were obtained. The median time-to-progression and overall survival were 3 months and 8 months, respectively. Severe toxicity (grade 3 or 4) was observed in 34% of the patients for a decrease in the white blood count, in 26% for neutropenia, in 17% for nausea/vomiting and in 6% for diarrhea. Although this study suggests that irinotecan is a clinically useful treatment of anthracycline- and/or taxane-resistant breast cancer, its anti-tumor effect was not satisfactory. The activity of first-line irinotecan therapy or the combined use of irinotecan with other agents should be investigated in clinical studies.

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Gan To Kagaku Ryoho. 2003 Oct;30(11):1651-4.
[Examination of therapy using trastuzumab in patients with metastatic breast carcinoma]
[Article in Japanese]
Nohara T, Iwamoto M, Kobayashi T, Lee SW, Sumiyoshi K, Tanigawa N.
Dept. of General and Gastro-Enterological Surgery, Osaka Medical College.

We evaluated the effect of combination therapy of trastuzumab and paclitaxel for metastatic breast carcinoma. Among the 23 metastatic breast carcinoma patients treated in our institution from September 2001 to December 2002, 10 (43%) patients were immunohistochemically positive for the HER2 protein. Four of these patients had bone, 3 had lung, 2 had liver and 1 had supraclavicular lymph node metastases. The combination chemotherapy for these 10 patients was evaluated as follows: CR in 1 patient, PR in 4, NC in 2, and PD in 3. Two patients with liver metastases showed remarkable tumor regression. Combination therapy did not have to be stopped in any of the patients due to side effects. These results show that combination therapy of trastuzumab and paclitaxel may be a useful treatment regimen for chemotherapy-resistant metastatic breast carcinoma patients.

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Gan To Kagaku Ryoho. 2003 Oct;30(11):1583-6.
[Cryoimmunological therapy with local injection of OK-432 against advance or recurrent breast cancer]
[Article in Japanese]
Kawaguchi Y, Sugiyama Y, Saji S.
Dept. of Tumor and General Surgery, Gifu University School of Medicine.

A total of 5 breast cancer patients, 2 with far advanced primary breast tumor and 3 with local recurrent tumors on their anterior chest wall, underwent multimodal therapy in which cryosurgery was performed in combination with local injection of the non-specific immunopotentiator OK-432. This multimodal therapy was repeated as many times as possible. In addition, all patients were treated with mild chemotherapy. In every patient who underwent cryosurgery combined with locoregional immunotherapy, eradication or reduction of tumor was observed for several months. In 3 of the patients who underwent cryosurgery, locoregional immunotherapy and systemic chemotherapy, the tumor burden decreased markedly in 2 patients even though the diameter of tumor was over 5 cm in both cases. In case 1, we examined the concentration of IFN-gamma and IL-10 before and after cryosurgery. The value of IFN-gamma/IL-10 increased from 3.0 to 6.1 after treatment. All patients experienced high fever within 2 days after surgery, but no other side effects resulted from either cryosurgery or locoregional immunotherapy. All patients maintained good QOL throughout their therapy. These results indicate that cryosurgery in combination with local injection of OK-432 should be a feasible modality against unresectable breast cancer on the chest wall, and that this therapeutic effect may be augmented by mild chemotherapy.

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Semin Oncol. 2003 Oct;30(5 Suppl 16):174-84.
Erythropoietin as a critical component of breast cancer therapy: survival, synergistic,
and cognitive applications.
Leyland-Jones B, O'shaughnessy JA.
Department of Oncology, McGill University, Montreal, Canada.

Treatment with recombinant human erythropoietin (epoetin alfa) has been shown to enhance quality of life and cognitive function. The mechanism of action for these changes appears to involve more than the alleviation of cancer treatment-induced anemia. Rather, there is increasing evidence that epoetin alfa treatment may modulate a series of cascading events that involve hypoxia-induced activation of vascular endothelial growth factor and an induction in the expression of vascular endothelial growth factor receptors via a hypoxia-inducible factor-1-mediated transcription among several other hypoxia-related events. The use of epoetin alfa to interfere with this hypoxia-induced cascade could provide significant benefits for cancer patients by enhancing survival through a direct modulation of tumor angiogenesis and effectiveness of cancer therapy. The enhanced quality of life seen with erythropoietin treatment may also involve a modulation of hypoxia-induced decrement in cognitive functioning. It appears that epoetin alfa is a useful addition to the treatment of breast cancer.

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Semin Oncol. 2003 Oct;30(5 Suppl 16):117-24.
A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer.
Cobleigh MA, Langmuir VK, Sledge GW, Miller KD, Haney L, Novotny WF, Reimann JD, Vassel A.
Rush-Presbyterian-St Lukes Medical Center, Chicago, IL 60612, USA.

Vascular endothelial growth factor promotes angiogenesis, an important mediator of growth and metastasis in human breast cancer. Bevacizumab, a monoclonal antibody to vascular endothelial growth factor, is under investigation as an anti-angiogenic agent. This phase I/II trial evaluated the safety and efficacy of bevacizumab in patients with previously treated metastatic breast cancer. Seventy-five patients were treated with escalating doses of bevacizumab ranging from 3 mg/kg to 20 mg/kg administered intravenously every other week. Tumor response was assessed before the sixth (70 days) and 12th (154 days) doses. Safety was evaluated during every cycle. Eighteen patients were treated at 3 mg/kg, 41 at 10 mg/kg, and 16 at 20 mg/kg. Four patients discontinued study treatment because of an adverse event. Hypertension was reported as an adverse event in 17 patients (22%). The overall response rate was 9.3% (confirmed response rate, 6.7%). The median duration of confirmed response was 5.5 months (range, 2.3 to 13.7 months). At the final tumor assessment on day 154, 12 of 75 patients (16%) had stable disease or an ongoing response. The optimal dose of bevacizumab in this trial was 10 mg/kg every other week and toxicity was acceptable. These data support the initiation of trials in metastatic breast cancer combining bevacizumab with chemotherapy.

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Semin Oncol. 2003 Oct;30(5 Suppl 16):21-9.
Role of anastrozole in adjuvant therapy for postmenopausal patients.
Buzdar AU.
Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

For the past 25 years tamoxifen has been the mainstay for adjuvant treatment of postmenopausal patients with hormone-sensitive breast cancer. However, tamoxifen has some safety and tolerability issues, and its partial estrogen-receptor agonist activity may have efficacy implications. Highly specific aromatase inhibitors, of which anastrozole was the first, were introduced in the 1990s and have emerged as a potentially better tolerated and more effective class of agents targeting hormonally responsive breast cancer. This article provides a review of the clinical pharmacology of anastrozole (1 mg once daily) and reviews the first results of the ongoing Arimidex, Tamoxifen, Alone or in Combination early breast cancer trial, initiated in 1996. This randomized, double-blind multicenter trial compared tamoxifen (20 mg once daily) with anastrozole (1 mg once daily) alone and the combination of anastrozole plus tamoxifen, as adjuvant endocrine treatment for postmenopausal patients with operable, invasive, early breast cancer. The results of the Arimidex, Tamoxifen, Alone or in Combination trial show anastrozole to be an effective and well tolerated endocrine option for early breast cancer and provide evidence for its potential role in chemoprevention.

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Eur J Cancer. 2003 Oct;39(15):2192-9.
Impact of locoregional treatment on the early-stage breast cancer patients: a retrospective analysis.
van der Hage JA, Putter H, Bonnema J, Bartelink H, Therasse P, van de Velde CJ; EORTC Breast Cancer Group.
Department of Surgery, D6-43, Leiden University Medical Center, PO box 9600, 2300 RC Leiden, The Netherlands.

Although adequate locoregional treatment improves local and regional control in early-stage breast cancer, uncertainty still exists about the role of locoregional therapy with respect to survival. To study the impact of surgery and radiotherapy on locoregional control and survival, we combined the data of three European Organisation for Research and Treatment of Cancer (EORTC) Breast Cancer Group trials including early-stage breast cancer patients with long-term follow-up. Risk ratios (RR) were estimated for locoregional recurrence and overall survival using Cox regression models. All analyses were adjusted for tumour size, nodal status, age, adjuvant radiotherapy, adjuvant chemotherapy and trial. The combined data-set consisted of 3648 patients. The median follow-up period was 11 years. 5.9% of the patients who underwent mastectomy and 10.8% of the patients who underwent breast-conserving therapy had a locoregional recurrence (P<0.0001). The risk of death after breast-conserving therapy was similar compared with mastectomy (RR 1.07, P=0.37). Adjuvant radiotherapy after mastectomy was associated with a lower risk for locoregional recurrence (RR 0.43, P<0.001) and death (RR 0.73, P=0.001). Patients with 1-3 positive nodes benefited the most from radiotherapy after mastectomy. Breast-conserving therapy was associated with an impaired locoregional control. However, breast-conserving therapy was not associated with a worse overall survival. Adjuvant radiotherapy in mastectomised patients was associated with both a significantly superior locoregional control and overall survival. The effect of adjuvant radiotherapy was most profound in patients who had 1-3 positive nodes.

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Cancer. 2003 Oct 1;98(7):1369-76.
Radiofrequency ablation of invasive breast carcinoma followed by delayed surgical excision.
Burak WE Jr, Agnese DM, Povoski SP, Yanssens TL, Bloom KJ, Wakely PE, Spigos DG.
Department of Surgical Oncology, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Medical Center, Columbus, Ohio 43210, USA. Burak.1@osu.edu

BACKGROUND: Radiofrequency ablation (RFA) is gaining acceptance as a treatment modality for several tumor types. However, its use in patients with breast carcinoma remains investigational. The current study was undertaken to determine the feasibility of treating small breast malignancies with RFA and to evaluate the postablation magnetic resonance imaging scans (MRI) and histologic findings. METHODS: Patients with core-needle biopsy-proven invasive carcinoma (< 2 cm in greatest dimension) underwent ultrasound-guided RFA under local anesthesia. Surgical excision was undertaken 1-3 weeks later. All patients had breast MRI scans performed before ablation and repeated within 24 hours of surgery. RESULTS: Ten patients completed the treatment and experienced minimal or no discomfort. The mean tumor size was 1.2 cm (range, 0.8-1.6 cm). The mean time required for ablation was 13.8 minutes (range, 7-21 minutes). There were no treatment-related complications other than minimal breast ecchymosis. A pre-RFA MRI scan showed enhancing tumors in 9 of 10 (90%) patients. A post-RFA MRI scan revealed no residual lesion enhancement in 8 of these 9 patients (89%), and the zone of ablation was demonstrated in all patients. One patient had residual enhancement anteriorly consistent with residual tumor, which was confirmed histologically. Evaluation of the remaining ablated lesions revealed a spectrum of changes ranging from no residual tumor to coagulation necrosis with recognizable malignant cells. Immunostains for cytokeratin 8/18 were negative in these recognizable malignant cells. CONCLUSIONS: RFA of small breast malignancies can be performed under local anesthesia in an office-based setting. A postablation MRI scan appears to predict histologic findings, although tumor viability needs to be assessed in a long-term study. Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11642

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J Surg Oncol. 2003 Oct;84(2):94-101; discussion 102.
Minimally invasive surgery for small breast cancer.
Noguchi M.
Surgical Center, Kanazawa University Hospital, Kanazawa, Japan. nogumasa@med.kanazawa-u.ac.jp

BACKGROUND AND METHODS: So-called minimally invasive techniques make percutaneous eradication of breast tumors possible, thus leading to breast-conserving treatment (BCT) without surgery. This paper reviews and discusses the feasibility of minimally invasive techniques for breast cancer. RESULTS: Although a wide variety of ablation techniques have been investigated for the treatment of primary breast cancer, radiofrequency ablation (RFA) remains one of the most promising and potentially useful tools. RFA therapy results in effective cell killing in a predictable volume of tissue with a low complication rate. On the other hand, ultrasonography is useful for guiding the needle within the tumor but cannot predict the extent of thermal ablation accurately. Early post-procedural magnetic resonance imaging (MRI) may be useful for assessing whether complete tumor ablation has been achieved by RFA. Whether adequate ablation of the tumor has been achieved can be confirmed by extensive core needle sampling of the treated area. However, validation of the margin status is also important and this needs to be tackled in further studies. CONCLUSIONS: There are many problems that remain before RFA therapy can be considered for conventional treatment. Further studies are needed to determine whether the use of RFA alone for local treatment of primary breast cancer will result in local recurrence and survival rates equivalent to those seen with BCT. Copyright 2003 Wiley-Liss, Inc.

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Semin Oncol. 2003 Oct;30(5 Suppl 16):14-20
Fulvestrant: an estrogen receptor antagonist that downregulates the estrogen receptor.
Jones SE.
Baylor-Charles A Sammons Cancer Center, Dallas, TX 75246, USA.

Fulvestrant, a novel antiestrogen classified as an estrogen receptor antagonist without known agonist effects, was recently approved in the United States for the treatment of postmenopausal, hormone receptor-positive women with progressive metastatic breast cancer after antiestrogen therapy. In a phase II trial, monthly administration of fulvestrant, 250 mg intramuscularly, conferred clinical benefit (partial response or stable disease for >or= 24 weeks) in 69% of patients with tamoxifen-resistant advanced breast cancer. Furthermore, the median duration of response and survival for this population (26 and 54 months, respectively) was twice as high as those documented for a megestrol acetate-treated historical cohort (14 months and 30 months, respectively). Comparative phase III trials conducted in North America and internationally, which used time to progression as the primary endpoint, demonstrated fulvestrant's tolerability and equivalence to anastrozole in postmenopausal women with tamoxifen-resistant advanced breast cancer, which led to its approval in this setting. Vasodilation and nausea were the principal treatment-related adverse events in the fulvestrant arms, and mild injection-site reactions occurred in 4.6% and 1.1% of monthly fulvestrant courses given in the North American and international trials, respectively. Recent subanalyses of the pivotal phase III data have found that fulvestrant produces a 30% longer mean duration of response compared with anastrozole and that fulvestrant-induced estrogen receptor downregulation does not preclude response to subsequent hormonal therapy. Ongoing trials in patients with advanced breast cancer will provide further insight into the relative merits of fulvestrant versus tamoxifen as first-line therapy for metastatic disease, the use of fulvestrant within combination and sequential regimens, and the efficacy of fulvestrant specifically in premenopausal women. Research efforts focusing on alternate administration schedules for fulvestrant and its potential as an adjuvant hormonal therapy are also anticipated.

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Int J Radiat Oncol Biol Phys. 2003 Oct 1;57(2):336-44.
Locoregional recurrence after doxorubicin-based chemotherapy and postmastectomy: Implications for breast cancer patients with early-stage disease and predictors for recurrence after postmastectomy radiation.
Woodward WA, Strom EA, Tucker SL, Katz A, McNeese MD, Perkins GH, Buzdar AU, Hortobagyi GN, Hunt KK, Sahin A, Meric F, Sneige N, Buchholz TA.
Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.

PURPOSE: To compare rates of locoregional recurrence (LRR) after mastectomy, doxorubicin-based chemotherapy, and radiation with those of patients receiving mastectomy and doxorubicin-based chemotherapy without radiation and to determine predictors of LRR after postmastectomy radiation. METHODS: Kaplan-Meier freedom-from-LRR rates were calculated for 470 patients treated with mastectomy, doxorubicin-based chemotherapy, and postmastectomy radiation in five single-institution clinical trials. The LRR rates in these patients were compared to previously reported rates in 1031 patients treated without radiation in the same trials. RESULTS: Median follow-up was 14 years. Irradiated patients had significantly less favorable prognostic factors for LRR than did unirradiated patients. Despite this, in all subsets of node-positive patients, postmastectomy radiation led to lower rates of LRR. This included patients with T1 or T2 tumors and one to three positive nodes (10-year LRR rates of 3% vs. 13%, p = 0.003). Multivariate analysis of LRR for patients with this stage of disease revealed that no radiation, close/positive margins, gross extracapsular extension, and dissection of <10 nodes predicted for increased LRR (hazard ratios 6.25, 4.61, 3.27, and 2.66, respectively). Significant predictors of LRR for patients treated with postmastectomy radiation were higher number and >or=20% positive nodes, larger tumor size, lymphovascular space invasion, and estrogen receptor (ER)-negative disease. Recursive partitioning analysis revealed ER-negative status to be the most powerful discriminator of LRR in irradiated patients. CONCLUSIONS: Postmastectomy radiation decreases LRR for patients with breast cancer, including those with Stage II breast cancer and one to three positive lymph nodes.

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Acta Oncol. 2003;42(5-6):532-45.
A systematic overview of radiation therapy effects in breast cancer.
Rutqvist LE, Rose C, Cavallin-Stahl E.
Department of Oncology, Huddinge University Hospital, Stockholm, Sweden. lars-erik.rutqvist@hs.se

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for breast cancer is based on data from 29 randomized trials, 6 meta-analyses and 5 retrospective studies. In total, 40 scientific articles are included, involving 41 204 patients. The results were compared with those of a similar overview from 1996 including 285 982 patients. The conclusions reached can be summarized as follows: There is strong evidence for a substantial reduction in locoregional recurrence rate following postmastectomy radiation therapy to the chest wall and the regional nodal areas. There is strong evidence that postmastectomy radiation therapy increases the disease-free survival rate. There are conflicting data regarding the impact of postmastectomy radiotherapy upon overall survival. There is strong evidence that breast cancer specific survival is improved by postmastectomy radiotherapy. There is strong evidence for a decrease in non-breast cancer specific survival after postmastectomy radiotherapy. There is some evidence that overall survival is increased by optimal postmastectomy radiation therapy. There is strong evidence that postmastectomy radiotherapy in addition to surgery and systemic therapy in mainly node-positive patients decreases local recurrence rate and improves survival. There is moderate evidence that the decrease in non-breast cancer specific survival is attributed to cardiovascular disease in irradiated patients. There are conflicting data whether breast conservation surgery plus radiotherapy is comparable to modified radical mastectomy alone in terms of local recurrence rate. There is strong evidence that breast conservation surgery plus radiotherapy is comparable to modified radical mastectomy alone in terms of disease-free survival and overall survival. There is strong evidence that postoperative radiotherapy to the breast following breast conservation surgery results in a statistically and clinically significant reduction of ipsilateral breast recurrences followed by diminished need for salvage mastectomies. There is strong evidence that the omission of postoperative radiotherapy to the breast following breast conservation surgery has no impact on overall survival. In one meta-analysis including three randomized studies a survival advantage is demonstrated by Bayesian statistics. There is strong evidence that the addition of a radiation boost after conventional radiotherapy to the tumour bed after breast conservation surgery significantly decreases the risk of ipsilateral breast recurrences but has no impact on overall survival after short follow-up. There is strong evidence for the use of postoperative radiotherapy to the breast following breast conservation surgery for DCIS (ductal breast cancer in situ). Radiotherapy leads to a clinically and statistically significant reduction of both non-invasive and invasive ipsilateral breast recurrences. There is insufficient evidence to define the optimal integration of systemic adjuvant therapy and postoperative radiotherapy. There are limited data on radiotherapy-related morbidity in breast cancer. No conclusions can be drawn.

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Cancer. 2003 Sep 15;98(6):1150-60.
Neoadjuvant chemotherapy for breast carcinoma: multidisciplinary considerations of benefits and risks.
Buchholz TA, Hunt KK, Whitman GJ, Sahin AA, Hortobagyi GN.
Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. tbuchhol@mdanderson.org

BACKGROUND: The majority of patients with breast carcinoma receive chemotherapy as a component of multimodality treatment. Over the past decade, it has become increasingly more common to deliver chemotherapy first, but this has raised new questions within all disciplines of cancer management. METHODS: The authors reviewed published studies on the effect of neoadjuvant chemotherapy for breast carcinoma on the practice of medical oncology, surgical oncology, radiation oncology, pathology, and radiology. RESULTS: Treating breast carcinoma with neoadjuvant chemotherapy has several advantages, such as providing the earliest possible treatment against preexisting micrometastases, offering selected patients breast conservation therapy, and allowing for measurement of disease response, which can then be used to customize subsequent chemotherapy. However, neoadjuvant chemotherapy affects the practice not only of medical oncology, but also has important implications for the specialties of surgery, radiology, pathology, and radiation oncology. The current review addressed the new opportunities and challenges within the multidisciplinary care of breast carcinoma provided by neoadjuvant chemotherapy. CONCLUSIONS: The complexity of the issues led the authors to conclude that patients who receive neoadjuvant chemotherapy are likely to benefit from a coordinated multidisciplinary approach to their care. Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11603

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J Clin Oncol. 2003 Sep 15;21(18):3454-61.
Phase I and II study of exisulind in combination with capecitabine in patients with metastatic breast cancer.
Pusztai L, Zhen JH, Arun B, Rivera E, Whitehead C, Thompson WJ, Nealy KM, Gibbs A, Symmans WF, Esteva FJ, Booser D, Murray JL, Valero V, Smith TL, Hortobagyi GN.
Box 424, Department of Breast Medical Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4009, USA. lpusztai@mdanderson.org

PURPOSE: We studied the safety and clinical activity of exisulind in combination with capecitabine in 35 patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: All patients had received previous anthracycline and taxane chemotherapies. Two dose levels of exisulind were explored, 125 and 250 mg orally bid as continuous daily therapy, concomitant with capecitabine 2,000 mg/m2 for 14 days in 21-day cycles. In the phase I study, the dose-limiting toxicities were hand-foot syndrome and diarrhea. The 125-mg bid dose was selected for phase II testing. RESULTS: The most common nonhematologic grade 2 to 3 adverse events were hand-foot syndrome (57%) and fatigue (48%). The most frequent grade 2 to 3 laboratory abnormality was granulocytopenia. No death, unexpected adverse events, or cumulative toxicity were encountered. One complete and four partial responses were achieved (objective response rate, 16%) in the 31 patients assessable for response. The median duration of response was 31 weeks; three patients experienced stable disease longer than 26 weeks. Overall clinical benefit (complete response, partial response, or stable disease > 26 weeks) was 23%. Fourteen specimens were available for immunohistochemical assessment of phosphodiesterase-5 isoenzyme (PDE-5) and PDE-2 expression, which are the targets of exisulind. Eighty percent of tumors showed some expression of PDE-5 in the invasive cancer cells including 35% that showed moderate or strong staining. PDE-2 showed moderate or strong staining in 78% of tumors. There was no apparent association between tumor response and staining intensity. CONCLUSION: Exisulind (125 mg orally bid) in combination with capecitabine is well tolerated and the combination has anticancer activity similar to that of capecitabine alone in heavily pretreated patients with MBC.

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Gan To Kagaku Ryoho. 2003 Aug;30(8):1131-8.
Combination of vinorelbine + doxorubicin in advanced breast cancer.
Lorvidhaya V, Kamnerdsupaphon P, Chitapanarux I, Srisukho S, Trakultivakorn H, Sumitsawan S, Sukthomya V, Tonusin A.
Department of Radiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.

OBJECTIVE: To assess the efficacy of a vinorelbine + doxorubicin combination in terms of response rate and time to progression in patients with locally advanced or metastatic breast cancer. METHODS: Vinorelbine (25 mg/m2) and doxorubicin (25 mg/m2) were administered intravenously in a rapid injection on days 1 and 8 every 21 days. Initially, 3 courses of vinorelbine + doxorubicin were given. Patients with responding or stable disease received 6 more courses to a maximum of 9 courses. RESULT: Twenty-nine patients were entered into the study and 27 eligible patients were considered evaluable for response. Median age was 45 years (range 33 to 63). Overall response rate was 66.67% (18/27) (CR = 5, PR = 13). Median time to progression was 7.8 months (range 4 to 16) and the median survival time was 25.9 months. Median follow-up time was 8.5 months (range 1.5 to 25). Toxicity was generally moderate. Hematologic complication was the dose limiting toxicity. WHO grade III/IV neutropenia was observed in 18.5%/3.7% of patients. The major non-hematologic toxicities were nausea and phlebitis. Grade III nausea/vomiting was observed in 7.4% and grade III/IV phlebitis in 3.7%/3.7% of patients. No toxic deaths were observed. CONCLUSION: The present vinorelbine + doxorubicin combination was highly effective and generally well tolerated in cases of advanced breast cancer. Further studies are required.

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J Natl Cancer Inst. 2003 Aug 20;95(16):1205-10.
Limited-field radiation therapy in the management of early-stage breast cancer.
Vicini FA, Kestin L, Chen P, Benitez P, Goldstein NS, Martinez A.
Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI 48072, USA. fvicini@beaumont.edu

BACKGROUND: Several phase III trials have demonstrated equivalent long-term survival between breast conserving surgery plus radiation therapy and mastectomy in patients with early-stage breast cancer but have not provided information on the optimal volume of breast tissue requiring post-lumpectomy radiation therapy. Therefore, we examined the 5-year results of a single institution's experience with radiation therapy limited to the region of the tumor bed (i.e., limited-field radiation therapy) in selected patients treated with breast-conserving therapy and compared them with results of matched breast-conserving therapy patients who underwent whole-breast radiation therapy. METHODS: A total of 199 patients with early-stage breast cancer were treated prospectively with breast-conserving therapy and limited-field radiation therapy using interstitial brachytherapy. To compare potential differences in local recurrence rates based on the volume of breast tissue irradiated, patients in the limited-field radiation therapy group were matched with 199 patients treated with whole-breast radiation therapy. Match criteria included tumor size, lymph-node status, patient age, margins of excision, estrogen receptor status, and use of adjuvant tamoxifen therapy. Local-regional control and disease-free and overall survival were analyzed using the Kaplan-Meier method, and the statistical significance of differences between treatment groups was calculated using the log-rank test. All statistical tests were two-sided. RESULTS: Median follow-up for surviving patients was 65 months (range = 12-115 months). Five ipsilateral breast failures (i.e., recurrences) were observed in patients treated with limited-field radiation therapy. The cumulative incidence of local recurrence was 1% (95% confidence interval [CI] = 0% to 2.8%). On matched-pair analysis, the rate of local recurrence was not statistically significantly different between the patient groups (1% [95% CI = 0% to 2.4%] for the whole-breast radiation therapy patients versus 1% [95% CI = 0% to 2.8%] for the limited-field radiation therapy patients; P =.65). CONCLUSIONS: Limited-field radiation therapy administered to the region of the tumor bed has comparable 5-year local control rates to whole-breast radiation therapy in selected patients.

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Jpn J Clin Oncol. 2003 Aug;33(8):371-6.
Multicenter phase II trial of weekly paclitaxel for advanced or metastatic breast cancer: the Saitama Breast Cancer Clinical Study Group (SBCCSG-01).
Sato K, Inoue K, Saito T, Kai T, Mihara H, Okubo K, Koh J, Mochizuki H, Tabei T; Saitama Breast Cancer Clinical Study Group.
Department of Surgery I, National Defense Medical College, Tokorozawa, Saitama, Japan. sato-k-a@mtg.biglobe.ne.jp

OBJECTIVE: Weekly dosing of paclitaxel has been demonstrated to be a well-tolerated, feasible and effective administration schedule. In this study, we evaluated the efficacy and safety of weekly paclitaxel in Japanese women with advanced or metastatic breast cancer. METHODS: Seventy-four patients were enrolled in the study. Paclitaxel was administered by 1 h intravenous infusion at a dose of 80 mg/m2 every week. Administration was continued for 3 weeks followed by a 1 week rest. A short premedication, consisting of dexamethasone 10 mg, ranitidine 50 mg and diphenylhydramine 50 mg, was given prior to each dose of paclitaxel. Eligibility criteria included an Eastern Cooperative Oncology Group performance status of 0, 1 or 2 and adequate hematological, hepatic and renal function. RESULTS: Of 74 patients treated and evaluable for toxicities, 70 were evaluable for response. The mean age was 57.7 years. Forty-nine patients (66.2%) had received prior anthracyclines for metastatic diseases. The overall response rate among 74 patients was 40.5%, including 4.1% complete responses and 36.5% partial responses. The median follow-up time was 481 days (range, 24-903 days). The median time to progression was 4.8 months and median overall survival was 15.8 months. The majority of patients tolerated the treatment very well. Although alopecia was observed in most of the patients (93.2%), grade 3 or 4 neutropenia was 10.8% and grade 2 or 3 peripheral neuropathy was 13.5%. CONCLUSION: Weekly paclitaxel as a 1 h infusion was active and generally well tolerated in previously treated patients. Further study of weekly paclitaxel in combination therapy is warranted.

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Semin Oncol. 2003 Aug;30(4 Suppl 14):46-57.
Aromatase inhibitors in early breast cancer treatment.
Mauriac L, Smith I.
Department of Medical Oncology, Istitut Bergonie, Regional Cancer Center, Bordeaux, France.

A recent National Institutes of Health consensus guideline recommends the general use of adjuvant hormonal therapy for the treatment of early breast cancer in postmenopausal women with estrogen receptor-positive tumors. Standard therapy has been 5 years of tamoxifen, but about 30% of those patients fail to survive 10 years, many as a consequence of tamoxifen resistance. Promising results with the third-generation aromatase inhibitors anastrozole, letrozole, and exemestane in first- and second-line treatment of metastatic breast cancer has prompted their evaluation as adjuvant therapy in patients progressing on tamoxifen or as alternative first-line treatment. Anastrozole has recently achieved significantly longer disease-free survival than tamoxifen in a first-line adjuvant therapy trial, and letrozole is being investigated in several large adjuvant trials. Aromatase inhibitors appear to be well tolerated for long-term adjuvant treatment. In the neoadjuvant setting, letrozole has been especially effective compared with tamoxifen in downstaging primary tumors in postmenopausal women, permitting significantly more breast-conserving surgery.

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Semin Oncol. 2003 Aug;30(4 Suppl 14):33-45.
The role of aromatase inhibitors in the treatment of metastatic breast cancer.
Mouridsen H, Gershanovich M.
Department of Oncology, Rigshospitalet, Copenhagen, Denmark.

Tamoxifen has been the gold standard of endocrine therapy for postmenopausal patients with hormone receptor-positive breast cancer for over 20 years. The development of the third-generation aromatase inhibitors anastrozole, letrozole, and exemestane is changing the algorithm for the treatment of the disease. Recent clinical trials have shown that all three third-generation aromatase inhibitors present significant advantages over traditional progestins and aminoglutethimide therapy after tamoxifen failure in postmenopausal women. These new agents are now accepted as first choice for second-line treatment of metastatic disease. Since 2000, phase III trials with anastrozole and letrozole have shown that third-generation aromatase inhibitors are at least as effective as tamoxifen in the first-line treatment of postmenopausal women with hormone receptor-positive or -unknown metastatic breast cancer. The first-line phase III trial of letrozole versus tamoxifen which, unlike the anastrozole trials, was prospectively designed to test superiority of the aromatase inhibitor, showed that this agent was superior to tamoxifen in all assessed outcome measures. A first-line phase III trial of exemestane versus tamoxifen in postmenopausal patients with hormone receptor-positive or -unknown advanced breast cancer is ongoing. The data presented in this article suggest that aromatase inhibitors may replace tamoxifen in the first-line hormonal management of this disease in postmenopausal women.

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Anticancer Res. 2003 May-Jun;23(3C):2879-80.
Primary systemic therapy (PST) of locally advanced breast cancer using Doxorubicin/Docetaxel combination.
Dank M, Zergenyi E, Domotori ZS, Lahm E, Kulka J.
Department of Diagnostic, Radiology and Oncotherapy, Semmelweis University, Ulloi ut 78a, 1082 Budapest, Hungary. dank@radi.sote.hu

BACKGROUND: PST of locally advanced breast carcinomas causes tumour shrinkage and down-staging, therefore, optimal circumstances for surgery. PATIENTS AND METHODS: We treated 25 stage IIIA-IIIB breast cancer patients with PST (Doxorubicin/Docetaxel). Histological diagnosis (core biopsy) was available in each case. Tumour regression and cardiac function were recorded regularly. RESULTS: Five patients showed complete pathological remission. Instead of 19 mastectomies, only nine were performed and 16 patients underwent breast-conserving therapy. CONCLUSION: Using PST breast conservation rate is improved.

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Anticancer Res. 2003 May-Jun;23(3C):2795-800.
Palliative chemotherapy after failure of high-dose chemotherapy in breast cancer—toxicity and efficacy.
Schrama JG, de Boer MM, Baars JW, Schornagel JH, Rodenhuis S.
Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. j.schrama@nki.nl

We evaluated the toxicity and efficacy of the first palliative chemotherapy regimen after failure of high-dose chemotherapy in 148 patients with primary or metastatic breast cancer treated with high-dose chemotherapy (one full dose CTC, (cyclophosphamide 6000 mg/m2, thiotepa 480 mg/m2, carboplatin 1600 mg/m2) or multiple courses CTC or 'tiny' CTC (tCTC) (two-thirds of the agents of the full-dose regimen), all divided over 4 days). After a median follow-up time of 46.8 (range 1-120) months, 79 patients had a relapse or progressive disease and 41 patients were treated with palliative chemotherapy. The most commonly used regimens were classical CMF (n = 13), docetaxel (n = 16) and less frequently anthracycline (n = 4), paclitaxel (n = 5), capecitabine (n = 2) and vinorelbine (n = 2). In both the CMF and docetaxel group, 3 patients required a dose reduction because of hematological toxicity. Objective responses were seen with CMF (23%) and docetaxel (69%) with a median duration of 161 (range 28-481) and 196 (range 62-437) days, respectively. We found no relationship of toxicity and response with treatment-free interval after high-dose chemotherapy. This report shows that conventional-dose palliative chemotherapy regimens may be safe and effective after failure of high-dose chemotherapy.

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Cochrane Database Syst Rev. 2003;(3):CD003366.
Taxane containing regimens for metastatic breast cancer.
Ghersi D, Wilcken N, Simes J, Donoghue E.
NHMRC Clinical Trials Centre, The University of Sydney, Locked Bag 77, Camperdown, NSW, Australia.

BACKGROUND: It is generally accepted that taxanes are among the most active chemotherapy agents in the management of metastatic breast cancer. OBJECTIVES: To identify and review the randomised evidence comparing taxane containing chemotherapy regimens with regimens not containing a taxane in the management of women with metastatic breast cancer. SEARCH STRATEGY: The specialised register maintained by the Editorial Base of the Cochrane Breast Cancer Group was searched on 2nd May 2003 using the codes for "advanced breast cancer", "chemotherapy". Details of the search strategy applied by the Group to create the register, and the procedure used to code references, are described in the Group's module on the Cochrane Library. SELECTION CRITERIA: Randomised trials comparing taxane-containing chemotherapy regimens with regimens not containing taxanes in women with metastatic breast cancer. DATA COLLECTION AND ANALYSIS: Data were collected from published trials. Studies were assessed for eligiblity and quality, and data were extracted, by two independent reviewers. Hazard ratios were derived for time-to-event outcomes where possible, and a fixed effect model was used for meta-analysis. Response rates were analysed as dichotomous variables. Toxicity and quality of life data were extracted where present. MAIN RESULTS: Twenty eligible trials were identified of which 17 had published at least some results, and 12 had published time-to-event data. The quality of randomisation was generally not described.An estimated 2659 deaths in 3643 randomised women demonstrate a statistically significant difference in favour of taxane-containing regimens with a HR for overall survival of 0.90 (95% CI=0.84-0.97, p=0.009) and no significant heterogeneity. If the analysis is restricted to trials of firstline chemotherapy the HR changes to 0.92 and is no longer statistically significant (95% CI 0.84-1.02, p=0.12). There was also a significant difference in favour of taxanes in relation to time to progression (overall HR 0.87, 95%CI 0.81-0.93, p<0.0001) and overall response (overall OR 1.29, 95%CI 1.13-1.47, p<0.0001) however there was strong statistical evidence of heterogeneity (P<0.00001), probably reflecting the varying efficacy of the comparator regimens used in the trials. REVIEWER'S CONCLUSIONS: When all trials are considered, taxane-containing regimens appear to improve overall survival, time to progression and overall response in women with metastatic breast cancer. The degree of heterogeneity encountered indicates that taxane-containing regimens are more effective than some, but not all non-taxane-containing regimens.

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Anticancer Res 2003 Jan-Feb;23(1B):785-91
A dose escalation study of docetaxel and oxaliplatin combination in patients with metastatic breast and non-small cell lung cancer.
Kouroussis C, Agelaki S, Mavroudis D, Kakolyris S, Androulakis N, Kalbakis K, Souglakos J, Mallas K, Bozionelou V, Pallis A, Adamtziki H, Georgoulias V.
Department of Medical Oncology, School of Medicine, University General Hospital of Heraklion, P.O. Box 1352, 71110, Heraklion, Crete, Greece.

OBJECTIVES: To determine the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of docetaxel in combination with oxaliplatin (L-OHP) as first-line treatment of patients with advanced breast (ABC) and non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifty-two patients (26 with NSCLC and 26 with ABC), who had not received prior chemotherapy for metastatic disease, were enrolled. The patients' median age was 64 years, and 42 (71%) had a performance status (WHO) 0-1. Docetaxel was given as a 1-hour infusion after standard premedication on day 1 and L-OHP as a 2 to 6-hour infusion on day 2 every 3 weeks. Doses were escalated at increments of 10 mg/m2. RESULTS: The DLT1 was reached at the doses of docetaxel 75 mg/m2 and L-OHP 80 mg/m2. The addition of rhG-CSF permitted further dose escalation (DLT2: docetaxel 90 mg/m2 and L-OHP 130 mg/m2). The dose-limiting events were grade 4 neutropenia, febrile neutropenia, grades 3 or 4 diarrhea and grade 3 fatigue. Out of 239 delivered cycles, grades 3 or 4 neutropenia occurred in 22 (9%) cycles with 5 (2%) neutropenic febrile episodes. There was one septic death. Grades 3 or 4 fatigue was observed in seven (13%) patients and grades 3-4 diarrhea in five (10%). Out of 42 patients evaluable for response, seven (27%) patients with ABC and five (19%) patients with NSCLC experienced a partial response. CONCLUSION: The combination of docetaxel and oxaliplatin is a feasible and well-tolerated regimen. The recommended doses for future phase II studies are 75 mg/m2 for docetaxel on day 1 and 70 mg/m2 for L-OHP on day 2 without rhG-CSF support and 85 mg/m2 and 130 mg/m2, respectively, with rhG-CSF support.

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Anticancer Res 2003 Jan-Feb;23(1B):765-71
Paclitaxel and epidoxorubicin or doxorubicin versus cyclophosphamide and epidoxorubicin as first-line chemotherapy for metastatic breast carcinoma: a randomised phase II study.
Gebbia V, Blasi L, Borsellino N, Caruso M, Leonardi V, Agostara B, Valenza R.
University of Palermo, Medical Oncology Unit, La Maddalena Clinic for Cancer, Palermo, Italy.

Fifty-eight patients with metastatic breast cancer were randomly treated with a combination of cyclophosphamide 500 mg/m2 on days 1 and 2 plus epidoxorubicin 90 mg/m2 on day 1 every 3 weeks (group A = 18 patients), or paclitaxel 175 mg/m2 cycle plus doxorubicin 50 mg/m2/cycle every 3 weeks (group B = 20 patients), or paclitaxel as above plus epidoxorubicin 90 mg/m2/cycle every 21 days (group C = 20 patients). The trial was designed as a randomized, multi-institutional phase II study where the cyclophosphamide/epidoxorubicin regimen represented the calibration arm. The overall response rate was 50% (95% CL 26-74%) for arm A, 65% (95% CL 41-85%) for arm B and 70% (95% CL 46-88%) for arm C. The complete response rate was 6% for arm A, 10% for arm B and 15% for arm C. Although this trial was non comparative, the median duration of response and median overall survival were almost superimposable in all arms. The taxane-based regimens were associated with significant neurotoxicity in nearly 20% of cases, while febrile neutropenia represented the most severe side-effect. Our data suggest that the anthracycline/taxane combinations are more effective than the epidoxorubicin/cyclophosphamide regimen, at least in terms of objective response rates. These regimens may represent the treatment of choice when oncologists are faced with aggressive visceral metastatic breast cancer in non elderly women.

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Anticancer Res 2003 Jan-Feb;23(1B):737-44
Prolonged administration of weekly paclitaxel and trastuzumab in patients with advanced breast cancer.
Christodoulou C, Klouvas G, Pateli A, Mellou S, Sgouros J, Skarlos DV.
Oncology Department, Henry Dynan Hospital, Athens, Greece. hecogiat@otenet.gr

PURPOSE: To evaluate the efficacy and safety of weekly paclitaxel and trastuzumab in patients with HER2-positive metastatic breast cancer, with trastuzumab administered beyond disease progression. PATIENTS AND METHODS: Twenty-six women with metastatic breast cancer, that was HER2-positive as determined by immunohistochemistry, were treated with weekly paclitaxel 70 or 90 mg/m2 and trastuzumab (4 mg/kg initial dose followed by 2 mg/kg weekly). RESULTS: The median duration of treatment was 28 (8-72) weeks for paclitaxel and 59 (14-150) weeks for trastuzumab. Two (8%) patients experienced complete and 14 (54%) partial responses, for an overall response rate of 62%. The median time to disease progression was 11 (2.89-36) months and median survival 34+ months. Grade 3/4 adverse events were alopecia (46%), neurotoxicity (15%), leukopenia (12%) and neutropenia (12%). Infusion-related reactions were mild to moderate. No symptomatic cardiac toxicity was observed. No patient discontinued trastuzumab due to toxicity. CONCLUSION: Prolonged administration of weekly paclitaxel and trastuzumab is effective and well-tolerated in women with HER2-positive metastatic breast cancer.

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Anticancer Res 2003 Jan-Feb;23(1B):733-6
Antiprolactinemic approach in the treatment of metastatic breast cancer: a phase II study of polyneuroendocrine therapy with LHRH-analogue, tamoxifen and the long-acting antiprolactinemic drug cabergoline.
Lissoni P, Vaghi M, Villa S, Bodraska A, Cerizza L, Tancini G, Gardani GS.
Division of Radiation, Oncology, San Gerardo Hospital, 20052 Monza, Milan, Italy.

Despite the well-demonstrated stimulatory role of prolactin (PRL) on breast cancer cell growth and the possible existence of a PRL-dependency in estrogen-independent mammary tumors, the therapeutic role of the antiprolactinemic drugs in the treatment of human breast cancer has still to be investigated and defined. Previous preliminary studies have already shown that the concomitant administration of antiprolactinemic agents may enhance the efficacy of cancer chemotherapy for breast carcinoma, whereas their impact on the efficacy of the endocrine therapy is still unknown. At present, the classic endocrine therapy for breast cancer consists of anti-estrogens plus LHRH-analogue. The concomitant administration of antiprolactinemic drugs could enhance the efficacy of treatment by blocking not only the action of estrogens, but also that of another growth factor for breast cancer, such as PRL. The present phase II study was performed to evaluate the efficacy and tolerability of a polyneuroendocrine approach for breast cancer, consisting of LHRH-analogue plus the anti-estrogen tamoxifen plus a long-acting antiprolactinemic agent, cabergoline. The study included 14 consecutive metastatic breast cancer women, heavily pretreated with the standard anticancer therapies and for whom no other conventional treatment was available. The LHRH-analogue, triptorelin, was given intramuscularly at a dose of 3.75 mg every 28 days, tamoxifen was given orally at 20 mg/day and cabergoline was given orally at 0.5 mg once/week. The clinical response consisted of partial response (PR) in 4 out of 14 (29%) patients, including one who had progressed on a previous treatment with triptorelin plus tamoxifen alone. A stable disease (SD) was achieved in another 5 patients, whereas the other 5 patients had a progressive disease (PD). Mean serum levels of PRL significantly decreased on treatment within the first month of therapy, and its decline was significantly more evident in patients with PR or SD than in those with PD. The treatment was well-tolerated in all patients, and in particular no cabergoline-related toxicity occurred. This preliminary study would suggest that the association of the long-acting antiprolactinemic drug cabergoline may further enhance the efficacy of the classical endocrine therapy for advanced breast cancer with anti-estrogens plus LHRH-analogues.

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Cancer Chemother Pharmacol 2003 Feb;51(2):179-83
Vinorelbine and docetaxel as first-line chemotherapy in metastatic breast cancer.
Vassilomanolakis M, Koumakis G, Drufakou S, Aperis G, Demiri M, Barbounis V, Missitzis J, Efremidis AP.
Second Department of Medical Oncology, St. Savas Regional Oncology Hospital, 171 Alexandra's Ave., Athens 115-22, Greece.

PURPOSE: To evaluate the efficacy and tolerability of a combination of vinorelbine (VNR) and docetaxel (DOC) as first-line chemotherapy in patients with metastatic breast cancer. PATIENTS AND METHODS: The study group comprised 40 women with untreated metastatic breast cancer with visceral (85%) and bone (70%) metastases. Of the 40 patients, 24 (60%) had previously received adjuvant chemotherapy, which had included anthracyclines in 12 patients (30%). Treatment consisted of VNR 25 mg/m(2) on days 1 and 5, and DOC 75 mg/m(2) on day 1 every 3 weeks. Depending on the neutrophil nadir (grade 3 or 4 neutropenia by WHO criteria) recombinant human granulocyte colony-stimulating factor (G-CSF) 5 micro g/kg on days 2-4 and 6-13 was given for all subsequent treatment cycles. RESULTS: The overall response rate (ORR) was 40% (95% confidence interval, CI 15-65). Six patients (15%) achieved a complete response (CR) and ten patients (25%) achieved a partial response (PR). Stable disease (SD) was observed in six patients (15%), and 18 patients (45%) had progressive disease (PD). The median duration of response was 8 months and the median predictive time to progression (TTP) was 6 months. The main toxicity was neutropenia grade 3 and 4 in 28 patients (70%). Febrile neutropenia requiring hospitalization occurred in 12 patients (30%). Grade 3 or 4 anemia was seen in two patients (5%) and grade 3 or 4 thrombocytopenia was seen in one patient (2.5%). Severe nonhematologic toxicity, except alopecia, was uncommon and included stomatitis in two patients (5%), vomiting in two (5%) and diarrhea in one (2.5%). There were no treatment-related deaths. CONCLUSIONS: The combination of VNR and DOC at the doses used in this study showed moderate activity as first-line chemotherapy in metastatic breast cancer. Neutropenia was considerable despite G-CSF administration.

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Semin Oncol 2003 Feb;30(1 Suppl 1):49-55
New directions for ZD1839 in the treatment of solid tumors.
Schiller JH.
Section of Medical Oncology, Department of Medicine, University of Wisconsin Medical School, Comprehensive Cancer Center, Madison, WI 53792-6164, USA.

Among molecular mechanisms of tumor growth and progression, activated epidermal growth factor receptor-tyrosine kinase is remarkable for its prevalence and impact on many different solid tumor types, as well as its link to diverse stages of disease. ZD1839, (Iressa; AstraZeneca Pharmaceuticals LP, Wilmington, DE) an oral epidermal growth factor receptor-tyrosine kinase inhibitor, is also being explored for its potential in the treatment of other common solid tumors, including breast cancer, colorectal cancer, and hormone-refractory prostate cancer. Clinical trials include studies of ZD1839 as monotherapy and in combination with various chemotherapy, radiation, and hormone therapy regimens. ZD1839 is also being studied in conjunction with other targeted therapies, such as trastuzumab. In addition to advanced and refractory disease, ZD1839 may also be applicable for use in earlier stage cancers. Chemoprevention trials have been initiated to assess the potential of ZD1839 to delay or prevent the progression of common solid tumors such as non-small cell lung cancer. Copyright 2003, Elsevier Science (USA). All rights reserved.

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J Clin Oncol 2003 Mar 15;21(6):1015-21
Immunotherapy of advanced breast cancer with a heterophilic ganglioside (NeuGcGM3) cancer vaccine.
Carr A, Rodriguez E, Arango Mdel C, Camacho R, Osorio M, Gabri M, Carrillo G, Valdes Z, Bebelagua Y, Perez R, Fernandez LE.
Center of Molecular Immunology and National Institute of Oncology and Radiobiology, Havana, Cuba. adriana@ict.cim.sld.cu

PURPOSE: A heterophilic ganglioside cancer vaccine was developed by combining NeuGcGM3 with the outer membrane protein complex of Neisseria meningitidis to form very small size proteoliposomes (VSSP). A phase I clinical trial was performed to determine safety and immunogenicity of this vaccine. PATIENTS AND METHODS: Stage III to IV breast cancer patients received up to 15 (200 micro g) doses of the vaccine by intramuscular injection. The first five doses (induction phase) were given at 2-week intervals, with the remaining treatment (maintenance) administered on a monthly basis. RESULTS: Twenty-one patients, 11 of whom had metastatic disease, were included. Main toxicities included erythema and induration at the injection site, sometimes associated with mild pain, and low-grade fever (World Health Organization grades 1 and 2). All treated patients who completed the induction phase developed anti-NeuGcGM3 antibody titers between 1:1,280 and 1:164,000 immunoglobulin G (IgG), and 1:640 and 1:164,000 IgM. Noteworthy specific IgA antibodies were induced by vaccination in all stage III patients and in three stage IV patients. Serum antibody levels were higher in the stage III patients, with the larger increases observed after week 32. The antiganglioside IgG subclasses were mainly IgG1 and IgG3. Hyperimmune sera increased complement-mediated cytotoxicity versus P3X63 myeloma cells and a marked IgG differential reactivity against human mammary ductal carcinoma samples. CONCLUSION: NeuGcGM3/VSSP/Montanide ISA 51 is an unusual immunogenic ganglioside vaccine and also seems to be safe in this small trial. Immunologic surrogates of activity indicate that this reagent warrants further investigation.

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J Clin Oncol 2003 Mar 15;21(6):1007-14
Phase II, randomized, double-blind study of two dose levels of arzoxifene in patients with locally advanced or metastatic breast cancer.
Buzdar A, O'Shaughnessy JA, Booser DJ, Pippen JE Jr, Jones SE, Munster PN, Peterson P, Melemed AS, Winer E, Hudis C.
M.D. Anderson Cancer Center and US Oncology Research, Houston, and Baylor-Sammons Cancer Center and Texas Oncology, Dallas, TX. 77030, USA. abuzdar@mdanderson.org

PURPOSE: To select a daily dose of arzoxifene (LY353381), a selective estrogen receptor modulator, for use in future studies in women with locally advanced or metastatic breast cancer who are either potentially tamoxifen sensitive (TS) or tamoxifen refractory (TR). PATIENTS AND METHODS: This trial was a randomized, double-blind, phase II study of arzoxifene 20 mg (n = 55) and 50 mg (n = 57) in women with advanced or metastatic breast cancer. Patients were randomly assigned to balance for number of metastatic disease sites, prior tamoxifen therapy, and estrogen receptor status. The primary end point was tumor response rate (RR). Secondary end points included clinical benefit rate (CBR), time to progression (TTP), and toxicity. RESULTS: Forty-nine patients were TS and 63 were TR. According to independent review, among TS patients, RR was higher in the 20-mg arm than the 50-mg arm (26.1% v 8.0%), with a longer TTP (8.3 v 3.2 months; P >.05). Among the TR patients, response rate was the same in the 20-mg and 50-mg arms (10.3%) with similar TTP (2.7 and 2.8 months, respectively; P >.05). CBR was higher in the 20-mg arm than in the 50-mg arm among TS patients (39.1% v 20.0%) and TR patients (13.8% v 10.3%). Arzoxifene was well tolerated. Dose-dependent toxicity was not demonstrated. There were no deaths during study. CONCLUSION: Arzoxifene is effective in the treatment of TS and TR patients with advanced or metastatic breast cancer at the 20-mg and 50-mg dose levels. Toxicities are minimal, and the therapy is tolerated. The 20-mg dose seems to be at least as effective as the 50-mg dose. Accordingly, arzoxifene 20 mg/d was selected for further study in patients with breast cancer.

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J Clin Oncol 2003 Mar 15;21(6):999-1006
Multicenter phase II study of oral bexarotene for patients with metastatic breast cancer.
Esteva FJ, Glaspy J, Baidas S, Laufman L, Hutchins L, Dickler M, Tripathy D, Cohen R, DeMichele A, Yocum RC, Osborne CK, Hayes DF, Hortobagyi GN, Winer E, Demetri GD.
University of Texas M.D. Anderson Cancer Center, and Baylor College of Medicine, Houston, Texas 77030, USA. festeva@mdanderson.org

Purpose: Bexarotene is a retinoid X receptor-selective retinoid that has preclinical antitumor activity in breast cancer. We evaluated the efficacy and safety of oral bexarotene in the treatment of patients with metastatic breast cancer. Patients and Methods: The following three groups of patients were treated: hormone-refractory, chemotherapy-refractory, and tamoxifen-resistant patients. Patients in the first two groups were treated with bexarotene alone, whereas the tamoxifen-resistant patients received both tamoxifen and bexarotene. Patients in all groups were randomly assigned to receive bexarotene at either 200 or 500 mg/m(2)/d. Results: One hundred forty-eight patients were randomized; 145 patients were treated. Of 48 hormone-refractory patients, there were two partial responses (6%) and 10 patients with stable disease lasting more than 6 months; of 47 chemotherapy-refractory patients, there were two partial responses (6%) and five patients with stable disease; and of 51 tamoxifen-resistant patients, there was one partial response (3%) and 11 patients with stable disease. All partial responses occurred at the 200-mg/m(2)/d dose. The projected median time to progression across all of the arms was 8 to 10 weeks. There were no drug-related deaths, and only two patients had drug-related serious adverse events. The most common drug-related adverse events were hypertriglyceridemia (84%), dry skin (34%), asthenia (30%), and headache (27%). There were no cases of pancreatitis. Conclusion: The efficacy of bexarotene in patients with refractory metastatic breast cancer is limited. However, it is an oral agent with minimal toxicity and a unique mechanism of action, which produced clinical benefit in approximately 20% of patients. Future efforts should define populations likely to benefit from this agent.

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J Clin Oncol 2003 Mar 15;21(6):991-8
Randomized controlled trial comparing oral doxifluridine plus oral cyclophosphamide with doxifluridine alone in women with node-positive breast cancer after primary surgery.
Tominaga T, Koyama H, Toge T, Miura S, Sugimachi K, Yamaguchi S, Hirata K, Monden Y, Nomura Y, Toi M, Kimijima I, Noguchi S, Sonoo H, Asaishi K, Ikeda T, Morimoto T, Ota J, Ohashi Y, Abe O.
Breast Cancer Center, Toyosu Hospital, Showa University School of Medicine, Tokyo, Japan. t-tominaga@hkg.odn.ne.jp

PURPOSE: We compared the therapeutic usefulness of doxifluridine (5'-DFUR) alone and a combination of 5'-DFUR plus cyclophosphamide (CPM), both of which are considered effective against advanced and recurrent breast cancer, to determine which treatment is more beneficial as postoperative adjuvant chemotherapy. PATIENTS AND METHODS: A total of 1,131 women with node-positive primary breast cancer were randomly assigned after primary surgery to receive 5'-DFUR alone or 5'-DFUR plus CPM. All patients initially received 5'-DFUR in an oral dose of 1,200 mg/d for 4 weeks, starting 4 weeks after surgery. Chemotherapy was then not given for 2 weeks. Patients in the 5'-DFUR group subsequently received five 4-week cycles of treatment consisting of oral 5'-DFUR (1,200 mg/d) for the first 2 weeks and no chemotherapy for the next 2 weeks. Those assigned to the 5'-DFUR plus CPM group also received oral CPM 100 mg/d for the first 2 weeks and no chemotherapy for the next 2 weeks. Women 50 years or older concurrently received 20 mg/d of tamoxifen for 2 years in both groups. RESULTS: Of the 1,088 eligible women, 546 were assigned to receive 5'-DFUR alone and 542 were assigned to receive 5'-DFUR plus CPM. Overall disease-free survival was significantly better in women who received 5'-DFUR plus CPM than in those who received 5'-DFUR alone (log-rank test, P =.021). Toxic effects occurred in 20.0% of patients (109 of 546) in the 5'-DFUR group and 32.3% of patients (175 of 542) in the 5'-DFUR plus CPM group (chi(2) test, P <.001). CONCLUSION: Combination therapy with 5'-DFUR plus CPM is more effective in preventing recurrence than 5'-DFUR alone.

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J Clin Oncol 2003 Mar 15;21(6):976-83
Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer.
Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, Ingle JN, Cooper MR, Hayes DF, Tkaczuk KH, Fleming G, Holland JF, Duggan DB, Carpenter JT, Frei E 3rd, Schilsky RL, Wood WC, Muss HB, Norton L.
University of California at San Francisco, San, Francisco, CA 94143, USA. craig.henderson@accessoncology.com

Purpose: This study was designed to determine whether increasing the dose of doxorubicin in or adding paclitaxel to a standard adjuvant chemotherapy regimen for breast cancer patients would prolong time to recurrence and survival. PATIENTS AND METHODS: After surgical treatment, 3,121 women with operable breast cancer and involved lymph nodes were randomly assigned to receive a combination of cyclophosphamide (C), 600 mg/m(2), with one of three doses of doxorubicin (A), 60, 75, or 90 mg/m(2), for four cycles followed by either no further therapy or four cycles of paclitaxel at 175 mg/m(2). Tamoxifen was given to 94% of patients with hormone receptor-positive tumors. Results: There was no evidence of a doxorubicin dose effect. At 5 years, disease-free survival was 69%, 66%, and 67% for patients randomly assigned to 60, 75, and 90 mg/m(2), respectively. The hazard reductions from adding paclitaxel to CA were 17% for recurrence (adjusted Wald chi(2) P =.0023; unadjusted Wilcoxon P =.0011) and 18% for death (adjusted P =.0064; unadjusted P =.0098). At 5 years, the disease-free survival (+/- SE) was 65% (+/- 1) and 70% (+/- 1), and overall survival was 77% (+/- 1) and 80% (+/- 1) after CA alone or CA plus paclitaxel, respectively. The effects of adding paclitaxel were not significantly different in subsets defined by the protocol, but in an unplanned subset analysis, the hazard ratio of CA plus paclitaxel versus CA alone was 0.72 (95% confidence interval, 0.59 to 0.86) for those with estrogen receptor-negative tumors and only 0.91 (95% confidence interval, 0.78 to 1.07) for patients with estrogen receptor-positive tumors, almost all of whom received adjuvant tamoxifen. The additional toxicity from adding four cycles of paclitaxel was generally modest. Conclusion: The addition of four cycles of paclitaxel after the completion of a standard course of CA improves the disease-free and overall survival of patients with early breast cancer.

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J Clin Oncol 2003 Mar 15;21(6):968-75
Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial.
Nabholtz JM, Falkson C, Campos D, Szanto J, Martin M, Chan S, Pienkowski T, Zaluski J, Pinter T, Krzakowski M, Vorobiof D, Leonard R, Kennedy I, Azli N, Murawsky M, Riva A, Pouillart P; TAX 306 Study Group.
University of California at Los Angeles, CA 90095-7077, USA. jmnabholtz@hotmail.com

PURPOSE: This randomized, multicenter, phase III study compared doxorubicin and docetaxel (AT) with doxorubicin and cyclophosphamide (AC) as first-line chemotherapy (CT) in metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients (n = 429) were randomly assigned to receive doxorubicin 50 mg/m(2) plus docetaxel 75 mg/m(2) (n = 214) or doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2) (n = 215) on day 1, every 3 weeks for up to eight cycles. RESULTS: Time to progression (TTP; primary end point) and time to treatment failure (TTF) were significantly longer with AT than AC (median TTP, 37.3 v 31.9 weeks; log-rank P =.014; median TTF, 25.6 v 23.7 weeks; log-rank P =.048). The overall response rate (ORR) was significantly greater for patients taking AT (59%, with 10% complete response [CR], 49% partial response [PR]) than for those taking AC (47%, with 7% CR, 39% PR) (P =.009). The ORR was also higher with AT in patients with visceral involvement (58% v 41%; liver, 62% v 42%; lung, 58% v 35%), three or more organs involved (59% v 40%), or prior adjuvant CT (53% v 41%). Overall survival (OS) was comparable in both arms. Grade 3/4 neutropenia was frequent in both groups, although febrile neutropenia and infections were more frequent for patients taking AT (respectively, 33% v 10%, P <.001; 8% v 2%, P =.01). Severe nonhematologic toxicity was infrequent in both groups, including grade 3/4 cardiac events (AT, 3%; AC, 4%). CONCLUSION: AT significantly improves TTP and ORR compared with AC in patients with MBC, but there is no difference in OS. AT represents a valid option for the treatment of MBC.

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Eur J Surg Oncol 2003 Mar;29(2):191-7
Towards optimal management of ductal carcinoma in situ of the breast.
Mokbel K.
Brunel Institute of Cancer Genetics, London, SW17 0QT, UK. kefahmokbel@hotmail.com

Ductal carcinoma in situ (DCIS) represents a spectrum of heterogenous disease that accounts for approximately one fifth of all screen-detected breast cancers and is considered as a precursor of invasive breast cancer if left untreated (35-50% risk). DCIS can be treated by total mastectomy with or without immediate breast reconstruction, local excision (LE) plus adjuvant radiotherapy (RT) or LE alone. Total mastectomy is associated with low rates of local recurrence (1.4%) and breast cancer-specific mortality (0.59%). Three recent randomized controlled trials (RCTs) have demonstrated that adjuvant RT after LE of localized DCIS significantly reduces the incidence of local recurrence. However these trials did not identify any subgroups of patients where RT could be safely omitted. Retrospective studies suggest that RT can be safely omitted after adequate LE (margin width > or =1 cm) of small (< 15 mm), non-high grade DCIS not associated with necrosis. Further RCTs are required to validate these retrospective findings, with an emphasis on standardized and meticulous tissue processing and pathological evaluation.The role of adjuvant tamoxifen in the management of DCIS continues to evolve. Formal axillary dissection is not appropriate for DCIS, however, the potential role of the sentinel node biopsy (SNB) in selected high risk cases requires further evaluation. The International Breast Cancer Intervention Study (IBIS-II) trial aims to evaluate the potential role of third generation aromatase inhibitors in postmenopausal women with hormone-sensitive DCIS.Future research will focus on the relevance of gene expression profiling, proteomics, Laser therapy and mammary ductoscopy to the management of DCIS.

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Cancer 2003 Jan 15;97(2):359-66
Sentinel lymph node versus axillary lymph node dissection for early-stage breast carcinoma: a comparison using a utility-adjusted number needed to treat analysis.
Jani AB, Basu A, Heimann R, Hellman S.
Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, Illinois 60637, USA.

BACKGROUND: The current study was performed to compare the value of sentinel lymph node dissection (SND) and axillary lymph node dissection (AND) in improving the utility-adjusted survival for early-stage breast carcinoma patients. METHODS: A number needed to treat (NNT) analysis was used to compare SND with AND. In the NNT equation, 1/(S(SND) - S(AND)), S is the 5-year utility-adjusted survival. A literature review was performed to estimate 1) the prevalence of axillary lymph node disease for early-stage breast carcinoma, 2) the sensitivity and specificity of SND and AND, 3) the 5-year overall survival as a function of axillary lymph node involvement, 4) the risk of arm lymphedema as a function of the intervention performed, and 5) the utility correction (Uc; impairment of quality of life) for arm lymphedema. RESULTS: The NNT method of analysis favored SND over nearly the entire range of parameters with a sign change to a negative value occurring only as Uc becomes very close to unity. This suggests the superiority of the SND approach. Only when there is minimal loss of utility does AND become favored and then only minimally. CONCLUSIONS: Compared with AND, SND improves the utility-adjusted survival in patients with early-stage breast carcinoma. This finding is quite robust and was found to remain constant over a range of values for utility and lymph node prevalence. Copyright 2003 American Cancer Society

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Plast Reconstr Surg 2003 Mar;111(3):1078-83; discussion 1084-6
Surgical treatment of breast cancer in previously augmented patients.
Karanas YL, Leong DS, Da Lio A, Waldron K, Watson JP, Chang H, Shaw WW.
Division of Plastic and Reconstructive Surgery and Surgical Oncology, Revlon/UCLA Breast Center, UCLA Medical Center, Los Angeles, CA, USA. ykaranas@stanford.edu

The incidence of breast cancer is increasing each year. Concomitantly, cosmetic breast augmentation has become the second most often performed cosmetic surgical procedure. As the augmented patient population ages, an increasing number of breast cancer cases among previously augmented women can be anticipated. The surgical treatment of these patients is controversial, with several questions remaining unanswered. Is breast conservation therapy feasible in this patient population and can these patients retain their implants? A retrospective review of all breast cancer patients with a history of previous augmentation mammaplasty who were treated at the Revlon/UCLA Breast Center between 1991 and 2001 was performed. During the study period, 58 patients were treated. Thirty patients (52 percent) were treated with a modified radical mastectomy with implant removal. Twenty-eight patients (48 percent) underwent breast conservation therapy, which consisted of lumpectomy, axillary lymph node dissection, and radiotherapy. Twenty-two of the patients who underwent breast conservation therapy initially retained their implants. Eleven of those 22 patients (50 percent) ultimately required completion mastectomies with implant removal because of implant complications (two patients), local recurrences (five patients), or the inability to obtain negative margins (four patients). Nine additional patients experienced complications resulting from their implants, including contracture, erosion, pain, and rupture. The data illustrate that breast conservation therapy with maintenance of the implant is not ideal for the majority of augmented patients. Breast conservation therapy with explantation and mastopexy might be appropriate for rare patients with large volumes of native breast tissue. Mastectomy with immediate reconstruction might be a more suitable choice for these patients.

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Nat Rev Drug Discov 2003 Mar;2(3):205-13
Tamoxifen: a most unlikely pioneering medicine.
Jordan VC.
The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, 303 East Chicago Avenue, Olson Pavilion 8258, Chicago, Illinois 60611, USA. vcjordan@northwestern.edu

For more than 25 years, tamoxifen has been the gold standard for the endocrine treatment of all stages of oestrogen-receptor-positive breast cancer, and the World Health Organization lists tamoxifen as an essential drug for the treatment of breast cancer. It is estimated that more than 400,000 women are alive today as a result of tamoxifen therapy, and millions more have benefited from palliation and extended disease-free survival. Interestingly, tamoxifen also became the first cancer chemopreventive approved by the Food and Drug Administration (FDA) for the reduction of breast-cancer incidence in both pre- and post-menopausal women at high risk. However, 40 years ago, it was hard to imagine that a non-toxic targeted treatment for breast cancer could be developed at all.

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Presse Med 2003 Jan 25;32(3):134-40
[Ductal carcinomas in situ]
[Article in French]
de Roquancourt A, Cottu PH, Cuvier C, Nowak H, Espie M.
Anatomopathologie, Centre des Maladies du Sein, Oncologie Medicale, Hopital Saint Louis, Paris.

EPIDEMIOLOGY: Presently representing 15 to 30% of new cases of breast cancer, ductal carcinomas in situ do not have specific epidemiological characteristics. The age at which they occur is between 49 and 54 years. DIAGNOSTIC METHODS: The diagnosis is evoked primarily when confronted with an area of micro-calcifications discovered on a mammography. Needle aspiration cytology, useful in cases of palpable abnormalities or infra-clinical masses, is of no interest in isolated micro-calcifications for which surgical biopsy following radiological localisation is the technique of choice. Needle micro-biopsy permits collecting analysable tissue for histological but not cytological examination. Macro-biopsies combine stereotaxic localisation of micro-calcification areas and their excision when isolated. The choice of the method varies depending on the case. FROM AN ANATOMOPATHOLOGICAL POINT OF VIEW: Ductal or intra-galactophoric carcinomas are carcinomas of the glactophores that do not infiltrate the connective tissue. They are defined histologically by architectural and cytological characteristics, which differentiate them from lobular carcinomas in situ. They constitute a group of heterogenic lesions not only morphologically but also histologically and with regard to their progression. THERAPEUTIC MODALITIES: The aim of treatment is to ensure that the patients have a maximum of chances of cure at the cost of the least possible therapeutic consequences. Mastectomy, treatment of choice for many years, is still recommended in certain situations. In other cases, conservative treatment is possible so long as excision of the micro-calcifications is complete on the post-surgical mammography and, in the case of biopsy excision, that healthy margins of at least 10 millimetres exist. Following surgery, there is no sufficient consensus to propose essential recommendations concerning the place of monitoring alone, irradiation or tamoxifen.

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J Clin Oncol 2003 Mar 1;21(5):864-70
Preoperative twice-weekly paclitaxel with concurrent radiation therapy followed by surgery and postoperative doxorubicin-based chemotherapy in locally advanced breast cancer: a phase I/II trial.
Formenti SC, Volm M, Skinner KA, Spicer D, Cohen D, Perez E, Bettini AC, Groshen S, Gee C, Florentine B, Press M, Danenberg P, Muggia F.
Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, NY, USA. silvia.formenti@med.nyu.edu

PURPOSE: Preoperative chemotherapy is the conventional primary treatment in locally advanced breast cancer (LABC). We investigated the safety and efficacy of primary twice-weekly paclitaxel and concurrent radiation (RT) before modified radical mastectomy followed by adjuvant doxorubicin-based chemotherapy. PATIENTS AND METHODS: Stage IIB (T3N0) to III LABC patients were eligible. Primary chemoradiation consisted of paclitaxel, 30 mg/m(2) delivered intravenously for 1 hour twice weekly for a total of 8 to 10 weeks, and concurrent RT (45 Gy at 1.8 Gy/fraction). Modified radical mastectomy was performed at least 2 weeks after completion of chemoradiation or on recovery of skin toxicity. Postoperatively, patients who responded to paclitaxel and RT received four cycles of doxorubicin/paclitaxel, whereas patients who did not respond received doxorubicin/cytoxan. RESULTS: Forty-four patients were accrued. Toxicity from paclitaxel/RT included grade 3 skin desquamation (7%), hypersensitivity (2%), and stomatitis (2%). Postsurgery complications occurred in six patients (14%). The only grade 4 toxicity of postmastectomy chemotherapy was hematologic (10%). Grade 3 toxicities were leukopenia (24%), infection (22%), peripheral neuropathy (17%), arthralgia and pain (17%), stomatitis (12%), fatigue (10%), esophagitis (5%), and nausea (2%). Overall clinical response rate to preoperative paclitaxel and RT was 91%. Thirty-four percent of patients achieved a pathologic response in the mastectomy specimen: 16% pathologic complete responses (clearance of invasive cancer in the breast and axillary contents) and 18% pathologic partial responses (< 10 residual microscopic foci of invasive breast cancer). CONCLUSION: Twice-weekly paclitaxel with concurrent RT is a feasible and effective primary treatment for LABC. Future studies should compare primary chemoradiation to chemotherapy in LABC.

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Sb Lek 2002;103(3):349-57
[Intensive therapy with paclitaxel (Taxol) and cyclophosphamide followed by administration of G-CSF as a mobilization regimen in patients with breast carcinoma and indications for autologous hematopoietic cell transplantation]
[Article in Czech]
Trneny M, Apltauerova M, Mares P, Gasova Z, Hruba A, Jelinek J, Marinov I, Klener P.
1. interni klinika 1. lekarske fakulty Univerzity Karlovy a Vseobecne fakultni nemocnice, U nemocnice 2, 128 08 Praha 2, Czech Republic.

Cyclophosphamide (4 g/m2) and paclitaxel (Taxol) (175, 200 or 250 mg/m2) therapy with subsequent administration of G-CSF (10 micrograms/kg) has been used as intensification and as mobilization therapy for patients with breast cancer. This regimen was used in 19 patients, as part of adjuvant therapy in 14 and as part of therapy of metastatic disease in five. Median number of collected CD34+ cells was 17.5 x 10(6)/kg (2.9-48.1). All patients except one (94.7%) reached minimal required number of CD34+ cells (> or = 3 x 10(6)/kg). Median number of leukapheresis was two. The required number of cells (> or = 3 x 10(6)/kg) was collected in one leukapheresis in 17 out of 19 patients (89.5%) and more than five and 10 x 10(6)/kg CD34+ cells respectively were collected in 14 (73.7%) and 11 (57.9%) patients respectively. No factor significantly influencing the amount of collected cells (except the trend in favour of later year of therapy and large-volume leukapheresis) was identified. Leukopenia gr. 4 was observed in 88.9% of treated patients and febrile neutropenia developed in 46.2% patients. Although the antitumour activity of this chemotherapy was not possible to assess it seems that this intensification could be successfully used as a therapy and as very potent mobilization regimen.

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Forum (Genova) 2002;12(1):64-70
Chemotherapy in the elderly with breast cancer.
Repetto L, Pietropaolo M, Aapro M.
U.O. Oncologia, INRCA, Rome.

The number of elderly women diagnosed with breast cancer by 2025, will increase by 72%. These elderly women do not yet participate in most screening programmes. One notes more favourable biological characteristics of the tumour, including more expression of steroid receptors (oestrogen receptor, progesterone receptor), low proliferative rate, good differentiation, normal p53 and low expression of epidermal growth factor. Elderly breast cancer patients are frequently treated with breast conservation, omitting axillary dissection, radiation therapy and chemotherapy. There is a paucity of data to substantiate that such an approach is better than a more radical one. The efficacy of chemotherapy and guidelines for its use vary by tumour stage and patient age. Drugs like modified anthracyclines, vinorelbine, the taxanes and capecitabine may be changing the paradigm of combination therapy superiority.

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Forum (Genova) 2002;12(1):45-59
Interactions of antioestrogens and aromatase inhibitors.
Schmid P, Possinger K.
Department of Oncology and Hematology, Charite Campus Mitte, Humboldt University Berlin, Germany.

Aromatase inhibitors and antioestrogens have shown substantial activity in primary and advanced breast cancer. Since they exhibit different modes of action, attempts have been made to combine them or to use them sequentially in order to potentially increase their efficacy. In preclinical studies, combined, sequential or alternating treatments with aromatase inhibitors and antioestrogens have failed to provide higher antitumoural activity. There are relevant pharmacokinetic interactions resulting in decreased plasma concentrations of third generation aromatase inhibitors when combined with tamoxifen. Several randomised clinical trials comparing single agent and combined treatment with tamoxifen and aminoglutethimide failed to show any benefit for the combination. Early results of the adjuvant ATAC trial indicate that single agent anastrozole is superior to tamoxifen or the combination of both. Several trials are ongoing which might help to further define the role of sequential or combined treatment with aromatase inhibitors and antioestrogens. However, to date, looking at the current evidence, combined treatment with aromatase inhibitors and antioestrogens does not appear to provide additional benefit compared to single agent treatment.

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Forum (Genova) 2002;12(1):4-15
New cytotoxic agents and molecular-targeted therapies in the treatment of metastatic breast cancer.
Awada A.
Clinique Adjoint, Medical Oncology, Chemotherapy Unit, Jules Bordet Institute, Brussels, Belgium.

Cytotoxic chemotherapy is important for treatment of patients with hormone-insensitive advanced breast cancer. A variety of new cytotoxic agents are promising alone or in combination. The originality, the clinical activity and side effects, as well as the current development status of these agents are reviewed. These agents include the new antimicrotubules (analogues of taxanes and vinorelbine; epothilone derivatives), oral formulations of 5-fluorouracil and other antimetabolites (tomudex, alimta, gemcitabine), liposomal anthracyclines, platinum analogues, topoisomerase I inhibitors and other compounds such as ET-743. Finally, new molecular-targeted therapies of potential interest in the treatment of metastatic breast cancer are reviewed. The growing availability of such biological therapies given alone and mainly in combination with hormonal and chemotherapeutic agents may improve in the near future the outcome of patients with metastatic breast cancer.

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Tumori 2002 Nov-Dec;88(6):470-3
Weekly paclitaxel in metastatic breast cancer patients: a phase II study.
Gori S, Mosconi AM, Basurtol C, Cherubinil R, De Angelis V, Tonato M, Colozza M.
Medical Oncology Division, Policlinico Hospital, Perugia, Italy. oncmedpg@krenet.it

AIMS ANID BACKGROUND: Paclitaxel, a microtubule inhibitor, is one of the most active drugs in metastatic breast cancer. A weekly schedule, at a median dose-intensity of 91 mg/m2, is effective and has less side effects than a 3-week schedule. In this phase II study, we evaluated the toxicity and the activity of weekly 1 hr paclitaxel infusions in metastatic breast cancer patients. STUDY DESIGN: Between February 1999 and February 2001, 26 patients with metastatic breast cancer were treated with weekly paclitaxel (60-90 mg/m2/1 hour iv infusion/weekly). The treatment was planned to continue until disease progression or prohibitive toxicity; in patients with responsive or stable disease, paclitaxel was stopped after 6 months of therapy. RESULTS: At a median follow-up of 18.7 months (range, 6.8-30.8), all patients are assessable for response and toxicity. We obtained 8 partial responses (30.8%), 8 stable disease (30.8%) and 10 disease progression (38.4.%). The overall response was 30.8% (95% CI, 13.1-48.5). The median duration of response was 7.6 months (range, 1.8-12.4); median time to progression was 4.86 months (range, 1.4-12.4); median overall survival was 9.9 months (range, 1.7-29.2+). Treatment was well tolerated. Hematological toxicity was mild and only one patient developed grade 3 anemia. Two patients experienced grade 3 cardiovascular toxicity; both had received anthracycline-based regimens. CONCLUSIONS: In our experience, weekly administration of paclitaxel shows a substantial degree of activity even in pretreated metastatic breast cancer patients. The toxicity profile is favorable.

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Br J Cancer 2003 Feb 24;88(4):491-5
Phase I/II study of gemcitabine plus mitoxantrone as salvage chemotherapy in metastatic breast cancer.
Lorusso V, Crucitta E, Silvestris N, Catino A, Caporusso L, Mazzei A, Guida M, Latorre A, Sambiasi D, D'Amico C, Schittulli F, Calabrese P, De Lena M.
Operative Unit of Medical Oncology, Oncology Institute, Bari, Italy. vitolorusso@inwind.it

The purpose of this study was to determine the maximum-tolerated dose of gemcitabine plus mitoxantrone in women with metastatic breast cancer (MBC) and to evaluate activity and toxicity of this combination in a phase II trial. Sixty-three patients with MBC, previously treated with chemotherapy including anthracycline and/or taxanes, were treated with mitoxantrone 10 or 12 mg m(-2) intravenously on day 1 plus gemcitabine in escalating doses from 600 to 1200 mg m(-2) intravenously on days 1 and 8, every 3 weeks. In phase I, on 23 patients entered on study, dose-limiting toxicity occurred at the dosage of 1200 mg m(-2) gemcitabine and 10 mg m(-2) mitoxantrone, with three out of five patients developing grade 4 neutropenia. In phase II, with gemcitabine administered at 1000 mg m(-2) and mitoxantrone at 10 mg m(-2), 12 (30%) out of 40 assessable patients responded, even if no complete response was obtained. Moreover, stable disease was observed in eight (20%) patients. The median time to treatment failure was 22 weeks (range, 2-33), and median survival was 42 weeks (range, 2-92). Grade 3 and 4 neutropenia were observed in 12 (30%) and one (2.5%) cases respectively; grade 3 thrombocytopenia was observed in two patients (5%), grade 2 mucositis in two patients (5%), grade 3 anaemia in two patients (5%), grade 3 alopecia in one patient (2.5%) and asymptomatic cardiotoxicity in three patients (8%), respectively. In conclusion, the doses of 10 mg m(-2) (day 1) for mitoxantrone and 1000 mg m(-2) for gemcitabine (days 1-8) every 3 weeks resulted active and safe in MBC. Further investigations in less heavily pretreated patients are warranted.

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J Clin Oncol 2003 Feb 15;21(4):588-92
Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193).
Sledge GW, Neuberg D, Bernardo P, Ingle JN, Martino S, Rowinsky EK, Wood WC.
Cancer Pavillion, Indiana University Medical Center, 535 Barnhill Drive, Room RT473, Indianapolis, IN 46202-5112, USA. gsledge@iupui.edu

PURPOSE: Between February 1993 and September 1995, 739 patients with metastatic breast cancer were entered on an Intergroup trial (E1193) comparing doxorubicin (60 mg/m(2)), paclitaxel (175 mg/m(2)/24 h), and the combination of doxorubicin and paclitaxel (AT, 50 mg/m(2) and 150 mg/m(2)/24 h, plus granulocyte colony-stimulating factor 5 mg/kg) as first-line therapy. Patients receiving single-agent doxorubicin or paclitaxel were crossed over to the other agent at time of progression. PATIENTS AND METHODS: Patients were well balanced for on-study characteristics. RESULTS: Responses (complete response and partial response) were seen in 36% of doxorubicin, 34% of paclitaxel, and 47% of AT patients (P =.84 for doxorubicin v paclitaxel, P =.007 for v AT, P =.004 for paclitaxel v AT). Median time to treatment failure (TTF) is 5.8, 6.0, and 8.0 months for doxorubicin, paclitaxel, and AT, respectively (P =.68 for doxorubicin v paclitaxel, P =.003 for doxorubicin v AT, P =.009 for paclitaxel v AT). Median survivals are 18.9 months for patients taking doxorubicin, 22.2 months for patients taking paclitaxel, and 22.0 months for patients taking AT (P = not significant). Responses were seen in 20% of patients crossing from doxorubicin --> paclitaxel and 22% of patients crossing from paclitaxel --> doxorubicin (P = not significant). Changes in global quality-of-life measurements from on-study to week 16 were similar in all three groups. CONCLUSION: (1) doxorubicin and paclitaxel, in the doses used here, have equivalent activity; (2) the combination of AT results in superior overall response rates and time to TTF; and (3) despite these results, combination therapy with AT did not improve either survival or quality of life compared to sequential single-agent therapy.

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Semin Oncol 2002 Dec;29(6 Suppl 18):57-62
Pemetrexed: an active new agent for breast cancer.
O'Shaughnessy JA.
Baylor-Charles A. Sammons Cancer Center, US Oncology, Dallas, TX 75246, USA.

Pemetrexed is a novel antifolate that inhibits three enzymes in the de novo purine and pyrimidine pathways including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. It becomes highly polyglutamated once inside cancer cells, resulting in prolonged intracellular retention and 60-fold greater inhibition of thymidylate synthase than the monoglutamated form. Several phase II and III studies have shown that pemetrexed has significant antitumor activity against a variety of tumor types including mesothelioma, non-small cell lung cancer, and colon, pancreatic, and breast cancers. Pemetrexed appears to provide non-cross-resistant cytotoxic activity against breast cancers that have been treated with anthracyclines, taxanes, and capecitabine. Preclinical studies have suggested that pemetrexed enhances the cytotoxicity of several other important chemotherapeutic agents active against breast cancer including doxorubicin, paclitaxel, cisplatin, and gemcitabine. In vitro studies have shown that pemetrexed treatment synchronizes cancer cells at the G(2)/S interphase, leading to synchronous entry into S phase. Ongoing phase II studies of pemetrexed combinations in breast cancer hope to exploit the cell cycle modulatory effects of this drug as well as its excellent tolerability. Copyright 2002, Elsevier Science (USA). All rights reserved.

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Semin Oncol 2002 Dec;29(6 Suppl 18):30-4
Preclinical and clinical studies with combinations of pemetrexed and gemcitabine.
Adjei AA.
Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA.

The novel antimetabolite pemetrexed inhibits the folate-dependent enzymes thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. This agent is broadly active in a wide variety of solid tumors, including non-small cell lung, breast, bladder, head and neck, and ovarian cancers, as well as mesothelioma. Gemcitabine is a pyrimidine nucleoside antimetabolite that is approved worldwide for the treatment of pancreatic and non-small cell lung cancers, and bladder cancer outside the United States. In addition, gemcitabine is active against a broad range of tumors including breast, ovarian, and other cancers. Preclinical studies have shown cytotoxic synergy when pemetrexed is combined with gemcitabine. Based on these data, a phase I study of this combination was performed that showed striking activity. Phase II studies of this combination are being performed in breast and non-small cell lung cancer. In addition, a phase III study in pancreatic cancer is ongoing. Copyright 2002, Elsevier Science (USA). All rights reserved.

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Oncology 2003;64(2):124-30
Phase II study of concurrent administration of doxorubicin and docetaxel as first-line chemotherapy for metastatic breast cancer.
Aihara T, Takatsuka Y, Itoh K, Sasaki Y, Katsumata N, Watanabe T, Noguchi S, Horikoshi N, Tabei T, Sonoo H, Hiraki S, Inaji H.
Department of Surgery, Kansai Rosai Hospital, Hyogo, Japan. aiharat@kanrou.net

OBJECTIVE: To evaluate the efficacy and toxicity of concurrent administration of doxorubicin and docetaxel, without prophylactic use of granulocyte colony-stimulating factor, as first-line chemotherapy in patients with metastatic breast cancer (MBC). METHODS: This multi-institutional study enrolled 40 women; 37 were assessable for efficacy and all 40 patients were evaluated for toxicity. Treatment consisted of 50 mg/m(2) doxorubicin and 60 mg/m(2) docetaxel on day 1 every 3-4 weeks. RESULTS: Patients received a total of 251 cycles of chemotherapy (median, 5 cycles; range, 1-13 cycles). Of the 37 patients assessable for efficacy, 2 had a complete response and 24 had partial responses, which accounted for a 70% objective response rate (95% confidence interval, 53-84%). The median time to treatment failure was 30.1 weeks (range, 3.3-80.7 weeks). Grade 4 neutropenia was observed in 88% of patients and was the most frequent haematological toxicity. Febrile neutropenia was seen in 40% of patients, but no severe infections were observed. Non-haematological toxicity was generally tolerable. There were 2 grade 4 adverse events, which included 1 bleeding duodenal ulcer and 1 hypersensitivity reaction, but grade 3 episodes were infrequent. None of the patients developed congestive heart failure or asymptomatic decrease of left ventricular ejection fraction to less than 50%. Fluid retention syndrome <or= grade 2 was observed in 25% of patients at a median cumulative dose of docetaxel of 270 mg/m(2). CONCLUSION: Concurrent administration of 50 mg/m(2) doxorubicin and 60 mg/m(2) docetaxel is active with a manageable toxicity profile as first-line chemotherapy for MBC. Copyright 2003 S. Karger AG, Basel

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Eur J Surg Oncol 2003 Feb;29(1):17-9
Does local surgery have a role in the management of stage IV breast cancer?
Carmichael AR, Anderson ED, Chetty U, Dixon JM.
Edinburgh Breast Unit, Western General Hospital, Edinburgh, Scotland, UK. homepac@doctors.org.uk

AIMS: There are no uniformly agreed guidelines regarding the treatment of local breast cancer in patients who have stable metastatic disease. The aim of this study was to define the role of breast surgery in the management of stage IV disease by reviewing the clinical outcome in patients with stage IV disease submitted to surgery in a regional breast cancer unit. METHODS: All patients who underwent breast surgery from 1993 to 1999 and had known metastatic disease or who were diagnosed with metastases within one month of surgery were identified and their clinical outcome was studied using death and local recurrence as end points. RESULTS: Median survival after breast surgery was 23 months. Ten of the 20 patients were alive with no local disease at 20 months mean follow-up. Three of 10 patients who died developed local recurrence and had local disease at the time of death. CONCLUSION: The local surgery does have a role in controlling the primary cancer and controlling local symptoms in a selected group of patients with stable metastatic disease.

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Cancer 2003 Feb 1;97(3 Suppl):880-6
Current and future status of adjuvant therapy for breast cancer.
Coleman RE.
Cancer Research Centre, Yorkshire Cancer Research Academic Unit of Clinical Oncology, Weston Park Hospital, Sheffield, United Kingdom. r.e.coleman@sheffield.ac.uk

Adjuvant systemic treatments have greatly improved the prognosis of women with early breast cancer. Combination chemotherapy and, for patients with oestrogen receptor-positive (ER+) tumours, endocrine treatment has been found to reduce the frequency of relapse and improve survival. New adjuvant strategies include the introduction of taxanes into adjuvant chemotherapy schedules, the use of aromatase inhibitors in place of, or in addition to, tamoxifen, and the use of adjuvant bisphosphonates. Combination chemotherapy has been found to reduce the annual odds of recurrence and death in pre- and postmenopausal women. The benefits, however, are on average less in older patients. Anthracycline-based regimens are more effective than traditional regimens of cyclophosphamide, methotrexate, and fluorouracil (CMF). The benefits of adjuvant cytotoxic and endocrine treatments are additive. There is considerable debate as to the role of taxanes in adjuvant therapy. Improved outcome has been observed in one large trial, especially in those patients with ER-negative tumours. High-dose chemotherapy has not fulfilled its early promise. Ovarian suppression and/or tamoxifen remain the treatments of choice. The annual odds of relapse and death have been reduced by approximately one-third and one-quarter, respectively. Several very large studies are in progress to assess the potential of aromatase inhibitors in the adjuvant setting. Direct comparisons with tamoxifen, as well as switching after several years from tamoxifen to an aromatase inhibitor, are strategies under evaluation. Early results from one of these trials evaluating anastrozole (the Arimidex, Tamoxifen, Alone or in Combination [ATAC] trial) has reported a reduced relapse rate after a median follow-up of 3 years in favour of anastrozole. However, this was at the expense of accelerated bone loss, and strategies to minimise this side effect of aromatase inhibitors are under investigation. Although many studies have indicated that bisphosphonates prevent the development of metastatic bone disease in animals, the clinical role of prophylactic bisphosphonates in early breast cancer is not clearly defined. Three studies with oral clodronate have been published, two of them indicating a protective effect on the development of bone metastases and improved survival, and one suggesting a disadvantage to the use of adjuvant clodronate. Further large adjuvant trials with clodronate and zoledronic acid are in progress. Adjuvant bisphosphonates also have been found to reduce bone loss associated with cancer treatments and preserve skeletal health. It may be possible to replace the current oral regimens for prevention of bone loss with a single annual infusion of the highly potent bisphosphonate zoledronic acid. Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11124

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