Ovarian Cancer Research: 2002-2006  
     
Curr Opin Oncol. 2006 Sep;18(5):507-15.
Intraperitoneal chemotherapy for ovarian cancer.
Hamilton CA, Berek JS.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford Cancer Center, Stanford University School of Medicine, Stanford, California, USA.

PURPOSE OF REVIEW: Intraperitoneal chemotherapy for ovarian cancer is based on sound pharmacological principles and is technically feasible. There is mounting evidence, bolstered by a recent randomized trial, that in certain patients, this route of delivery may be superior to traditional intravenous chemotherapy. This review explores the background and pharmacokinetic principles of intraperitoneal chemotherapy, the recent evidence supporting an intraperitoneal approach, and some of the logistical and technical challenges involved. RECENT FINDINGS: Intraperitoneal chemotherapy has been evaluated in several settings. Most phase I and II data came from second-line treatment of ovarian cancer, and there have been a few series, including one recent phase III trial, exploring intraperitoneal consolidation. The greatest impact among recent studies will be from a large, intergroup phase III trial evaluating intraperitoneal therapy in the front-line setting. This study will probably change the dialogue of standard treatment for optimally cytoreduced, advanced epithelial ovarian cancer. SUMMARY: Based on recent findings, intraperitoneal chemotherapy should be considered for the front-line treatment of women with minimal residual advanced ovarian cancer. Efforts should continue to facilitate the integration of intraperitoneal treatment into mainstream practice, and future trials should be designed to address lingering controversy surrounding this route of treatment.

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J Surg Oncol. 2006 Sep 15;94(4):316-24.
Radical surgery-peritonectomy and intraoperative intraperitoneal chemotherapy for the treatment of peritoneal carcinomatosis in recurrent or primary ovarian cancer.
Rufian S, Munoz-Casares FC, Briceno J, Diaz CJ, Rubio MJ, Ortega R, Ciria R, Morillo M, Aranda E, Muntane J, Pera C.
Department of General Surgery, Reina Sofia University Hospital, Cordoba, Spain.

BACKGROUND AND OBJECTIVES: Advanced ovarian cancer typically spreads in a diffuse intra-abdominal fashion. This characteristic suggests that combined radical surgery and intraperitoneal chemotherapy may be a useful treatment procedure. The purpose of this study was to review patients submitted to surgical debulking and hyperthermic intraoperative intraperitoneal chemotherapy (HIIC) and to evaluate the potential prognostic survival factors for advanced epithelial ovarian cancer in our center. METHODS: A series of patients (N = 33) diagnosed of peritoneal carcinomatosis for epithelial ovarian cancer (stage III) from January 1997 to December 2004 submitted to radical surgery-peritonectomy and HIIC with paclitaxel was included in this study; 19 primary ovarian cancer and 14 recurrent ovarian cancer. RESULTS: Cytoreduction R0 (P = 0.018) and negative lymph nodes (P = 0.005) were covariables for major prognostic survival. Patients with optimal cytoreduction R0 obtained survival rates of 63% at 5 years in recurrent ovarian cancer and 60% in primary ovarian cancer, 71% and 63%, respectively with associated subtotal infra-abdominal peritonectomy, and even better results if negative lymph nodes. CONCLUSIONS: Radical surgery-peritonectomy with HIIQ has been shown to be a surgical procedure with high tolerability, low morbimortality, enhanced survival, and prolonged disease-free interval in patients with peritoneal carcinomatosis so much for recurrent or primary ovarian cancer. J. Surg. Oncol. 2006;94:316-324. (c) 2006 Wiley-Liss, Inc.

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Curr Opin Oncol. 2006 Sep;18(5):488-93.
The management of borderline tumours of the ovary.
Cadron I, Amant F, Van Gorp T, Neven P, Leunen K, Vergote I.
Division of Gynaecological Oncology, Department of Obstetrics and Gynaecology, University Hospitals Leuven, Katholieke Universiteit Leuven, Belgium.

PURPOSE OF REVIEW: The treatment of borderline ovarian tumours has been similar to that for their invasive counterparts for a long time. However, in view of the good prognosis for borderline ovarian tumours, their occurrence in a younger age group and the development of less invasive techniques, the question can be asked as to whether a more conservative treatment is warranted. RECENT FINDINGS: Recent articles discuss the mode of surgery (laparotomy or laparoscopy), the possibility of fertility-sparing surgery, the need for restaging procedures and adjuvant therapy. SUMMARY: The ultimate goal in treating patients with borderline ovarian cancer is defining those patients with bad prognostic factors and risk for recurrence and who consequently require more aggressive therapy. A proper staging procedure is crucial to estimate the risk. Translational research might help identify borderline tumours with poor prognosis. Fertility-sparing surgery is often a good option in young patients with Federation International de Gynecologie et Obstetrie (FIGO) stage I disease or in selected cases with noninvasive implants, since long-term survival does not seem to be negatively influenced by conservative surgery.

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Cancer Treat Rev. 2006 Aug 28; [Epub ahead of print]
Treatment of ovarian cancer using intraperitoneal chemotherapy with taxanes: From laboratory bench to bedside.
De Bree E, Theodoropoulos PA, Rosing H, Michalakis J, Romanos J, Beijnen JH, Tsiftsis DD.
Department of Surgical Oncology, Medical School of Crete University Hospital, P.O. Box 1352, 71110 Herakleion, Greece.

The combination of a taxane, paclitaxel or docetaxel, and a platinum compound has become the systemic chemotherapy of choice for primary ovarian cancer and has demonstrated high efficacy. However, ultimately most patients will die from this disease. Hence, there is a need for even more effective systemic chemotherapy or different treatment strategies. Intraperitoneal chemotherapy with taxanes is such an alternative treatment option. Ovarian cancer is theoretically an attractive malignancy for this regional treatment, because the disease remains largely confined to the peritoneal cavity. The choice of taxanes for this kind of chemotherapy is rational, because of its high activity against ovarian cancer cells and expected favourable pharmacokinetics because of limited absorption from the peritoneal cavity due to their large molecular weight and first-pass effect in the liver. In animal model and human pharmacokinetic studies, very high intraperitoneal drug concentrations and exposure and high peritoneal tumour concentrations were achieved, while systemic drug levels were low. The combination of intraperitoneal chemotherapy with hyperthermia enhances the penetration and cytotoxic activity of many drugs. Although data concerning thermal enhancement of taxane cytotoxicity are inconsistent, experimental studies show that at high locoregional concentrations there seems to be such an effect. Recently, feasibility and efficacy of this treatment have evidently been demonstrated in various clinical studies. A large randomized trial revealed improvement of outcome by intraperitoneal instillation chemotherapy with paclitaxel and cisplatin as first-line treatment. Moreover, promising results have been observed after intraoperative hyperthermic intraperitoneal chemotherapy with docetaxel for recurrent disease.

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Br J Cancer. 2006 Aug 29; [Epub ahead of print]
Randomised study of systematic lymphadenectomy in patients with epithelial ovarian cancer macroscopically confined to the pelvis.
Maggioni A, Benedetti Panici P, Dell'anna T, Landoni F, Lissoni A, Pellegrino A, Rossi RS, Chiari S, Campagnutta E, Greggi S, Angioli R, Manci N, Calcagno M, Scambia G, Fossati R, Floriani I, Torri V, Grassi R, Mangioni C.
1Istituto Europeo di Oncologia, Milan, Italy.

No randomised trials have addressed the value of systematic aortic and pelvic lymphadenectomy (SL) in ovarian cancer macroscopically confined to the pelvis. This study was conducted to investigate the role of SL compared with lymph nodes sampling (CONTROL) in the management of early stage ovarian cancer. A total of 268 eligible patients with macroscopically intrapelvic ovarian carcinoma were randomised to SL (N=138) or CONTROL (N=130). The primary objective was to compare the proportion of patients with retroperitoneal nodal involvement between the two groups. Median operating time was longer and more patients required blood transfusions in the SL arm than the CONTROL arm (240 vs 150 min, P<0.001, and 36 vs 22%, P=0.012, respectively). More patients in the SL group had positive nodes at histologic examination than patients on CONTROL (9 vs 22%, P=0.007). Postoperative chemotherapy was delivered in 66% and 51% of patients with negative nodes on CONTROL and SL, respectively (P=0.03). At a median follow-up of 87.8 months, the adjusted risks for progression (hazard ratio [HR]=0.72, 95%CI=0.46-1.21, P=0.16) and death (HR=0.85, 95%CI=0.49-1.47, P=0.56) were lower, but not statistically significant, in the SL than the CONTROL arm. Five-year progression-free survival was 71.3 and 78.3% (difference=7.0%, 95% CI=-3.4-14.3%) and 5-year overall survival was 81.3 and 84.2% (difference=2.9%, 95% CI=-7.0-9.2%) respectively for CONTROL and SL. SL detects a higher proportion of patients with metastatic lymph nodes. This trial may have lacked power to exclude clinically important effects of SL on progression free and overall survival.British Journal of Cancer advance online publication, 29 August 2006; doi:10.1038/sj.bjc.6603323 www.bjcancer.com.

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Am J Clin Oncol. 2006 Aug;29(4):399-404.
Phase I study of pegylated liposomal doxorubicin in combination with ifosfamide in pretreated ovarian cancer patients.
Bourgeois H, Joly F, Pujade-Lauraine E, Cure H, Guastalla JP, Ferru A, Chabrun V, Chieze S, Tourani JM.
Medical Oncology Unit, CHU de Poitiers, Poitiers, France.

OBJECTIVES: To determine the dose limiting toxicity, the maximum tolerated dose and the recommended dose of pegylated liposomal doxorubicin (PLD) in association with a fixed dose of ifosfamide (IFO) to patients with recurrent, advanced ovarian cancer (AOC). METHODS: Patients with progressing platinum-sensitive or resistant disease were included in 5 dose levels consisting of PLD (25 mg/m2 to 45 mg/m2, day 1) combined with a fixed IFO dose administered as a continuous infusion (1700 mg/m2/d, day 1 to 3) to define the MTD on the basis of acute toxicity during the first 2 cycles, then confirm the MTD, by the evaluation of delayed toxicity (hand-foot syndrome). RESULTS: Forty-eight patients were treated. The MTD was determined in the first 29 patients to be dose level V (45 mg/m2), with 2 cases of febrile neutropenia. The recommended dose (level IV) combines 40 mg/m2 PLD on day 1 and 1700 mg/m2/d IFO day 1 to day 3. The principal toxicity was hematotoxicity (grade 3-4 neutropenia 61.8% of patients, grade 3/4 thrombcytopenia 7.2%, and grade 3/4 anemia 21.8%). Nonhematological toxicity essentially consisted of grade 3/4 nausea and vomiting (14%). Nineteen additional patients were included in levels III (11 patients) and IV (8 patients), to evaluate late-onset toxicity. No hand-foot syndrome was observed in the 48 treated patients, confirming the identification of dose level IV as recommended dose. CONCLUSION: This study regimen presents an acceptable tolerance. The preliminary assessment of efficacy merits confirmation in a phase II study.

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Am J Obstet Gynecol. 2006 Aug;195(2):568-74; discussion 574-6.
Initial chemotherapy followed by surgical cytoreduction for the treatment of stage III/IV epithelial ovarian cancer.
Everett EN, French AE, Stone RL, Pastore LM, Jazaeri AA, Andersen WA, Taylor PT Jr.
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Virginia Health System, Charlottesville, VA 22908-0712, USA. ee6c@virginia.edu

OBJECTIVE: The purpose of this study was to evaluate differences in morbidity, progression-free interval, and survival in women with advanced epithelial ovarian cancer treated with initial chemotherapy versus initial surgery. STUDY DESIGN: All women with epithelial ovarian cancer who were treated surgically at our hospital between January 1, 1995, and January 1, 2003, were eligible; the cases of 200 patients met the criteria and underwent retrospective chart review. RESULTS: Ninety-eight patients (49%) had initial chemotherapy, and 102 patients (51%) had initial surgery. Patients who received initial chemotherapy were more likely to have stage IV disease (initial chemotherapy, 27%, vs initial surgery, 8%; P = .042) and grade 3 disease (initial chemotherapy, 73%, vs initial surgery, 61%; P = .025). Optimal cytoreduction was achieved more often in patients who received initial chemotherapy (initial chemotherapy, 86%, vs initial surgery, 54%; P < .001). Only optimal cytoreduction (P = .022), and not treatment choice (P = .089), had an impact on median survival. CONCLUSION: Initial chemotherapy is a reasonable alternative to initial surgery for the treatment of selected patients with advanced epithelial ovarian cancer.

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Gynecol Oncol. 2006 Aug 2; [Epub ahead of print]
The addition of extensive upper abdominal surgery to achieve optimal cytoreduction improves survival in patients with stages IIIC-IV epithelial ovarian cancer.
Eisenhauer EL, Abu-Rustum NR, Sonoda Y, Levine DA, Poynor EA, Aghajanian C, Jarnagin WR, Dematteo RP, D'Angelica MI, Barakat RR, Chi DS.
Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, MRI-1026, New York, NY 10021, USA.

OBJECTIVES: To determine the survival impact of adding extensive upper abdominal surgical cytoreduction to standard surgical techniques for advanced ovarian cancer. METHODS: The records of all patients with stages IIIC-IV epithelial ovarian cancer who underwent primary surgery at our institution from 1998 to 2003 were reviewed. The cohort was divided into 3 groups. Group 1 patients required extensive upper abdominal surgery, such as diaphragm peritonectomy/resection, resection of parenchymal liver or porta hepatis disease and/or splenectomy with or without distal pancreatectomy, to achieve optimal cytoreduction (residual disease </=1 cm). Group 2 patients were optimally cytoreduced by standard surgical techniques, including hysterectomy, oophorectomy, omentectomy, and bowel resection. Group 3 patients were suboptimally cytoreduced. Primary outcome measures were response to primary chemotherapy, progression-free survival, and overall survival. RESULTS: The cohort of 262 patients was divided as follows: Group 1, 57 patients; Group 2, 122 patients; and Group 3, 83 patients. The median follow-up was 36 months (range, 1-94 months). Frequency of clinical complete response in Groups 1, 2, and 3 was 82%, 78%, and 57%, respectively. The median progression-free survival for Groups 1, 2, and 3 was 24, 23, and 11 months, respectively. Progression-free survival for Groups 1 and 2 were equivalent (P=0.53) and were significantly longer than for Group 3 (P<0.001). The median overall survival was 84 and 38 months for Groups 2 and 3, respectively, and had not been reached for Group 1 by 68 months. Patients in Group 1 had equivalent overall survival to patients in Group 2 (P=0.74) and improved survival over patients in Group 3 (P<0.001). Prognostic factors significant on multivariate analysis included stage, optimal status, and ascites. CONCLUSIONS: Patients requiring extensive upper abdominal procedures to achieve optimal cytoreduction demonstrated a similar initial response, progression-free survival, and overall survival to patients optimally cytoreduced by standard surgical techniques. The presence of bulky upper abdominal disease alone did not appear to indicate poor tumor biology. This initial maximal surgical effort was associated with improved survival in patients who would have otherwise been suboptimally cytoreduced.

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J Natl Cancer Inst. 2006 Aug 2;98(15):1036-45. Comment in: J Natl Cancer Inst. 2006 Aug 2;98(15):1024-6.
Randomized phase III trial of topotecan following carboplatin and paclitaxel in first-line treatment of advanced ovarian cancer: a gynecologic cancer intergroup trial of the AGO-OVAR and GINECO.
Pfisterer J, Weber B, Reuss A, Kimmig R, du Bois A, Wagner U, Bourgeois H, Meier W, Costa S, Blohmer JU, Lortholary A, Olbricht S, Stahle A, Jackisch C, Hardy-Bessard AC, Mobus V, Quaas J, Richter B, Schroder W, Geay JF, Luck HJ, Kuhn W, Meden H, Nitz U, Pujade-Lauraine E; AGO-OVAR; GINECO.
Klinik fur Gynakologie und Geburtshilfe, Campus Kiel, Universitatsklinikum Schleswig-Holstein, Michaelisstr. 16, D-24105 Kiel, Germany. jpfisterer@email.uni-kiel.de

BACKGROUND: The combination of carboplatin and paclitaxel is the standard of care for the treatment of ovarian cancer, yet rates of recurrence and death remain high. We performed a prospective randomized phase III study to examine whether sequential administration of topotecan can improve the efficacy of carboplatin and paclitaxel in first-line treatment of advanced epithelial ovarian cancer. METHODS: A total of 1308 patients with previously untreated ovarian cancer (International Federation of Gynecology and Obstetrics stages IIB-IV) were randomly assigned to receive six cycles of paclitaxel and carboplatin followed by either four cycles of topotecan (TC-Top; 658 patients) or surveillance (TC; 650 patients) on a 3-week per cycle schedule. The primary endpoint was overall survival, and secondary endpoints were progression-free survival, response rate, toxicity, and quality of life. Time-to-event data were analyzed using the Kaplan-Meier method, and a stratified log-rank test was used to compare distributions between treatment groups. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using a Cox proportional hazards model. Categorical data were compared using a stratified Cochran-Mantel-Haenszel test. All statistical tests were two-sided. RESULTS: Median progression-free survival was 18.2 months in the TC-Top arm versus 18.5 months in the TC arm (stratum-adjusted HR = 0.97 [95% CI = 0.85 to 1.10]; P = .688). Median overall survival was 43.1 months for the TC-Top arm versus 44.5 months for the TC arm (stratum-adjusted HR = 1.01 [95% CI = 0.86 to 1.18]; P = .885). At 3 years, overall survival in both arms was 57% (58.5% in the TC arm and 55.7% in the TC-Top arm). Compared with patients in the TC arm, patients in the TC-Top arm had more grade 3-4 hematologic toxic effects (requiring more supportive care) and more grade 3-4 infections (5.1% versus 2.7%; P = .034) but did not have a statistically significant increase in febrile neutropenia (3.3% versus 3.1%; P = .80). Among patients who had measurable disease (TC, n = 147; TC-Top, n = 145), overall (i.e., complete or partial) response was 69.0% (95% CI = 61.4% to 76.5%) in the TC-Top arm and 76.2% (95% CI = 69.3% to 83.1%) in the TC arm (P = .166). CONCLUSIONS: The sequential addition of topotecan to carboplatin-paclitaxel did not result in superior overall response or progression-free or overall survival. Therefore, this regimen is not recommended as standard of care treatment for ovarian cancer.

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BMC Cancer. 2006 Aug 1;6:202.
Safety of a 3-weekly schedule of carboplatin plus pegylated liposomal doxorubicin as first line chemotherapy in patients with ovarian cancer: preliminary results of the MITO-2 randomized trial.
Pignata S, Scambia G, Savarese A, Breda E, Scollo P, De Vivo R, Rossi E, Gebbia V, Natale D, Del Gaizo F, Naglieri E, Ferro A, Musso P, D'Arco AM, Sorio R, Pisano C, Di Maio M, Signoriello G, Annunziata A, Perrone F; MITO Investigators.
Medical Oncology B, National Cancer Institute, Naples, Italy. sandro.pignata@fondazionepascale.it

Free full text at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16882344

BACKGROUND: The MITO-2 (Multicentre Italian Trials in Ovarian cancer) study is a randomized phase III trial comparing carboplatin plus paclitaxel to carboplatin plus pegylated liposomal doxorubicin in first-line chemotherapy of patients with ovarian cancer. Due to the paucity of published phase I data on the 3-weekly experimental schedule used, an early safety analysis was planned. METHODS: Patients with ovarian cancer (stage Ic-IV), aged < 75 years, ECOG performance status <or= 2, were randomized to carboplatin AUC 5 plus paclitaxel 175 mg/m2, every 3 weeks or to carboplatin AUC 5 plus pegylated liposomal doxorubicin 30 mg/m2, every 3 weeks. Treatment was planned for 6 cycles. Toxicity was coded according to the NCI-CTC version 2.0. RESULTS: The pre-planned safety analysis was performed in July 2004. Data from the first 50 patients treated with carboplatin plus pegylated liposomal doxorubicin were evaluated. Median age was 60 years (range 34-75). Forty-three patients (86%) completed 6 cycles. Two thirds of the patients had at least one cycle delayed due to toxicity, but 63% of the cycles were administered on time. In most cases the reason for chemotherapy delay was neutropenia or other hematological toxicity. No delay due to palmar-plantar erythrodysesthesia (PPE) was recorded. No toxic death was recorded. Reported hematological toxicities were: grade (G) 3 anemia 16%, G3/G4 neutropenia 36% and 10% respectively, G3/4 thrombocytopenia 22% and 4% respectively. Non-haematological toxicity was infrequent: pulmonary G1 6%, heart rhythm G1 4%, liver toxicity G1 6%, G2 4% and G3 2%. Complete hair loss was reported in 6% of patients, and G1 neuropathy in 2%. PPE was recorded in 14% of the cases (G1 10%, G2 2%, G3 2%). CONCLUSION: This safety analysis shows that the adopted schedule of carboplatin plus pegylated liposomal doxorubicin given every 3 weeks is feasible as first line treatment in ovarian cancer patients, although 37% of the cycles were delayed due to haematological toxicity. Toxicities that are common with standard combination of carboplatin plus paclitaxel (neurotoxicity and hair loss) are infrequent with this experimental schedule, and skin toxicity appears manageable.

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Eur J Cancer Prev. 2006 Apr;15(2):117-24.
Oral contraceptives and ovarian cancer: an update, 1998-2004.
La Vecchia C.
Istituto di Ricerche Farmacologiche "Mario Negri", 20157 Milan, and Istituto di Statistica Medica e Biometria, Universita degli Studi di Milano, 20133 Milan, Italy.

Over the last two decades, ovarian cancer incidence and mortality for younger generations have been declining in most developed countries, and the decline has been greatest in countries where oral contraceptive (OC) use had spread earlier. The overall estimated protection from cohort and case-control studies is approximately 30% for ever OC users, and increases with duration of use by approximately 5% per year of use to about 50% for long-term (>/=10 years) users. The favourable effect of OC against ovarian cancer risk persists for at least 20 years after OC use has ceased, and it is not confined to any particular type of OC formulation. The reduced risk among OC users is observed in women without or with family history or genetic predisposition to ovarian cancer, and for most histological types of epithelial ovarian cancer, although the pattern of risk is less consistent for mucinous than for other types. The protection of OC on ovarian cancer risk, also in view of its long-term persistence, corresponds to the avoidance of 3000-5000 ovarian cancers (and 2000-3000 deaths) per year in Europe, and a similar figure in North America.

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Cancer. 2006 Mar 29
Guidelines and selection criteria for secondary cytoreductive surgery in patients with recurrent, platinum-sensitive epithelial ovarian carcinoma.
Chi DS, McCaughty K, Diaz JP, Huh J, Schwabenbauer S, Hummer AJ, Venkatraman ES, Aghajanian C, Sonoda Y, Abu-Rustum NR, Barakat RR.
Gynecology Service, Department of Surgery; Memorial Sloan-Kettering Cancer Center, New York, New York.

BACKGROUND: The benefit of cytoreductive surgery for patients with recurrent epithelial ovarian cancer has not been defined clearly. The objective of this study was to identify prognostic factors for survival in patients who underwent secondary cytoreduction for recurrent, platinum-sensitive epithelial ovarian cancer and to establish generally applicable guidelines and selection criteria. METHODS: The authors reviewed all patients who underwent secondary cytoreduction for recurrent epithelial ovarian cancer from 1987 to 2001. Potential prognostic factors were evaluated in univariate and multivariate analyses. RESULTS: In total, 157 patients underwent secondary cytoreduction, and 153 of those patients were evaluable. After secondary cytoreduction, the median follow-up was 36.9 months (range, 0.2-125.6 months), and the median survival was 41.7 months (95% confidence interval, 36.0-47.2 months). For patients who had a disease-free interval prior to recurrence of between 6 months and 12 months, the median survival was 30 months compared with 39 months for patients who had a disease-free interval between 13 months and 30 months and 51 months for patients who had a disease-free interval >30 months (P = .005). For patients who had a single site of recurrence, the median survival was 60 months compared with 42 months for patients who had multiple sites of recurrence and 28 months for patients who had carcinomatosis (P <.001). The median survival for patients who had residual disease that measured </=0.5 cm was 56 months compared with 27 months for patients who had residual disease that measured >0.5 cm (P <.001). On multivariate analysis, disease-free interval (P = .004), the number of recurrence sites (P = .01), and residual disease (P <.001) were significant prognostic factors. CONCLUSIONS: In the authors' analysis of secondary cytoreduction for recurrent epithelial ovarian cancer, a significant survival benefit was demonstrated for residual disease that measured </= 0.5 cm. The disease-free interval and the number of recurrence sites should be used as selection criteria for offering secondary cytoreduction. Cancer 2006. (c) 2006 American Cancer Society.

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Eur J Surg Oncol. 2006 Mar 25; [Epub ahead of print]
The interval from surgery to chemotherapy in the treatment of advanced epithelial ovarian carcinoma.
Rosa DD, Clamp A, Mullamitha S, Ton NC, Lau S, Byrd L, Clayton R, Slade RJ, Kitchener HC, Shanks JH, Wilson G, McVey R, Hasan J, Swindell R, Jayson GC.
Cancer Research UK Department of Medical Oncology, Christie Hospital NHS Trust, 512/1 Wilmslow Road, Withington, Manchester M20 4BX, UK.

BACKGROUND: To study the effect of the interval between surgery and the start of chemotherapy in the treatment of patients with advanced ovarian cancer. METHODS: We stratified patients according to the start of platinum-based chemotherapy in group 1 (within 4 weeks from surgery), group 2 (between 4 and 8 weeks) and group 3 (between 8 and 12 weeks). RESULTS: Three hundred and ninty-four stage III ovarian cancer patients were analysed. In the multivariate analysis there were no differences in survival according to the interval between surgery and chemotherapy among the three groups. The independent prognostic variables were type of procedure (p=0.014), performance status (p=0.040) and post-chemotherapy CA-125 (p<0.0001). CONCLUSIONS: The interval between surgery and chemotherapy does not affect outcome.

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Ann Oncol. 2006 Mar 17; [Epub ahead of print]
High dose chemotherapy with autologous hematopoietic stem cell support for solid tumors other than breast cancer in adults.
Pedrazzoli P, Ledermann JA, Lotz JP, Leyvraz S, Aglietta M, Rosti G, Champion KM, Secondino S, Selle F, Ketterer N, Grignani G, Siena S, Demirer T.
Falck Division of Medical Oncology, Ospedale Niguarda Ca' Granda, Milano, Italy.

Since the early 1980s high dose chemotherapy with autologous hematopoietic stem cell support was adopted by many oncologists as a potentially curative option for solid tumors, supported by a strong rationale from laboratory studies and apparently convincing results of early phase II studies. As a result, the number and size of randomized trials comparing this approach with conventional chemotherapy initiated (and often abandoned before completion) to prove or disprove its value was largely insufficient. In fact, with the possible exception of breast carcinoma, the benefit of a greater escalation of dose of chemotherapy with stem cell support in solid tumors is still unsettled and many oncologists believe that this approach should cease. In this article, we critically review and comment on the data from studies of high dose chemotherapy so far reported in adult patients with small cell lung cancer, ovarian cancer, germ cell tumors and sarcomas.

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Oncology (Williston Park). 2006 Feb;20(2):135-43; discussion 144, 146, 151-2.
Management of cancer in the elderly.
Balducci L.
Division of Geriatric Oncology, Department of Interdisciplinary Oncology, University of South Florida College of Medicine and H Lee Moffitt Cancer Center, Tampa, USA. balducci@moffitt.usf.edu

With the aging of the Western population, cancer in the older person is becoming increasingly common. After considering the relatively brief history of geriatric oncology, this article explores the causes and clinical implications of the association between cancer and aging. Age is a risk factor for cancer due to the duration of carcinogenesis, the vulnerability of aging tissues to environmental carcinogens, and other bodily changes that favor the development and the growth of cancer. Age may also influence cancer biology: Some tumors become more aggressive (ovarian cancer) and others, more indolent (breast cancer) with aging. Aging implies a reduced life expectancy and limited tolerance to stress. A comprehensive geriatric assessment (CGA) indicates which patients are more likely to benefit from cytotoxic treatment. Some physiologic changes (including reduced glomerular filtration rate, increased susceptibility to myelotoxicity, mucositis, and cardiac and neurotoxicity) are common in persons aged 65 years and older. The administration of chemotherapy to older cancer patients involves adjustment of the dose to renal function, prophylactic use of myelopoietic growth factors, maintenance of hemoglobin levels around 12 g/dL, and proper drug selection. Age is not a contraindication to cancer treatment: With appropriate caution, older individuals may benefit from cytotoxic chemotherapy to the same extent as the youngest patients.

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Fut Oncol. 2005 Feb;1(1):7-17.
Role of gemcitabine in cancer therapy.
Cappuzzo F, Toschi L, Finocchiaro G, Bartolini S, Gioia V.
Bellaria Hospital , Division of Medical Oncology, Department of Oncology, Via Altura 3, 40139, Bologna, Italy Tel.: +39 151 622 5655 Fax: +39 151 622 5057 federico.cappuzzo@ausl.bo.it.

Gemcitabine, a pyrimidine nucleoside antimetabolite, is one of the most promising new cytotoxic agents. The drug has shown activity in a variety of solid tumors, and has been approved for the treatment of non-small cell lung cancer, pancreatic, bladder, and breast cancer. Recent data showed that gemcitabine is also active against ovarian cancer. Gemcitabine has a good toxicity profile, with myelosuppression being the most common side effect, while non-hematological events are relatively uncommon. The low toxicity profile makes the drug a valid option for unfit and elderly patients. Due to the synergistic activity with other chemotherapeutic compounds, mainly cisplatinum, several trials have been conducted to evaluate the efficacy and tolerability of gemcitabine in combination with other cytotoxic agents. Current clinical trials are evaluating the role of gemcitabine in combination with new targeted therapies.

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Eur J Gynaecol Oncol. 2006;27(1):25-8.
Clinical outcomes of neoadjuvant chemotherapy and primary debulking surgery in advanced ovarian carcinoma.
Giannopoulos T, Butler-Manuel S, Taylor A, Ngeh N, Thomas H.
Gynaecological Oncology Department, Royal Surrey County Hospital, Guildford, UK.

BACKGROUND: Primary debulking surgery (PDS) and paclitaxel-platinum chemotherapy remains the mainstay of treatment for advanced ovarian cancer. However, there is considerable morbidity and even mortality associated with this approach. The concept of primary chemotherapy followed by interval debulking surgery (IDS) has emerged for advanced stage disease with the aim of improving sensitivity to chemotherapy and improving survival. The purpose of our study was to examine the impact of IDS on clinical outcomes of patients considered unsuitable for PDS and compare them with outcomes of women that had conventional PDS followed by chemotherapy. PATIENTS AND METHODS: A non-randomised prospective cohort study of 35 patients who underwent IDS and 29 patients treated with PDS were included. All patients had Stage IIIC or IV disease. The IDS patients were considered unresectable based on an initial laparoscopy or preoperative computed tomography findings. All patients were treated by the same lead surgeons and received the same regimen of chemotherapy. RESULTS: The median intraoperative blood loss, the incidence of pelvic lymphadenectomies, the median hospital stay and the possibility of admission to the Intensive Care Unit were significantly less in the IDS group. Optimal cytoreduction was higher in the IDS compared to the PDS group, but did not reach statistical significance. CONCLUSIONS: IDS for advanced ovarian cancer may be associated with less morbidity compared to PDS and appears to require less use of hospital resources. If the ongoing randomised studies confirm that IDS does not adversely affect the long-term survival of these patients, morbidity related to ovarian cancer surgery may evolve as a crucial factor for choosing treatment options.

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Int J Gynecol Cancer. 2006 Jan-Feb;16 Suppl 1:79-85.
A phase II study of pegylated liposomal doxorubicin oxaliplatin and cyclophosphamide as second-line treatment in relapsed ovarian carcinoma.
Valerio MR, Tagliaferri P, Raspagliesi F, Fulfaro F, Badalamenti G, Arcara C, Cicero G, Russo A, Venuta S, Guarneri G, Gebbia N.
Operative Unit of Medical Oncology, Department of Oncology, Universita degli Studi di Palermo, Palermo, Italy.

We carried out a phase II nonrandomized study to examine the level of activity of oxaliplatin, pegylated liposomal doxorubicin, and cyclophosphamide in a patient population with relapsed ovarian cancer pretreated with platinum derivatives and paclitaxel. Patients received oxaliplatin (85 mg/m2), pegylated liposomal doxorubicin (30 mg/m2), and cyclophosphamide (750 mg/m2). A total of 49 patients (39 assessable for toxicity and response) were enrolled in this trial. Neutropenia grade 3 was observed in six patients (15%) and anemia grade 3 in one patient (0.2%). Fatigue grade 1-2 occurred in 26 patients (66%), nausea/vomiting grade 1 in 23 patients (58%), and alopecia grade 1-2 in 19 patients (48%). Twenty-one (53%) patients experienced grade 1-2 peripheral neuropathy. The overall response rate was 46% (95% CI 23.6-68.7). Median progression-free survival was 28 weeks (range 12-52 weeks) and median survival was 45 weeks (range 26-136+ weeks). The mean duration of response was 34 weeks (range 16-52 weeks). In platinum-resistant and -refractory ovarian cancer patients, the overall response rate was 37% (CI 95% 14.4-60.8) with a progression-free survival of 28 weeks (range 12-52 weeks) and a median survival of 42 weeks (range 28-84 weeks). This combination chemotherapy is generally well tolerated and is an active second-line regimen against ovarian cancer.

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Expert Rev Anticancer Ther. 2006 Jan;6(1):43-47.
Hormonal therapy in epithelial ovarian cancer.
Rao GG, Miller DS.
Vanderbilt University Medical Center, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, B-1100 MCN, Nashville, TN 37232-2516, USA. gautam.rao@vanderbilt.edu , University of Texas Southwestern Medical Center at Dallas, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, 5323 Harry Hines Blvd, J7.124, Dallas, TX 75390-9032, USA. david.miller@utsouthwestern.edu.

The ovary is an endocrine and end organ. Hormones and their receptors have been associated with ovarian cancer and may be related to its causation. Some data suggest that hormonal therapies may have an effect on ovarian cancer in palliative settings. The most well studied anticancer drugs are tamoxifen, megestrol acetate, medroxyprogesterone acetate, leuprolide acetate, anastrozole and letrozole. Presently, no hormonal therapy is approved by the US FDA for the treatment of any type of ovarian malignancy or is listed as an active agent by any of the authoritative compendia. Owing to the endocrine associations with ovarian cancer, the minimal side effects of hormonal therapy and the demonstrated activity of hormonal therapies in other endocrine organ-associated malignancies, further study of hormonal therapies for ovarian cancer is warranted.

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Gynecol Oncol. 2006 Jan;100(1):27-32.
Intraperitoneal catheter outcomes in a phase III trial of intravenous versus intraperitoneal chemotherapy in optimal stage III ovarian and primary peritoneal cancer: A Gynecologic Oncology Group Study.
Walker JL, Armstrong DK, Huang HQ, Fowler J, Webster K, Burger RA, Clarke-Pearson D.
Department of Obstetrics and Gynecology, University of Oklahoma, PO Box 26901, Oklahoma City, OK 73190, USA.

OBJECTIVES.: To evaluate reasons for discontinuing intraperitoneal (IP) chemotherapy, and to compare characteristics of patients who did versus did not successfully complete six cycles of IP chemotherapy. METHODS.: In a phase III trial, women with optimal stage III ovarian or peritoneal carcinoma were randomly allocated to receive IP therapy (paclitaxel 135 mg/m(2) intravenously (IV) over 24 h, cisplatin 100 mg/m(2) IP day 2, paclitaxel 60 mg/m(2) IP day 8) every 21 days for six cycles. Patients unable to receive IP therapy were treated with the alternate (IV) regimen. Variables compared included surgical procedures prior to enrollment, timing of IP catheter insertion, and primary and contributing reasons for discontinuing IP therapy. RESULTS.: Among 205 eligible patients randomly allocated to the IP arm, 119 (58%) did not complete six cycles of IP therapy. Forty (34%) patients discontinued IP therapy primarily due to catheter complications and 34 (29%) discontinued for unrelated reasons. Hysterectomy, appendectomy, small bowel resection, and ileocecal resection were not associated with failure to complete six cycles. IP therapy was not initiated in 16% of patients who did versus 5% of those who did not have a left colon or rectosigmoid colon resection (P = 0.015). There was no association between timing of catheter insertion and failure to complete IP therapy. CONCLUSIONS.: In this multi-institutional setting, it was difficult to deliver six cycles of IP therapy without complications. There appears to be an association between rectosigmoid colon resection and the inability to initiate IP therapy. Catheter choice, timing of insertion, and how surgical treatment of ovarian cancer influences the successful completion of intraperitoneal chemotherapy require further study.

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Cancer Invest. 2005;23(8):665-70.
Phase I clinical trial of topotecan and pegylated liposomal Doxorubicin.
Garcia AA, Roman L, Muderspach L, O'meara A, Facio G, Edwards S, Burnett A.
Division of Medical Oncology, University of Southern California Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA.

Background: The objective of this study was to determine the feasibility and maximum tolerated dose (MTD) of combination topotecan and pegylated liposomal doxorubicin (PLD) administered in 4- or 3-week cycles in patients with advanced or refractory solid tumors. Patients and Methods: Patients were treated with intravenous topotecan (0.75-1.25 mg/m(2)) for 3 days followed by PLD (25-40 mg/m(2)) on Day 4. The following dose combinations (topotecan/PLD, mg/m(2)) were explored: 0.75/40, 1.0/40, and 1.25/40 every 28 days; and 1.0/25 and 1.0/30 every 21 days. Results: Thirty-two patients were enrolled, and all had received prior chemotherapy. Most (84 percent) patients had ovarian cancer. A total of 157 cycles (median, 4 cycles; range, 1-19 cycles) of chemotherapy were administered. Dose-limiting toxicities were Grade 4 neutropenia and death at dose level 3 (1.25/40 mg/m(2) every 28 days), and neutropenic fever, Grade 3 stomatitis, and Grade 3 peripheral neuropathy (all in one patient) at dose level 5 (1/30 mg/m(2) every 21 days). Myelosuppression was the most common serious toxicity. Twenty-six patients were evaluable for response and 7 (27 percent) had partial responses. All responses were seen in patients with ovarian cancer. Conclusions: This combination is feasible and well tolerated; encouraging activity was observed in heavily pretreated patients with ovarian cancer. The recommended regimens for a Phase II study are topotecan 1.0 mg/m(2) on Days 1-3 followed by PLD 40 mg/m(2) on Day 4 of a 28-day cycle, and topotecan 1.0 mg/m(2) on Days 1-3 and PLD 30 mg/m(2) on Day 4 of a 21-day cycle.

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Gynecol Oncol. 2005 Dec 19; [Epub ahead of print]
Feasibility study comparing docetaxel-cisplatin versus docetaxel-carboplatin as first-line chemotherapy for ovarian cancer.
Minagawa Y, Kigawa J, Kanamori Y, Itamochi H, Terakawa N, Okada M, Kitada F.
Department of Obstetrics and Gynecology, Tottori Prefectural Central Hospital, 730 Ezu, Tottori 680-0901, Japan.

OBJECTIVE.: To determine the feasibility of docetaxel-cisplatin combination therapy compared with docetaxel-carboplatin combination therapy as first-line chemotherapy for patients with ovarian cancer. METHODS.: Fifty patients with International Federation of Gynecology and Obstetrics stage Ic-IV ovarian cancer who underwent primary surgery were randomly assigned to receive treatment with docetaxel-cisplatin (n = 23) or docetaxel-carboplatin (n = 27). Docetaxel 70 mg/m(2) and cisplatin 60 mg/m(2) or carboplatin to an area under the curve of 5 were administered consecutively on Day 1 of a 3-week cycle, for 3 cycles in patients with stage Ic-II cancer and for over 5 cycles in patients with stage III-IV cancer. Patients were evaluated for treatment-related toxicity in each cycle using the National Cancer Institute Common Toxicity Criteria version 2.0. RESULTS.: Five patients (2 in the docetaxel-cisplatin arm and 3 in the docetaxel-carboplatin arm) discontinued the treatment at the end of the second course of chemotherapy because of apparent disease progression; however, no patients came off the protocol therapy because of treatment-related toxicity. Overall, 103 cycles of docetaxel-cisplatin treatment and 130 cycles of docetaxel-carboplatin treatment were delivered. The major toxicity was neutropenia in both regimens. The total incidence of grades 3 and 4 neutropenia was 83% (19/23) in the docetaxel-cisplatin arm and 96% (26/27) in the docetaxel-carboplatin arm. The incidence of grade 4 neutropenia was significantly lower in the docetaxel-cisplatin arm [39% (9/23) versus 74% (20/27)]. CONCLUSION.: Docetaxel-cisplatin combination therapy may be feasible as first-line chemotherapy for patients with ovarian cancer.

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Best Pract Res Clin Obstet Gynaecol. 2005 Dec 16; [Epub ahead of print]
Prevention of ovarian cancer.
Hanna L, Adams M.
Clinical Oncology Department, Velindre Hospital, Velindre Road, Whitchurch, Cardiff CF14 2TL, UK.

Ovarian cancer is the leading cause of death from gynaecological malignancy. The incidence is high in the Western world. The incidence of ovarian cancer is reduced by pregnancy, lactation, the oral contraceptive pill and tubal ligation. Lifestyle factors are important in the aetiology of ovarian cancer and current evidence suggests the risk can be reduced by eating a diet rich in fruit and vegetables, taking regular exercise, avoiding smoking, avoiding being overweight and avoiding long-term use of hormonal replacement therapy (HRT). Familial ovarian cancer is responsible for about 10% of ovarian cancer cases. Strategies available to high-risk women include screening (covered elsewhere) and prophylactic salpingo-oophorectomy. The precise role of chemoprevention for high-risk women in the form of the oral contraceptive pill is unclear.

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Cancer Treat Rev. 2005;31 Suppl 4:S29-37.
Gemcitabine in patients with ovarian cancer.
Poveda A.

Standard first-line treatment of ovarian cancer (OC) consists of platinum-taxane combined chemotherapy. However, this regimen only cures about 25% of women with OC. Phase II studies have shown that platinum-gemcitabine doublet and platinum-taxane-gemcitabine triplet regimens are active first-line chemotherapy in advanced OC, with overall response rates (ORR) above 55%. Several phase III studies of gemcitabine-based doublet and triplet chemotherapy in OC are currently underway. Preliminary data show that these regimens are well-tolerated, with manageable haematological toxicity, and the efficacy results are eagerly awaited. Gemcitabine is also active as second-line monotherapy in women with recurrent OC, and studies combining gemcitabine with paclitaxel, docetaxel, liposomal doxorubicin or topotecan resulted in higher ORR than gemcitabine alone. Gemcitabine-cisplatin and gemcitabine-carboplatin are active in women with platinum-resistant recurrent OC suggesting in vivo synergy between these two classes of drug. These studies show that gemcitabine-based chemotherapy may have an important role as second-line treatment in women with platinum-resistant OC. Gemcitabine combinations are also highly recommended as they avoid the problems of neurotoxicity and alopecia seen with other regimens. In order to respect the quality of life of women with recurrent OC, assessment of prognostic factors is recommended so that the most appropriate chemotherapy can be administered.

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J Obstet Gynaecol Res. 2005 Dec;31(6):556-61.
Surgical indications for combined partial rectosigmoidectomy in ovarian cancer.
Takahashi O, Sato N, Miura Y, Ogawa M, Fujimoto T, Tanaka H, Sato H, Tanaka T.
Department of Obstetrics and Gynecology, Akita University School of Medicine, Akita, Japan.

Abstract Aim: To evaluate surgical indications for combined partial rectosigmoidectomy in ovarian cancer with direct invasion of the rectum and sigmoid colon or dissemination into the pouch of Douglas. Methods: Subjects comprised 25 patients with ovarian cancer who underwent primary surgery and rectosigmoidectomy between 1990 and 2002 at our hospital. Federation of Obstetrics and Gynecology staging of tumors was II (n = 6), III (n = 17) or IV (n = 2). The histologic type was serous adenocarcinoma (n = 18), clear cell adenocarcinoma (n = 4), and others (n = 3). Bowel resection was performed during primary surgery in 18 patients, and after neoadjuvant chemotherapy (NAC) in seven patients. Cumulative survival rate was compared between NAC and non-NAC groups. Patients were divided into three groups based on extent of surgical resection to compare survival rates: no residual tumor (n = 19); maximum residual tumor diameter <1 cm (n = 5); and maximum residual tumor diameter >/=1 cm (n = 1). Results: Cumulative 5-year survival was 41.3% for all patients. Cumulative 5-year survival in the 18 patients who underwent bowel resection during primary surgery was 62.2%, compared to 13.9% in the seven patients who underwent bowel resection after NAC. Cumulative 5-year survival based on extent of surgical resection was: no residual tumor, 60.8%; residual <1 cm, 0%; and residual >/=1 cm, 0%. Cumulative 5-year survival for patients with complete tumor resection (no residual tumor), excluding clear cell adenocarcinoma, was 79.5%. Conclusion: In ovarian cancer with direct invasion of the rectum or sigmoid colon or dissemination into the pouch of Douglas, complete tumor resection with rectosigmoidectomy during primary surgery is associated with good clinical outcomes.

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Int J Gynecol Cancer. 2005 Nov-Dec;15 Suppl 3:233-40.
What is the role of dose-dense therapy?
van der Burg ME, van der Gaast A, Vergote I, Burger CW, van Doorn HC, de Wit R, Stoter G, Verweij J.
Department of Medical Oncology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.

The introduction of paclitaxel/platinum combination chemotherapy and (interval) debulking surgery has significantly improved the prognosis of patients with ovarian cancer. Yet, many patients die of drug-resistant disease. Second-line chemotherapy may result in prolonged secondary remissions with alleviation of symptoms and improvement of quality of life. The response to second-line chemotherapy is strongly related to platinum sensitivity. More than 60% of platinum-sensitive patients respond to a re-challenge with platinum-containing chemotherapy. In platinum-resistant patients, on the contrary, the response rate to a re-challenge with 3-weekly platinum or any nonplatinum chemotherapy is less than 20%. The response to dose-dense weekly platinum-based regimens ranged from 48% to 64% in platinum-resistant patients. Moreover, the majority of the patients responded within 8 weeks after the start of the treatment. The progression-free survival ranged from a median of 5 months in a study using cisplatin/etoposide, to 11 months in a study with paclitaxel/carboplatin. The median survival was 11-15 months. The outpatient weekly paclitaxel/carboplatin regimen, with paclitaxel at a dose of 90 mg/m(2) and carboplatin at area under the curve 4, seems similarly effective and is better tolerated. Dose-dense weekly paclitaxel/carboplatin is an effective and well-tolerated therapy for platinum-sensitive, as well as platinum-resistant tumors. Responses to therapy are observed within 8 weeks in the majority of the patients. Whether a weekly regimen indeed is more effective than 3-weekly paclitaxel/carboplatin needs to be answered in a randomized study.

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Int J Gynecol Cancer. 2005 Nov-Dec;15 Suppl 3:226-32.
"Dose dense" chemotherapy in ovarian cancer.
Vasey PA.
School of Medicine, University of Queensland, Herston, Queensland, Australia. paul_vasey@health.qld.gov.au

In essence, dose densification is "accelerated therapy" (a commonly used phrase in radiotherapeutics) and is a form of dose intensification because the amount of drug per unit time (dose intensity = mg/m(2)/week) is increased. There is general consensus that increasing platinum dose intensity in ovarian carcinoma has not been proven despite a dozen or more randomized trials evaluating up to twofold increases in dose intensity. Few randomized trials in ovarian carcinoma have compared weekly "dose dense" chemotherapy with more conventional dosing schedules although there are plenty of phase II studies. In these, dose densification of single agent therapy, for some drugs at least, appears to be relatively well tolerated, with encouraging levels of activity in patients purportedly refractory to the same agents when scheduled in the standard way. However, many studies ostensibly evaluating "dose density" do not actually evaluate this entity, but actually split the standard 3-weekly dose into weekly fragments thus maintaining the same dose intensity. Furthermore, as the aim of treatment in recurrent ovarian cancer is palliation, weekly treatments are less convenient, are probably less cost effective, and have different dose-limiting toxicities. This article will review the clinical data supporting dose density as a therapeutic maneuver in ovarian cancer.

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Int J Gynecol Cancer. 2005 Nov-Dec;15 Suppl 3:222-3.
Epirubicin/paclitaxel/carboplatin (TEC) vs paclitaxel/carboplatin (TC) in first-line treatment of ovarian cancer FIGO stages IIB-IV. Results of a randomized AGO-GINECO GCIG Intergroup phase III trial.
Pujade-Lauraine E, Bois A, Goupil A, Rochon J, Mobus V, Weber B, Olbricht S, Nitz U, Warm M, Richter B.
Departement d'Hematologie et d'Oncologie Medicale, Hopital Hotel-Dieu, Paris, France.

A randomized phase III trial was conducted in patients with advanced ovarian cancer FIGO IIB-IV in order to determine whether epirubicin (E) in addition to paclitaxel (T) and carboplatin (C) will increase survival in comparison to TC alone. The rationale of this study was based not only on the evidence of activity of free and liposomal anthracylins in patients who have been pretreated with the platinum-paclitaxel regimen but also on the evidence of meta-analyses performed before the taxane era of a 7% improvement in survival when doxorubicin was added as the third agent in first-line treatment. In addition, there were some reports suggesting a synergistic activity between paclitaxel and anthracylins in patients with ovarian cancer in relapse. Between November 1997 and February 2000, 1282 patients were randomized to receive six cycles of either T 175 mg/m(2) 3 h iv + C area under curve 5 (according to the Calvert formula) + E 60 mg/m(2) iv (TEC) or TC at same doses, both in 3-week intervals. Patients were stratified per centre and into one of two strata according to FIGO stage and residual tumor size: stratum I includes patients with FIGO IIB-IIIC and residual tumor < or =1 cm and stratum II patients with FIGO IIB-IIIC and residual tumor >1 cm or FIGO IV. The primary end point was overall survival (OS). Secondary end points included toxicity, response to treatment, quality of life, and progression-free survival (PFS). Median follow-up at the time of analysis was 51.9 months. The whole population is available for PFS and OS analysis. A total of 1264 patients received at least one cycle of treatment and are evaluable for toxicity. Patient characteristics are well balanced between the two arms with respect to median age, performance status, FIGO stage, histology, and stratification, with less than one third of the patients suboptimally debulked. The three-drug combination induced a markedly higher myelotoxicity resulting in increased demand on supportive care. Grade 3/4 febrile neutropenia occurred in 5.5% patients in TEC and in 1.3% patients in TC (P < 0.0001) and infection occurred in 8.7% in TEC and 3.1% in TC (P < 0.0001). Addition of E induced more grade 3/4 nausea (6.9% vs 3.3%, P= 0.004), emesis (6.4% vs 2.8%, P= 0.002), and mucositis (1.8% vs 0.2%, P= 0.004) but did not increase cardiac or other nonhematologic toxicity. The increased toxicity of TEC compared to TC was associated with a higher rate of course delay (12.7% vs 8.9%) and dose reduction (4.7% vs 2.0); mean dose effectively received by patients of each of the drugs included in the TEC triplet, however, was close to that planned (epirubicin, 58.8 mg/m(2); paclitaxel, 171.2 mg/m(2); carboplatin, area under curve 4.9). In addition, the percentage of patients receiving at least the six planned cycles was similar in the TEC and TC arms (86.6% vs 88.8%). Of 353 patients with measurable disease, response data were available from 295 patients, 137 in the TEC arm and 158 in the TC arm. The TEC regimen was associated with 73.7% clinically complete and partial responses, the TC regimen with 70.3% (ns). At the time of this analysis, 968 progressive diseases have been diagnosed and 732 patients have died. Median PFS for patients with/without E was 18.4 months (95% CI, 16.2-20.2 months) vs 17.9 months (95% CI, 16.3-19.7 months), corresponding to a hazard ratio of 0.94 (95% CI, 0.83-1.07). Patients in stratum I showed a slightly but still not significantly better PFS after TEC as compared to TC, whereas patients in stratum II showed virtually no difference. Median OS for all patients was 42.7 months (95% CI: 39.6-47.0) with a median OS of 41 months (95% CI, 38.2-46.1 months) for patients treated with TC and 45.8 months (95% CI, 39.9-49.6 months) for those treated with TEC, corresponding to a hazard ratio of 0.93 (95% CI, 0.83-1.07). The addition of E to TC did not result in significantly superior PFS and OS but induced more toxicity and costs.

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Int J Gynecol Cancer. 2005 Nov-Dec;15 Suppl 3:212-20.
Standard treatment in advanced ovarian cancer in 2005: the state of the art.
Bookman MA.
Division of Medical Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. michael.bookman@fccc.edu

What are standards? The oncology community expends considerable effort to review the results from definitive treatment studies and define recommendations for future studies, as well as standards of care for the community and patients who are not participating in clinical trials. This is a thoughtful and well-intentioned process but subject to considerable bias due to limitations in the data and/or their interpretation. While ovarian cancer is highly responsive to platinum-based therapy after initial cytoreductive surgery, there is a substantial risk of recurrence, which is accompanied by the emergence of drug-resistant disease. Better treatments with improved long-term outcomes are needed. From this perspective, standards can help to provide a baseline for assessing gaps in our current knowledge and defining priorities for future clinical trials. While not an exhaustive review, this study will focus on key clinical concepts that are guiding ovarian cancer research and treatment.

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Int J Gynecol Cancer. 2005 Nov-Dec;15 Suppl 3:199-205.
What is the role of conservative primary surgical management of epithelial ovarian cancer: the United States experience and debate.
Monk BJ, Disaia PJ.
Department of Obstetrics and Gynecology, Chao Family Comprehensive Cancer Center, University of California Irvine, Medical Center, Orange, California 92868, USA. bjmonk@uci.edu

Certification in Gynecologic Oncology and creation of the Society of Gynecologic Oncologists in the United States have led to the development of a specialty with individuals capable of performing complex abdominal and pelvic operations in the management of epithelial ovarian carcinoma. These operations can be divided into two types. 1) A staging operation to assess the extent of disease through careful palpation, histologic and cytologic assessment of all peritoneal surfaces along with removal of the uterus, ovaries and fallopian tubes, omentum, together with a bilateral pelvic and aortic lymphadenectomy. Such information allows the clinician to determine prognosis and if postoperative adjuvant therapy is indicated. 2) A debulking operation designed to resect or reduce the size of metastatic lesions as well as to remove the primary tumor including a bilateral salpingo-oophorectomy. This operation is designed to improve survival and cure. In spite of this apparently clear paradigm, there has been a steady debate as to the apparent justification of these operations, especially when the former is performed in a women who has not completed her childbearing and especially when the latter requires "ultraradical" procedures. Many feel that the pendulum is now swinging toward fertility-sparing surgery among young women with early invasive cancers and toward either neoadjuvant chemotherapy or less than ultraradical debulking among women with advanced ovarian cancer. The purpose of this study is not to provide an exhaustive review but rather to outline this debate and focus on the American experience with conservative surgery in the management of epithelial ovarian carcinoma.

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Int J Gynecol Cancer. 2005 Sep-Oct;15(5):830-5.
Palliative care for intestinal obstruction in recurrent ovarian cancer: a multivariate analysis.
Mangili G, Aletti G, Frigerio L, Franchi M, Panacci N, Vigano R, DE Marzi P, Zanetto F, Ferrari A.
Division of Gynecology and Obstetrics, University "Vita e Salute," S. Raffaele Hospital, Milano, Italy.

Bowel obstruction is the most common complication in patients with ovarian cancer. Management of this situation is controversial. The aim of our retrospective study was to determine the best approach for managing bowel obstruction in recurrent ovarian cancer. A retrospective analysis of data on 47 patients with intestinal obstruction by ovarian cancer was performed. Twenty-seven patients were submitted to surgery, with 21 intestinal procedures performed, 2 gastrostomy tubes placed, and 4 patients deemed inoperable. Twenty patients were managed medically with Octreotide (mean dosage of 0.48 mg/day), of which 1 patient required a nasogastric tube. Age, performance status, diagnosis of tumor to occlusion time, obstruction site, previous chemotherapy or radiotherapy, presence of ascites, or palpable masses were the variables analyzed. Student's t-test and Pearson chi-square test were used to compare the two different groups of treatment (surgical vs medical therapy). Disease-free-survival curves were plotted according to the Kaplan-Meier method and analyzed by the log-rank test. Cox's proportional hazards model was used for multivariate analysis. Values less than or equal to 0.05 were considered significant. The mean age of the patients was 58.7 years. Perioperative mortality and morbidity were both 22%. All patients died with minimal distress. Performance status results were significantly different between the patients submitted to surgery and patients treated with Octreotide (P= 0.03). No significant differences were found in the other variables analyzed. In multivariate analysis, only type of treatment emerges as a strong predictor of poor outcome (P < 0.001). Both surgery and Octreotide therapy are able to control distressing symptoms in end-stage ovarian cancer. Survival was significantly longer in the surgical group, and surgical palliation should be considered first in patients with good performance status.

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Int J Gynecol Cancer. 2005 Sep-Oct;15(5):811-6.
Quality of life assessments in epithelial ovarian cancer patients during and after chemotherapy.
LE T, Hopkins L, Fung Kee Fung M.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Ottawa, Ottawa, Ontario, Canada.

To study the immediate and long-term effects of chemotherapy on quality of life (QoL) of advanced ovarian cancer patients. All consecutive patients undergoing chemotherapy for metastatic ovarian cancer and those presenting for follow-up post chemotherapy were recruited. Participants were asked to fill out a short QoL questionnaire (Functional Assessment Cancer Therapy-Ovarian) during each clinic visit. Two-factor analysis of variance analyses were used to examine the effects of chemotherapy treatment and current disease status on QoL scores. Ninety-four patients on chemotherapy and 159 follow-up patients participated. Patients on chemotherapy for recurrent disease had a significantly worsened overall, emotional, and ovarian cancer-specific concerns QoL scores compared to those receiving first-line chemotherapy. There were favorable significant differences between those on follow-up compared to those on chemotherapy in the mean overall QoL scores and in the means of physical, functional, and concern scores. There were significant differences favoring patients with complete response compared to those with partial response or progressive disease in the mean overall QoL scores as well as the physical, emotional, functional, and concern domains mean scores. There were improvements in most QoL measures after completion of chemotherapy. Complete disease remission remained important in maintaining improved QoL.

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Int J Gynecol Cancer. 2005 Sep-Oct;15(5):793-8.
Efficacy and tolerability of lower-dose topotecan in recurrent ovarian cancer: a retrospective case review.
Mitchell SK, Carson LF, Judson P, Downs LS Jr.
Department of Obstetrics, Gynecology, and Women's Health, University of Minnesota Medical School, Minneapolis, Minnesota.

Topotecan (1.5 mg/m(2)/day for 5 consecutive days of a 21-day cycle) is an established recurrent ovarian cancer treatment, but myelosuppression can be dose limiting. This study evaluates the activity and tolerability of low-dose topotecan in our clinical experience. Case records were reviewed for patients with recurrent ovarian cancer in first through third relapse. Eligible patients had received >/=2 cycles of </=1.25 mg/m(2) topotecan. Adverse events were evaluated using laboratory and clinical evaluation data. Twenty-seven eligible patients, most with advanced disease, received a total of 209 cycles (median, six cycles). Grade 3 or 4 hematologic toxicities during 184 cycles in 24 assessed patients were neutropenia, leukopenia, thrombocytopenia, and anemia in 35%, 28%, 36%, and 11% of cycles, and 21, 19, 16, and 10 patients, respectively. Only four grade 4 toxicities occurred: anemia (one) and thrombocytopenia (three). Myelosuppression was reversible, noncumulative, and manageable. Moreover, nonhematologic toxicity was generally mild to moderate, and the only two grade 3 events were constipation and deep vein thrombosis. Low-dose topotecan was active in this setting. Lower-dose topotecan is generally well tolerated and active in patients with pretreated ovarian cancer. Prospective clinical trials of low-dose topotecan in recurrent ovarian cancer are warranted.

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Int J Gynecol Cancer. 2005 Sep-Oct;15(5):770-5.
Primary chemotherapy and adjuvant tumor debulking in the management of advanced-stage epithelial ovarian cancer.
LE T, Faught W, Hopkins L, Fung Kee Fung M.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Ottawa, Ottawa, Ontario, Canada.

The aim of this article was to review the experience with neoadjuvant chemotherapy and interval surgical debulking in patients with metastatic epithelial ovarian cancer. A retrospective chart review was carried out to identify patients treated with neoadjuvant platinum/Taxol chemotherapy and interval debulking. Cox regression modeling was used to identify significant predictors of progression-free interval. The Kaplan-Meier method was used to estimate the survival statistic for the study group. Sixty-one patients were identified after being treated with neoadjuvant chemotherapy and interval debulking surgeries. All surgeries were performed after three cycles of platinum/Taxol combination chemotherapy. Eighty percent of patients had a residual disease status of 2 cm or less after surgery. Suboptimal debulking was statistically associated with tumor involvement of the upper abdominal organs (P < 0.001) and nonnormalization of CA125 before surgery (P= 0.03). The perioperative complication rate was 7%. At a mean follow-up time of 19 months, 77% of patients were still alive. Cox regression modeling identified the microscopic tumor residual status as the only significant predictor of progression-free interval. The estimated median survival for the group was 41.70 months (95% confidence interval = 13.84-69.56 months). Neoadjuvant chemotherapy with interval debulking surgery appeared to be safe and feasible in patients with metastatic epithelial ovarian carcinoma.

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Gynecol Oncol. 2005 Sep 6; [Epub ahead of print]
Ovarian cancer surgical resectability: Relative impact of disease, patient status, and surgeon.
Aletti GD, Gostout BS, Podratz KC, Cliby WA.
Department of Obstetrics and Gynecology, Mayo Clinic and Foundation, Rochester, MN 55905, USA.

OBJECTIVES.: Currently, we are unable to predict which patients are most likely to undergo successful debulking of ovarian cancer. We investigated the impact of clinical and surgical-pathologic factors at the time of initial exploration on the ability to achieve optimal cytoreduction. METHODS.: All consecutive patients with IIIC epithelial ovarian cancer operated at Mayo Clinic between 1994 and 1998 were included. The following pre- and intraoperative factors were included as dichotomous variables: age, ASA, CA125, ascites volume, carcinomatosis, diaphragm and mesentery involvement, and tendency of the operating surgeon (defined by the performance of radical procedures in more vs. less than 50% of patients operated). Pearson chi(2) test and logistic regression analysis were used for statistical analysis. RESULTS.: ASA, ascites, carcinomatosis, diaphragmatic tumor, mesentery involvement, and surgeon tendency all significantly correlated with residual disease (RD) in univariate analysis. However, only ASA, carcinomatosis and surgeon were independently associated with optimal RD. The subset of patients having ASA 3 or 4 and carcinomatosis comprised a high-risk group with just 46% achieving optimal RD overall. Even within this high-risk group, the rate of optimal cytoreduction ranged from 67% to 42% dependent upon surgeon tendency to employ radical procedures. CONCLUSIONS.: High-risk factors such as patient condition and extent of disease impact the ability to achieve optimal RD. However, this is greatly influenced by surgical effort. Models to predict optimal surgical outcomes based only on tumor and patient characteristics will be highly practice-dependent: thus, their utility in selecting patient for non-traditional primary approach to ovarian cancer must be looked at cautiously.

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Clin Oncol (R Coll Radiol). 2005 Sep;17(6):399-411.
Epithelial ovarian cancer: a review of current management.
Guppy AE, Nathan PD, Rustin GJ.
Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, Middlesex, UK.

Epithelial ovarian cancer is the most lethal gynaecological cancer among women worldwide, with 6000 new cases diagnosed in the UK each year. Most women present with advanced disease, but, despite a good initial response to treatment, most relapse. The overall 5-year survival rate is 46%, although this drops to about 13% in women with advanced disease. Transvaginal ultrasound and the tumour marker CA125 are being investigated for screening in ongoing randomised trials. Treatment of ovarian cancer is dependent on clinical stage, and should always be managed within a multidisciplinary team. Most cases will require a pelvic clearance and adjuvant chemotherapy. Current guidelines by the National Institute of Clinical Excellence (NICE) recommend that first-line chemotherapy should include a platinum-based regimen with or without paclitaxel. Relapsed ovarian cancer is incurable; however, chemotherapy can improve quality of life and survival. Gene therapy, immunotherapy and signal transduction inhibitors are all potential future therapies, and are being investigated in ongoing clinical research. In this paper we review the literature on the epidemiology, pathology, clinical features and the current treatment options in epithelial ovarian cancer.

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J Clin Oncol. 2005 Sep 1;23(25):5943-9.
Phase I trial of bortezomib and carboplatin in recurrent ovarian or primary peritoneal cancer.
Aghajanian C, Dizon DS, Sabbatini P, Raizer JJ, Dupont J, Spriggs DR.
Developmental Chemotherapy Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA. aghajanc@mskcc.org

PURPOSE: To determine the maximum-tolerated dose, pharmacodynamics, and safety of the combination of bortezomib and carboplatin in recurrent ovarian cancer. PATIENTS AND METHODS: Fifteen patients were treated with a fixed dose of carboplatin (area under the curve [AUC] 5) and increasing doses of bortezomib (0.75, 1, 1.3, and 1.5 mg/m2/dose). Patients must have received upfront chemotherapy and up to two prior chemotherapy regimens for recurrent disease. Neurologic evaluation was performed at baseline and after every two cycles by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group neurotoxicity questionnaire and examination by an attending neurologist. All patients received carboplatin alone in cycle 1 to establish baseline pharmacodynamics for nuclear factor-kappa B (NF-kB). Starting with cycle 2, patients were treated with carboplatin on day 1 and bortezomib on days 1, 4, 8, and 11. RESULTS: Diarrhea, rash, neuropathy, and constipation (with colonic wall thickening on computed tomography) were dose-limiting toxicities, occurring in the two patients treated at the 1.5 mg/m2/dose level. The Functional Assessment of Cancer Therapy/Gynecologic Oncology Group neurotoxicity questionnaire was helpful in guiding the need for dose reductions. Neurotoxicity was manageable through six cycles, with appropriate dose reductions. Carboplatin had no effect on bortezomib pharmacodynamics as measured by percent inhibition of the 20S proteasome. Bortezomib decreased carboplatin-induced NF-kB. The overall response rate to this combination was 47%, with two complete responses (CR) and five partial responses, including one CR in a patient with platinum-resistant disease. CONCLUSION: The recommended phase II dose of bortezomib administered in combination with carboplatin (AUC 5) is 1.3 mg/m2/dose.

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Semin Oncol. 2005 Aug;32(4 Suppl 6):4-8.
Gemcitabine and Carboplatin in second-line ovarian cancer.
Ozols RF.
Fox Chase Cancer Center, Philadelphia, PA.

Most patients with advanced ovarian cancer achieve a clinical complete remission following cytoreductive surgery and chemotherapy with paclitaxel plus carboplatin. However, a majority of these patients will ultimately recur, and second-line treatment for this group of patients is an important aspect of management of this disease as well as an area of active clinical investigation. Until recently, for patients with platinum-sensitive ovarian cancer (more than 6-month disease-free interval), chemotherapy with single-agent carboplatin was frequently recommended. However, two recent prospective randomized trials have shown that combination chemotherapy produces higher response rates and improvement in progression-free survival compared with treatment with single-agent carboplatin. One trial compared treatment with paclitaxel plus a platinum compound with re-treatment with platinum, and a second trial compared carboplatin plus gemcitabine re-treatment against carboplatin in patients with platinum-sensitive recurrent ovarian cancer. Both trials showed a 3-month improvement in progression-free survival in patients treated with the combination, as well as acceptable toxicity. In the absence of a prospective randomized trial comparing these two regimens in patients with platinum-sensitive recurrent ovarian cancer, the choice of which combination to use may depend on toxicity considerations.

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World J Surg Oncol. 2005 Aug 31;3:57.
Neoadjuvant chemotherapy versus primary surgery in advanced ovarian carcinoma.
Hegazy MA, Hegazi RA, Elshafei MA, Setit AE, Elshamy MR, Eltatoongy M, Halim AA.
Surgical Oncology department, Mansoura University, Mansoura, Egypt. mhegazy68@yahoo.com.

BACKGROUND: Patients with advanced ovarian cancer should be treated by radical debulking surgery aiming at complete tumor resection. Unfortunately about 70% of the patients present with advanced disease, when optimal debulking can not be obtained, and therefore these patients gain little benefit from surgery. Neoadjuvant chemotherapy (NACT) has been proposed as a novel therapeutic approach in such cases. In this study, we report our results with primary surgery or neoadjuvant chemotherapy as treatment modalities in the specific indication of operable patients with advanced ovarian carcinoma (no medical contraindication to debulking surgery). PATIENTS AND METHODS: A total of 59 patients with stage III or IV epithelial ovarian carcinomas were evaluated between 1998 and 2003. All patients were submitted to surgical exploration aiming to evaluate tumor resectability. Neoadjuvant chemotherapy was given (in 27 patients) where optimal cytoreduction was not feasible. Conversely primary debulking surgery was performed when we considered that optimal cytoreduction could be achieved by the standard surgery (32 patients). RESULTS: Optimal cytoreduction was higher in the NACT group (72.2%) than the conventional group (62.4%), though not statistically significant (P = 0.5). More important was the finding that parameters of surgical aggressiveness (blood loss rates, ICU stay and total hospital stay) were significantly lower in NACT group than the conventional group. The median overall survival time was 28 months in the conventional group and 25 months in NACT group with a P value of 0.5. The median disease free survival was 19 months in the conventional group and 21 months in NACT group (P = 0.4). In multivariate analysis, the pathologic type and degree of debulking were found to affect the disease free survival significantly. Overall survival was not affected by any of the study parameters. CONCLUSION: Primary chemotherapy followed by interval debulking surgery in select group of patients doesn't appear to worsen the prognosis, but it permits a less aggressive surgery to be performed.

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Ann Oncol. 2005 Jul;16(7):1116-1122. Epub 2005 May 31.
Paclitaxel plus carboplatin versus paclitaxel plus alternating carboplatin and cisplatin for initial treatment of advanced ovarian cancer: long-term efficacy results: a Hellenic Cooperative Oncology Group (HeCOG) study.
Aravantinos G, Fountzilas G, Kosmidis P, Dimopoulos MA, Stathopoulos GP, Pavlidis N, Bafaloukos D, Papadimitriou C, Karpathios S, Georgoulias V, Papakostas P, Kalofonos HP, Grimani E, Skarlos DV.
'Agii Anargiri' Cancer Hospital, Athens.

Background: We compared the combination plus Carboplatin plus paclitaxel, which is considered the treatment of choice for initial chemotherapy of advanced ovarian cancer (AOC) with a regimen combining alternating carboplatin and cisplatin plus paclitaxel. The two platinum derivatives have been previously combined as they are not totally cross-resistant and as they share no overlapping toxicities. Patients and methods: Patients with AOC, after the initial cytoreductive surgery were randomized to either 6 courses of paclitaxel at 175 mg/m(2) as 3h infusion plus Carboplatin at 7 AUC (Arm A) or Paclitaxel at the same dose plus Carboplatin again at 7 AUC for cycles 1,3,5, while for cycles 2,4,6 Cisplatin at 75 mg/m(2) substituted for Carboplatin (Arm B). Results: 247 patients are analyzed. Significant differences were not found, both in terms of PFS (38 vs 39 months, p=0.95) and overall survival (40.6 vs 38.6 months, p=0.79). There was not also difference in 5-year survival rate (35% vs 39%) or 5-year PFS rate (23% vs 28%). Age >60, PS 2, stage IV disease and presence of residual disease were adversely related to the overall survival. Conclusion: Both regimens are well tolerated and effective. Alternating cisplatin with carboplatin does not improve the results compared with the standard combination.

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Gynecol Oncol. 2005 Jul;98(1):59-62.
Consolidation therapy with weekly paclitaxel infusion in advanced epithelial ovarian cancer and primary peritoneal cancer:
An extended follow-up.
Skinner EN, Boruta DM, Gehrig PA, Boggess JF, Fowler WC Jr, Van Le L.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, NC 27599, USA.

OBJECTIVE.: To determine the impact of weekly paclitaxel consolidation on progression-free survival (PFS) of women undergoing treatment for ovarian cancer. METHODS.: All women with advanced epithelial ovarian or primary peritoneal carcinoma, treated with paclitaxel consolidation therapy from August 1997 to March 2002, were identified. Patients received weekly paclitaxel infused at a median dose of 80 mg/m(2) (range: 60-80 mg/m(2)) for a maximum of 12 weeks. A chart review was performed to assess disease status and chemotherapy-related toxicities. PFS was calculated from the date of initiation of induction chemotherapy until the date of documented disease recurrence. RESULTS.: 31 women received paclitaxel consolidation therapy over the study period (29 stage III and 2 stage IV). 24 women had epithelial ovarian carcinoma and 7 were diagnosed with primary peritoneal carcinoma. The median PFS was 27 months (range: 12-62 months). The overall 2-year survival was 94%, where 17 women (55%) were without evidence of disease and 12 (39%) were alive with disease. The median follow-up was 41 months (range: 15-77 months). Over 337 weeks of consolidation therapy, 1 patient experienced Grade 3 neuropathy and 1 patient developed Grade 3 neutropenia. CONCLUSION.: Consolidation therapy with weekly paclitaxel infusion is a well-tolerated regimen that resulted in a median PFS of 27 months in women who obtained a complete clinical response following induction therapy. Given the lack of side effects and the potential for extending the PFS of those treated, a prospective randomized study of weekly paclitaxel should be considered.

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Gynecol Oncol. 2005 Jul;98(1):39-44.
Quality of life assessment during adjuvant and salvage chemotherapy for advance stage epithelial ovarian cancer.
Le T, Hopkins L, Fung Kee Fung M.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Ottawa, Ottawa General Hospital, 501 Smyth Road, Room 8130, Ottawa, Ontario, Canada K1H 8L6.

OBJECTIVES.: This report assessed the quality of life of ovarian cancer patients undergoing adjuvant and salvage chemotherapy treatment. METHODS.: All epithelial ovarian cancer patients requiring chemotherapy to manage their disease were recruited from university based gynecologic oncology clinics. Quality of life was measured using the FACT-O (Functional Assessment of Cancer Therapy-Ovarian module version 4) questionnaire. Descriptive statistics and two-way analysis of variance were used to compare the effect on the mean quality of life scores with respect to the indications of chemotherapy and best radiologic response. Any P value of less than 0.10 was considered worthy of interest. RESULTS.: Ninety-three patients participated. In the adjuvant setting, there was a trend towards better quality of life with better response to therapy. In patients with a first recurrence, complete response to therapy clearly had a beneficial effect on overall quality of life compared to stable or partial response. There was no significant quality of life difference between those with partial response versus stable disease in a first recurrent setting. In patients with more than one recurrence, no large change in overall quality of life was observed across the range of tumor responses. CONCLUSION.: Chemotherapy is beneficial to improve quality of life of ovarian cancer patients. Differential effect of tumor response status on quality of life at different treatment phases requires further investigations.

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Gynecol Oncol. 2005 Jul;98(1):134-40.
A multicenter phase II study of gemcitabine, paclitaxel, and cisplatin in chemonaive advanced ovarian cancer.
Gupta SK, John S, Naik R, Arora R, Selvamani B, Fuloria J, Ganesh N, Awasthy BS.
Dharamshila Cancer Hospital, Vasundhara Enclave, Delhi 110096, India.

OBJECTIVES: The objectives of this multicenter phase II study were to evaluate the effects of gemcitabine-paclitaxel-cisplatin combination chemotherapy on response rate, survival, and toxicity in patients with advanced epithelial ovarian cancer (AEOC). METHODS: Chemonaive AEOC patients with bidimensionally measurable disease or an elevated serum cancer antigen 125 level received cisplatin (70 mg/m(2)) on day 1 and paclitaxel (80 mg/m(2)) and gemcitabine (1000 mg/m(2)) on days 1 and 8, every 3 weeks. RESULTS: Between October 2000 and September 2001, 46 patients were enrolled. Sixteen patients underwent debulking surgery prior to chemotherapy. In 45 evaluable patients, overall response rate was 64.4% (7 CR and 22 PR). Median time-to-progression was 13.4 months (95% CI, 9.6-17.4 months); median progression-free survival was 12.3 months (95% CI, 8.8-15.6 months); median overall survival was 26.0 months (95% CI, 18 months-not reached); and 1-year survival was 74% (95% CI, 60-88%). The relative dose intensities of gemcitabine, paclitaxel, and cisplatin were 81.4%, 80.2%, and 89.8%, respectively. Grade 3/4 neutropenia was the predominant hematologic toxicity observed (73.9% of patients) followed by grade 3/4 leukopenia (56.5%), anemia (45.7%), thrombocytopenia (23.9%), and febrile neutropenia/neutropenic sepsis (26.1%). The predominant grade 3 nonhematologic toxicities were alopecia (43.5%) and diarrhea (19.6%). Grade 4 nonhematologic toxicities were nausea/vomiting, constipation, and uremia (2.2% each). Two treatment-related deaths occurred (neutropenic sepsis and uremia). CONCLUSION: Gemcitabine-paclitaxel-cisplatin combination chemotherapy is active with manageable toxicity in chemonaive patients with advanced ovarian cancer and should be explored in larger phase III trials.

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Int J Radiat Oncol Biol Phys. 2005 Jun 17; [Epub ahead of print]
Intraoperative radiation therapy in recurrent ovarian cancer.
Yap OW, Kapp DS, Teng NN, Husain A.
Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Stanford University School of Medicine, Stanford, CA, USA.

PURPOSE: To evaluate disease outcomes and complications in patients with recurrent ovarian cancer treated with cytoreductive surgery and intraoperative radiation therapy (IORT). METHODS AND MATERIALS: A retrospective study of 24 consecutive patients with ovarian carcinoma who underwent secondary cytoreduction and intraoperative radiation therapy at our institution between 1994 and 2002 was conducted. After optimal cytoreductive surgery, IORT was delivered with orthovoltage X-rays (200 kVp) using individually sized and beveled cone applications. Outcomes measures were local control of disease, progression-free interval, overall survival, and treatment-related complications. RESULTS: Of these 24 patients, 22 were available for follow-up analysis. Additional treatment at the time of and after IORT included whole abdominopelvic radiation, 9; pelvic or locoregional radiation, 5; chemotherapy, 6; and no adjuvant treatment, 2. IORT doses ranged from 9-14 Gy (median, 12 Gy). The anatomic sites treated were pelvis (sidewalls, vaginal cuff, presacral area, anterior pubis), para-aortic and paracaval lymph node beds, inguinal region, or porta hepatitis. At a median follow-up of 24 months, 5 patients remain free of disease, whereas 17 patients have recurred, of whom 4 are alive with disease and 13 died from disease. Five patients recurred within the radiation fields for a locoregional relapse rate of 32% and 12 patients recurred at distant sites with a median time to recurrence of 13.7 months. Five-year overall survival was 22% with a median survival of 26 months from time of IORT. Nine patients (41%) experienced Grade 3 toxicities from their treatments. CONCLUSIONS: In carefully selected patients with locally recurrent ovarian cancer, combined IORT and tumor reductive surgery is reasonably tolerated and may contribute to achieving local control and disease palliation.

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Expert Opin Pharmacother. 2005 May;6(5):743-54.
Treatment options in the management of ovarian cancer.
Kikuchi Y, Kita T, Takano M, Kudoh K, Yamamoto K.
Department of Obstetrics and Gynecology, National Defence Medical College, Tokorozawa, Saitama 359-8513, Japan. QWL04765@nifty.ne.jp

The standard regimen used as primary chemotherapy of ovarian cancer is combination chemotherapy using paclitaxel and carboplatin. The main objective of first-line chemotherapy is to induce complete response. Although most cases respond to the initial chemotherapy, many cases relapse within 3 years. Such relapsed and persistent cases become resistant to first-line chemotherapy and require second-line chemotherapy. Objectives of such a second-line chemotherapy are to obtain disease palliation to cease disease progression. Meanwhile, consolidation or maintenance chemotherapy may be added to prevent or inhibit disease relapse for patients with advanced disease after induction of complete remission by a primary chemotherapy. When the unresectable tumour is presumed by primary surgery, neoadjuvant chemotherapy may be selected. Recently, conventional cytotoxic anticancer drugs containing paclitaxel have been shown to be capable of inhibiting angiogenesis. The notion of 'redefining' chemotherapeutic drugs has been recognised; thus, continuous low-dose chemotherapy -- so-called metronomic chemotherapy -- has been approved as a new concept. Many new molecular-targeted therapies became available for clinical cancer therapy. The explosion of new molecular targets and the development and application of many powerful technologies should accelerate the discovery of innovative molecular therapeutics. Understanding the molecular mechanisms will help to clarify the pathways in ovarian cancer development and help to identify new therapeutic and diagnostic targets. These are exciting times for new drug development and the treatment of cancer. Cautious optimism should prevail for all investigators involved in translating these exciting new biological findings into new pharmacological agents for treatment of cancer.

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Expert Opin Emerg Drugs. 2005 May;10(2):413-24.
Emerging drugs for ovarian cancer.
Kelland LR.
Antisoma Research Laboratories, St Georges Hospital Medical School, Cranmer Terrace, London, SW17 0QS, UK. lloyd@antisoma.com

Because most patients presenting with advanced ovarian cancer are not curable by surgery alone, chemotherapy represents an essential component of treatment. The disease may be considered as chemosensitive, as in around three-quarters of patients major (complete) responses are seen to initial treatment with the platinum-containing drugs cisplatin and carboplatin either used alone or in combination with the taxane, paclitaxel. However, only 15-20% of patients experience long-term remission as tumours often become resistant. The probability of achieving a second response depends on the duration of remission after first-line therapy: if this is < 6 months (considered as platinum resistant) second responses are uncommon and usually short-lived; if this is > 6, and especially if > 12 months (platinum sensitive), responses may be seen in about a quarter of patients, to the same drugs as used first line or to drugs such as pegylated liposomal doxorubicin, topotecan and hexamethylmelamine (all three are approved in this setting by the FDA). Gemcitabine, oral etoposide, docetaxel and oxaliplatin also show some activity either in sequential addition to existing approved of first-line therapy (as with gemcitabine) or as second-line therapy. However, there is an urgent unmet clinical need for new drugs capable of prolonging survival either by increasing long-term remission rates and/or duration as first-line treatment or to improve on outcomes of second-line treatment. Strategies currently being exploited in clinical trials include attempts to deliver more killing selectively to tumours (e.g., intraperitoneal administration of cisplatin or radiolabelled monoclonal antibodies), agents designed to target drug resistance mechanisms (e.g., TLK-286 activated by glutathione transferase), agents targeting proteins/receptors shown to be selectively expressed in the disease (e.g., monoclonal antibodies recognising CA-125 or HER1; small molecules targeting HER1 such as gefitinib) and disrupting established tumour vasculature (e.g., 5,6-dimethyl xanthenone 4-acetic acid). At the pre-clinical level, agents being developed to target the phosphatidylinositol 3 kinase/AKT/mTOR pathway, and K-Ras inhibitors, may offer efficacy in the future.

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Crit Rev Oncol Hematol. 2005 May 9; [Epub ahead of print]
Consolidation and maintenance treatments for patients with advanced epithelial ovarian cancer in complete response after first-line chemotherapy: A review of the literature.
Gadducci A, Cosio S, Conte PF, Genazzani AR.
Department of Procreative Medicine, Division of Gynecology and Obstetrics, University of Pisa, Via Roma 56, Pisa 56127, Italy.

Most patients with advanced epithelial ovarian cancer experience objective responses to paclitaxel/platinum-based chemotherapy, but responses are generally short-lived and the clinical outcome is still unsatisfactory. Therefore, the strategy to consolidate and to prolong the duration of response is very attractive. Different consolidation or maintenance treatments have been attempted, such as whole abdomen radiotherapy, intraperitoneal chromic phosphate, radioimmunotherapy, intraperitoneal chemotherapy, high-dose chemotherapy with haematopoietic support, prolonged administration of the first-line regimen, second-line single-agent chemotherapy, and biological agents. Clinical studies have given conflicting, inconclusive, and generally disappointing results. A recent US randomised trial appeared to show that the prolonged administration of single-agent paclitaxel (175mg/m(2) every 3 weeks) significantly improved the progression-free survival of complete responders to paclitaxel/platinum-based chemotherapy. Alternative less toxic, and probably more effective schedules of administration of chemotherapy (i.e. weekly paclitaxel) might assure a better balance between quality of life and anti-tumor activity in patients previously exposed to chemotherapy.

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Oncol Rep. 2005 Apr;13(4):559-83.
Aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs in cancer prevention: A critical review of non-selective COX-2 blockade (Review).
Harris RE, Beebe-Donk J, Doss H, Doss DB.
The Ohio State University College of Medicine and Public Health, 320 West 10th Avenue, Columbus, OH 43210-1240, USA. harris.44@osu.edu.

We comprehensively reviewed the published scientific literature on non-steroidal anti-inflammatory drugs (NSAIDs) and cancer and evaluated results based upon epidemiologic criteria of judgment: consistency of results, strength of association, dose response, molecular specificity, and biological plausibility. Sufficient data from 91 epidemiologic studies were available to examine the dose response of relative risk and level of NSAID intake for ten human malignancies. Dose response curves were fitted by exponential regression. Results showed a significant exponential decline in the risk with increasing intake of NSAIDs (primarily aspirin or ibuprofen) for 7-10 malignancies including the four major types: colon, breast, lung, and prostate cancer. Daily intake of NSAIDs, primarily aspirin, produced risk reductions of 63% for colon, 39% for breast, 36% for lung, and 39% for prostate cancer. Significant risk reductions were also observed for esophageal (73%), stomach (62%), and ovarian cancer (47%). NSAID effects became apparent after five or more years of use and were stronger with longer duration. Observed protective effects were also consistently stronger for gastrointestinal malignancies (esophagus, stomach, and colon). Results for pancreatic, urinary bladder, and renal cancer were inconsistent. Initial epidemiologic studies of malignant melanoma, Hodgkin's disease, and adult leukemia also found that NSAIDs are protective. A few studies suggest that ibuprofen has stronger anticancer effects than aspirin, particularly against breast and lung cancer. Overexpression of cyclooxygenase-2 (COX-2) and increased prostaglandin biosynthesis correlates with carcinogenesis and metastasis at most anatomic sites. Preclinical investigations provide consistent evidence that both selective and non-selective NSAIDs effectively inhibit chemically-induced carcinogenesis of epithelial tumors. This review provides compelling and converging evidence that regular intake of NSAIDs that non-selectively block COX-2 protects against the development of many types of cancer.

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J Natl Cancer Inst Monogr. 2005;(34):43-7.
Fertility-sparing surgery for malignancies in women.
Gershenson DM.
Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center-Unit 1362, P.O. Box 301439, Houston, TX 77230-1439. dgershen@mdanderson.org.

Never before have women with newly diagnosed gynecologic malignancies had more options for preservation of fertility. Girls or women of childbearing age with several ovarian cancer subtypes have a high probability of unilateral ovarian involvement, and, thus, may be candidates for fertility-sparing surgery with preservation of a contralateral normal ovary and uterus. These subtypes include ovarian tumors of low malignant potential, malignant ovarian germ cell tumors, and ovarian sex cord-stromal tumors. For women with invasive epithelial ovarian cancer who have early-stage disease, fertility-sparing surgery may be an option. In some cases, fertility-sparing surgery may be followed by postoperative chemotherapy. For women with invasive cervical cancer, fertility-sparing surgery may be possible. Options include conization alone for stage IA(1) or IA(2) disease, radical trachelectomy with stage IA(2) or IB disease, or ovarian transposition for women undergoing chemoradiation. Non-operative options, such as hormonal therapy, may be considered for women with early-stage, low-grade endometrial cancer. For all women of childbearing age with gynecologic malignancies, in vitro fertilization techniques or cryopreservation of ovarian tissue may be an option prior to definitive treatment.

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J Clin Oncol. 2005 Mar 20;23(9):1867-74.
Trabectedin for women with ovarian carcinoma after treatment with platinum and taxanes fails.
Sessa C, De Braud F, Perotti A, Bauer J, Curigliano G, Noberasco C, Zanaboni F, Gianni L, Marsoni S, Jimeno J, D'Incalci M, Dall'o E, Colombo N.
Southern Europe New Drugs Organization Foundation, Via Visconti di Modrone 12, 20100 Milano, Italy. marsonis@sendo-org.it

PURPOSE: To assess the efficacy and toxicity of the marine-derived alkaloid trabectedin (ET-743) in patients with advanced ovarian cancer refractory to or experiencing disease relapse after platinum- and taxane-based chemotherapy. PATIENTS AND METHODS: Fifty-nine patients from four institutions either resistant (n = 30) or sensitive (n = 29) to prior platinum and taxanes were treated with a 3-hour infusion of trabectedin every 3 weeks. Patients were monitored weekly for toxicity and restaged every two cycles for response. Response was assessed according to Response Evaluation Criteria in Solid Tumors Group. RESULTS: The peer-reviewed objective response rate in platinum-sensitive patients was 43% (95% CI, 23% to 65%) with an estimated median time to progression of 7.9 months (95% CI, 7.5 to 14.1 months); in platinum-resistant patients two partial responses were observed. Responses were durable for up to 12.9 months (median, 5 months). The predominant toxicities at the recommended dose of 1,300 microg/m(2) were neutropenia, asthenia, and self-limited increase of aminotransferases never requiring treatment interruption. CONCLUSION: Trabectedin administered as a 3-hour infusion at 1,300 microg/m(2) is a safe new drug with promising activity in relapsed ovarian cancer, showing a 43% objective response rate in patients with platinum-sensitive disease, which favorably compares with other salvage treatments and warrants additional development either alone or in combination.

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Expert Rev Anticancer Ther. 2005 Feb;5(1):139-47.
Role of chemotherapy in the management of epithelial ovarian cancer.
Reed NS, Sadozye AH.
Beatson Oncology Centre, Western Infirmary, Glasgow G11 6NT, UK.

The management of ovarian cancer continues to provide major challenges and debates about optimal treatment. For first-line therapy there remain discussions about optimal chemotherapy for early disease, the use of taxanes as standard for advanced newly diagnosed patients, whether there is a definite role for neoadjuvant chemotherapy and the question of maintenance treatment. For relapsed disease, the management hinges around the distinction between platinum-sensitive and -resistant cancer, and the recent AGO-2.5 and ICON-4 studies suggest that treating with carboplatin and paclitaxel or carboplatin and gemcitabine is recommended. Intraperitoneal chemotherapy remains an enigma with at least three studies showing survival advantage; however, there has been no move to incorporate it into standard management of those patients who achieve complete remission after first-line chemotherapy. Finally, neoadjuvant chemotherapy prior to debulking surgery is the subject of several ongoing clinical trials and may turn out to be one of the most important developments since the concept of interval debulking surgery was established and proven in Europe.

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Expert Rev Anticancer Ther. 2005 Feb;5(1):87-96.
Monoclonal antibody therapy of ovarian cancer.
Nicodemus CF, Berek JS.
Unither Pharmaceuticals, Inc., 15 Walnut Street, Suite 300, Wellesley Hills, MA 02481-2101, USA. cnicodemus@unither.com.

Despite advances in understanding and treatment, ovarian cancer remains a major cause of cancer mortality worldwide. Debulking surgery and paclitaxel/carboplatin chemotherapy induce good initial responses in most patients, although most cases of advanced disease are not controlled. Monoclonal antibodies hold promise as a potential incremental advance for the treatment of the disease. Antibodies can be used to stimulate the immune response, target tumor-specific receptors to induce antibody-dependent cellular cytotoxicity or interfere with biologic pathways. They can also be used to deliver therapeutic radioisotopes to malignant cells. Oregovomab is in Phase III clinical trials as a consolidation treatment post front-line therapy to trigger tumor-specific cellular immunity. Bevacizumab, which blocks vascular endothelial growth factor, will be entering Phase III as an adjuvant to front-line chemotherapy with a direct effect on angiogenesis. Additional immunostimulating, immune counter-regulatory and receptor-targeting approaches are also reviewed. The family of epidermal growth factor receptors including epidermal growth factor receptor 1 (HER-1) and 2 (HER-2) are both expressed in ovarian cancer and are the subject of ongoing research and development. The recent disappointing results with 90-yttrium-labeled anti-HMFG by single intraperitoneal administration have left the radiopharmaceutical field without a Phase III candidate. Identification of novel targets may advance this therapeutic area in the future. The rapid advances in the fields of immunoregulation and tumor biology should permit an accelerated introduction of antibodies for the treatment of ovarian cancer. These antibodies could complement novel small molecules that are also in development.

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Eur J Gynaecol Oncol. 2005;26(1):79-82.
Preliminary experience with salvage weekly paclitaxel in women with advanced recurrent ovarian carcinoma.
Dunder I, Berker B, Atabekoglu C, Bilgin T.
Department of Obstetrics and Gynecology, Ankara University School of Medicine, Ankara, Turkey.

PURPOSE OF INVESTIGATION: To assess the role of palliative chemotherapy with weekly paclitaxel in patients with recurrent ovarian cancer. METHODS: Thirty-two patients with paclitaxel- and platinum-resistant ovarian cancer were treated with weekly paclitaxel at 80 mg/m2 as a 1-hour intravenous infusion weekly for six weeks every eight weeks (1 cycle). This schedule was considered to be given for three cycles. Evaluation of radiographically measurable disease was used in the assessment of response. CA-125 was used to classify responses only in the absence of a measurable lesion. RESULTS: Thirty-two patients were all assessable for response. Of these, nine patients (28.1%) achieved a partial response and one patient achieved a complete response, leading to an overall response rate of 31.2%. Stable disease occurred in six patients (18.8%), and 16 patients (50%) had progressive disease. Nine patients died of progressive disease while on treatment. The median survival for the entire group was 10.5 months (range 2.5-22 months). Grade 3 or 4 leukopenia and neutropenia occurred in eight and six patients, respectively. Four of these patients developed febrile neutropenia without infection. Grade 1 and 2 peripheral neuropathies were observed in 50% of the patients without causing any premature drop out. Severe (grade 3 or 4) peripheral neuropathy was not observed. There were 11 patients with grade 1 or 2 myalgias. CONCLUSION: Weekly paclitaxel regimen is well tolerated with acceptable toxicity. The favorable toxicity profile and the encouraging antitumor activity observed in this study makes this regimen an option for the salvage treatment of patients with recurrent ovarian cancer.

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Minerva Ginecol. 2004 Dec;56(6):503-14.
>From gene therapy to virotherapy for ovarian cancer.
Stoff-Khalili MA, Dall P, Curiel DT.
Division of Human Gene Therapy, Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL, USA.

Ovarian cancer has the highest mortality of all cancers of the female reproductive system. Although progress in conventional therapies (surgery, chemotherapy and irradiation) has been achieved, the 5-year survival rate for patients with advanced stage ovarian cancer is still low. On this basis it is clear that there is a need for novel therapeutic paradigms. Targeted approaches are based on the increasing knowledge of the molecular basics of ovarian cancer. In this regard, gene therapy is a novel targeted approach for the treatment of ovarian cancer. However, current gene therapy delivery systems (viral and non-viral vectors) have to address the issues of inefficient transduction of target ovarian cancer cells and/or ectopic non-target delivery with attendant toxicity. Of note, the limited tumor transduction associated with current gene therapy interventions is due, in large part, to the fact that the employed vectors have been replication-incompetent. In this regard, human clinical trials have shown that the approach of replication-incompetent vectors has yet to succeed in ovarian cancer patients. In contrast, replication-competent viruses offer a method to achieve efficient tumor cell oncolysis (virotherapy) in ovarian cancer. Thus, in this very promising approach of virotherapy the replicating virus itself is the anti-cancer agent. This review discusses the concepts of gene therapy and virotherapy as novel targeted therapeutic approaches for the treatment of ovarian cancer.

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Semin Oncol. 2004 Dec;31(6 Suppl 14):17-24.
Recent updates in the clinical use of platinum compounds for the treatment of gynecologic cancers.
Muggia FM.
New York University Cancer Institute, New York University School of Medicine, New York, NY 10016, USA. muggif01@gcrc.med.nyu.edu <muggif01@gcrc.med.nyu.edu>

Platinum compounds have long played a role in the treatment of gynecologic cancers. Single-agent cisplatin and carboplatin have shown activity in endometrial cancer, and more recent studies have begun to investigate a variety of new platinum-based combinations. In cervical cancer, chemotherapy is used primarily to treat advanced or recurrent disease. Agents with proven single-agent activity in this setting include cisplatin, ifosfamide, and doxorubicin, and a number of cisplatin-based combination therapies are under clinical investigation. A variety of cisplatin-based combinations have also been used in ovarian cancer chemotherapy, with more recent studies investigating the substitution of carboplatin or oxaliplatin for cisplatin and the addition of paclitaxel. This review will examine recent clinical data on the use of platinum-based chemotherapies for the treatment of these gynecologic cancers.

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Tumori. 2004 Nov-Dec;90(6):556-61.
A phase II study of liposomal doxorubicin in recurrent epithelial ovarian carcinoma.
Arcuri C, Sorio R, Tognon G, Gambino A, Scalone S, Lucenti A, Caffo O, Valduga F, Arisi E, Galligioni E.
Division of Medical Oncology, St. Chiara Hospital, Trento, Italy. arcuric@yahoo.it

BACKGROUND: We conducted a phase II trial to evaluate the efficacy and safety of liposomal formulation of doxorubicin in recurrent ovarian carcinoma patients. METHODS: Thirty patients were included in the study after having obtained an informed consent. Their main characteristics were: median age, 64 years (range, 45-80), ECOG performance status 0 in 17 patients (56%), 1 in 11 patients (36%) and 2 in 2 patients (6.6%). Eighteen patients had metastatic disease and 12 locally advanced disease. All patients were pretreated with a platinum-based chemotherapy: 3 were considered refractory to platinum (progression or stable disease), 2 were platinum resistant (relapse < 12 months), and 7 were platinum sensitive (relapse > or = 12 months). Treatment consisted of liposomal doxorubicin, 50 mg/m2 every 4 weeks. RESULTS: The overall response rate was 26.6%, with 2 complete responses and 6 partial responses lasting 3.5 months. The incidence of grade 3-4 toxicity was 23.3% for neutropenia, 10% for mucositis and 10% for plantar-palmar erythrodysesthesia. Median survival was 12+ months (range, 2-26+). CONCLUSIONS: Liposomal doxorubicin appears to be a moderately active drug in pretreated patients, and its activity seems to be similar to that reported for other active regimens in terms of response rate. The toxicological profile of liposomal doxorubicin suggests that it may be combined with other drugs in the treatment of patients with ovarian cancer.

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Oncol Rep. 2005 Jan;13(1):121-5.
Efficacy of intraperitoneal continuous hyperthermic chemotherapy as consolidation therapy in patients with advanced epithelial ovarian cancer: A long-term follow-up.
Yoshida Y, Sasaki H, Kurokawa T, Kawahara K, Shukunami K, Katayama K, Yamaguchi A, Kotsuji F.
Department of Obstetrics and Gynecology, University of Fukui, Fukui-ken 910-1103, Japan. yyoshida@fmsrsa.fukui-med.ac.jp.

This trial was performed to determine the efficacy and progression-free and overall survivals of patients with advanced ovarian cancer who had been treated with intraperitoneal hyperthermic chemotherapy (IPHC). Ten patients with advanced ovarian cancer participated in this trial and were treated with IPHC. The median progression-free and overall survival rates for all patients treated in this study were 41.2 and 70.2 months, respectively. Two of ten patients received optimal primary cytoreduction surgery followed by IPHC; four of ten, optimal interval debulking surgery followed by IPHC; and four of ten, negative second-look operation followed by IPHC. The groups had 5 and 14.5, 17.75 and 38, and 82.75 and 130.25 months median progression-free and overall survival rates, respectively. Grades 3-4 toxicity included myelosuppresion, and nephropathy was detected. One patient required blood transfusions due to grade 4 anemia and thrombocytopenia. Another patient developed grade 3 nephrotoxicity but did not require continuous hemodialysis. IPHC was feasible, produced manageable toxicity, and showed promise for the treatment of advanced ovarian cancer. Negative second-look laparotomy followed by IPHC was especially effective when consolidation intraperitoneal chemotherapy had been indicated. It produced excellent median progression-free and overall survival rates.

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Gynecol Oncol. 2004 Dec;95(3):686-90.
Phase II study of weekly topotecan in patients with recurrent or persistent epithelial ovarian cancer.
Levy T, Inbar M, Menczer J, Grisaru D, Glezerman M, Safra T.
Division of Gynecologic Oncology, Wolfson Medical Center, Holon, the Sackler Faculty of Medicine, Tel Aviv, Israel.

OBJECTIVE: To assess the toxicity and effectiveness of once-weekly administration of topotecan (Hycamtin(R); GlaxoSmithKline) for relapsed ovarian and primary peritoneal cancer. METHODS: Twenty-three patients with recurrent or persistent epithelial ovarian cancer (EOC) and primary peritoneal carcinoma (PPC) previously exposed to at least one line of platinum-based chemotherapy were treated with IV weekly topotecan as a 30-min bolus at a starting dose of 4 mg/m(2) administered weekly for 3 weeks in a 28-day cycle. RESULTS: The patients' median age was 62 years (42-83). Thirteen women (56.5%) were defined as having platinum-sensitive and 10 (43.5%) as having platinum-resistant disease. Altogether, 88 cycles were administered for a total of 264 weekly treatments, with a median of four courses (range 2-6). There were no treatment delays. The main bone marrow toxicity was grade II and III thrombocytopenia, necessitating dose reduction in four patients (17.4%) and treatment cessation in one patient. The most frequent nonhematologic toxicity was fatigue (nine patients, 39.1%). There were four complete responses (17.4%, three in the platinum-sensitive and one in the platinum-resistant patients) and seven (30.4%) partial responses, for an overall response rate of 47.8%. The ORR was similar in platinum-sensitive and platinum-resistant patients (47.8% and 52.2%, respectively). The median progression-free survival was 4.9 months with a mean survival time of 11.59 months. Two women sustained complete response lasting >6 months. CONCLUSION: Topotecan given as a weekly bolus is a highly active and well-tolerated treatment regimen for relapsed ovarian and primary peritoneal cancer and thus deserves further evaluation.

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Gynecol Oncol. 2004 Dec;95(3):506-12.
Phase II trial of vinorelbine for relapsed ovarian cancer: a Southwest Oncology Group study.
Rothenberg ML, Liu PY, Wilczynski S, Nahhas WA, Winakur GL, Jiang CS, Moinpour CM, Lyons B, Weiss GR, Essell JH, Smith HO, Markman M, Alberts DS.
Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA.

OBJECTIVES.: To assess the activity of vinorelbine in women with recurrent or resistant epithelial ovarian cancer following treatment with platinum and paclitaxel in terms of survival rate at 6 months, objective response rate (in the subset of patients with bidimensionally measurable disease), and health-related quality of life. METHODS.: Seventy-nine evaluable patients with progressive ovarian cancer following platinum and taxane therapy received vinorelbine 30 mg/m(2) days 1 and 8 of a 21-day treatment cycle. RESULTS.: Six-month survival rate for the entire group was 65% (95% CI: 54-75%) and median survival was 10.1 months (95% CI: 7.7-13.6 months). In the 71 women with measurable disease, 0 complete and 2 partial responses were observed (RR = 3%) (95% CI: 0.3-10%). Patients reported substantial symptom-related distress at baseline, which persisted, but did not worsen, during treatment. Patients also had impaired physical functioning at baseline and this continued to decline during treatment. CONCLUSIONS.: The 6-month survival rate achieved with salvage vinorelbine is comparable to the results obtained with other salvage therapies in patients with relapsed ovarian cancer. During the initial 10 weeks of treatment, vinorelbine did not appear to be effective in alleviating the symptom-related distress or progressive impairment of physical functioning associated with this disease.

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J Natl Cancer Inst. 2004 Nov 17;96(22):1682-91.
Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma.
Vasey PA, Jayson GC, Gordon A, Gabra H, Coleman R, Atkinson R, Parkin D, Paul J, Hay A, Kaye SB; Scottish Gynaecological Cancer Trials Group.
Cancer Research U.K. Department of Medical Oncology, Glasgow, UK. paul_vasey@health.qld.gov.au

BACKGROUND: Chemotherapy with a platinum agent and a taxane (paclitaxel) is considered the standard of care for treatment of ovarian carcinoma. We compared the combination of docetaxel-carboplatin with the combination of paclitaxel-carboplatin as first-line chemotherapy for stage Ic-IV epithelial ovarian or primary peritoneal cancer. METHODS: We randomly assigned 1077 patients to receive docetaxel at 75 mg/m2 of body surface area (1-hour intravenous infusion) or paclitaxel at 175 mg/m2 (3-hour intravenous infusion). Both treatments then were followed by carboplatin to an area under the plasma concentration-time curve of 5. The treatments were repeated every 3 weeks for six cycles; in responding patients, an additional three cycles of single-agent carboplatin was permitted. Survival curves were calculated by the Kaplan-Meier method, and hazard ratios were estimated with the Cox proportional hazards model. All statistical tests were two-sided. RESULTS: After a median follow-up of 23 months, both groups had similar progression-free survival (medians of 15.0 months for docetaxel-carboplatin and 14.8 months for paclitaxel-carboplatin; hazard ratio [HR] docetaxel-paclitaxel = 0.97, 95% confidence interval [CI] = 0.83 to 1.13; P = .707), overall survival rates at 2 years (64.2% and 68.9%, respectively; HR = 1.13, 95% CI = 0.92 to 1.39; P = .238), and objective tumor (58.7% and 59.5%, respectively; difference between docetaxel and paclitaxel = -0.8%, 95% CI = -8.6% to 7.1%; P = .868) and CA-125 (75.8% and 76.8%, respectively; difference docetaxel-paclitaxel = -1.0%, 95% CI = -7.2% to 5.1%; P = .794) response rates. However, docetaxel-carboplatin was associated with substantially less overall and grade 2 or higher neurotoxicity than paclitaxel-carboplatin (grade > or =2 neurosensory toxicity in 11% versus 30%, difference = 19%, 95% CI = 15% to 24%; P<.001; grade > or =2 neuromotor toxicity in 3% versus 7%, difference = 4%, 95% CI = 1% to 7%; P<.001). Treatment with docetaxel-carboplatin was associated with statistically significantly more grade 3-4 neutropenia (94% versus 84%, difference = 11%, 95% CI = 7% to 14%; P<.001) and neutropenic complications than treatment with paclitaxel-carboplatin, although myelosuppression did not influence dose delivery or patient safety. Global quality of life was similar in both arms, but substantive differences in many symptom scores favored docetaxel. CONCLUSIONS: Docetaxel-carboplatin appears to be similar to paclitaxel-carboplatin in terms of progression-free survival and response, although longer follow-up is required for a definitive statement on survival. Thus, docetaxel-carboplatin represents an alternative first-line chemotherapy regimen for patients with newly diagnosed ovarian cancer.

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Cancer Invest. 2004;22 Suppl 2:29-44.
Novel agents in epithelial ovarian cancer.
See HT, Kavanagh JJ.
Department of Gynecologic Medical Oncology and Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030-4009, USA.

The gold standard chemotherapy for previously untreated patients with ovarian cancer is currently a combination of taxane and platinum. However, most patients still suffer relapse, and less than 20% of the patients with stage III or IV disease survive long term. With more advanced technology, newer cytotoxic agents have been identified and are currently being tested in patients with ovarian cancer. Recent advances in the understanding of ovarian cancer biology have also led to the identification of multiple molecular targets that may soon change the standard treatment of ovarian cancer. Several of these targeted agents have entered clinical trials. Small molecular-weight inhibitors, monoclonal antibodies, antisense therapy, and gene therapy are all being evaluated alone and in combination with cytotoxic chemotherapy. Several of these cytotoxic and targeted therapies are reviewed here. Ultimately, the success of ovarian cancer therapy lies not just in the availability of new agents but in the ability to identify patients with biomarkers that may predict their response to these agents.

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Cancer Invest. 2004;22 Suppl 2:11-20.
Update on Gynecologic Oncology Group (GOG) trials in ovarian cancer.
Ozols RF.
Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.

The Gynecologic Oncology Group (GOG) has conducted a series of randomized trials in advanced ovarian cancer patients, both with early-stage disease (FIGO stages I and II) and advanced-stage disease (FIGO stages III and IV). In patients with early-stage disease, the current standard of therapy is three cycles of paclitaxel and carboplatin-based combination chemotherapy. In patients with advanced-stage ovarian cancer, the GOG standard is six cycles of the same regimen. The GOG has also performed prospective randomized trials of consolidation and maintenance therapy with intraperitoneal (IP) radioisotomes and additional cycles of paclitaxel, respectively. Neither of these modalities has shown improvement in survival. In addition, the GOG has performed randomized trials of IP chemotherapy, and while it has been demonstrated that the regimens that included IP cisplatin led to improved outcomes, the toxicity of this approach has precluded widespread acceptance of this modality. Currently, the GOG is performing additional pilot studies to evaluate less toxic IP regimens. The GOG has also been at the forefront of developing new combination chemotherapy regimens based on the activity of second-line agents, such as topotecan, gemcitabine, and encapsulated doxorubicin. The GOG is also exploring molecular-targeted therapies in phase II trials with the goal of ultimately incorporating biological therapies in newly diagnosed patients with advanced disease.

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World J Surg. 2004 Oct;28(10):1040-5. Epub 2004 Sep 29.
Cytoreductive surgery and intraperitoneal chemohyperthermia for recurrent peritoneal carcinomatosis from ovarian cancer.
Zanon C, Clara R, Chiappino I, Bortolini M, Cornaglia S, Simone P, Bruno F, De Riu L, Airoldi M, Pedani F.
Department of Oncology, S. Giovanni Battista Antica Sede Hospital, Via Cavour 31, 10100, Torino, Italy. zanoncl@tin.it

Aggressive surgical cytoreduction has been shown to have a positive impact on survival of patients with ovarian cancer. After first-line chemotherapy, 47% of patients relapse within 5 years, and median survival after second line chemotherapy is 10-15 months. Adding intraperitoneal chemohyperthermia (IPCH) to surgical cytoreduction could further control ceolomic spread of disease. The aim of this study was to determine morbidity and mortality, regional relapse-free survival and, preliminarily, overall survival after combining cytoreductive surgery with IPCH for the treatment of peritoneal carcinomatosis from ovarian epithelial cancer relapsed after prior chemotherapy. Thirty women affected with such a relapse were included. Patients underwent extensive cytoreductive surgery including tumor resections and peritonectomy, followed by intraoperative IPCH with cisplatin. Complete surgical cytoreduction down to nodules less than 2.5 mm (CC0-CC1) was obtained in 23 patients (77%). One patient died postoperatively from a pulmonary embolism. Major postoperative morbidity was 5/30 (16.7%). We registered one case of anastomotic leakage, a spontaneous ileum perforation, a postoperative cholecystitis, a hydrothorax, and one patient with bone marrow toxicity. Kaplan-Meier estimates of median locoregional relapse-free survival and median overall survival were 17.1 months and 28.1 months, respectively. Patients with CC0-CC1 had locoregional relapse-free and overall survival rates of 24.4 and 37.8 months, whereas the remainder had survival rates of 4.1 and 11.0 months. We concluded that cytoreductive surgery combined with IPCH is feasible with acceptable morbidity and mortality and seems to promise good results in selected patients affected with peritoneal carcinomatosis from ovarian cancer.

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Oncology. 2004;67(3-4):183-6.
A study of pegylated liposomal Doxorubicin in platinum-refractory epithelial ovarian cancer.
Wilailak S, Linasmita V.
Department of Obstetrics and Gynaecology, Faculty of Medicine, Ramathibodi Hospital, Bangkok, Thailand. raswl@mahidol.ac.th

OBJECTIVES: The purposes of this study were to determine the efficacy of pegylated liposomal doxorubicin (PLD), using a dose of 40 mg/m2 given every 3 weeks, in the treatment of platinum-refractory epithelial ovarian cancer (EOC) and to evaluate the toxicities. METHODS: Fourteen patients with platinum-resistant EOC were treated with intravenous PLD 40 mg/m2 every 3 weeks. Tumor responses were assessed every 2-3 cycles by CT scan. RESULTS: All 14 patients were evaluable for toxicity, but only 13 patients were evaluable for response because 1 patient who had grade 3 palmar-plantar erythrodysesthesia (PPE) refused to continue with the treatment. Three partial responses were observed in 13 patients. The overall response rate was 23% (95% confidence interval 10-38%). The median time to response was 2 months, and the median duration of response was 3 months. The median survival of the 13 patients was 14.5 months, and the median progression-free survival was 6 months. In this study, we had only 4 cases of grade 3 toxicity (2 cases of grade 3 leukopenia and 2 cases of grade 3 PPE). All toxicities that occurred were manageable. CONCLUSION: This is the first report of the use of a slightly modified dose schedule for PLD at a dose of 40 mg/m2 every 3 weeks, which is active in platinum-refractory EOC with manageable toxicities.

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Int J Cancer. 2004 Nov 10;112(3):465.
Green tea consumption enhances survival of epithelial ovarian cancer.
Zhang M, Lee AH, Binns CW, Xie X.
School of Public Health, Curtin University of Technology, Perth, WA, Australia.

Our study investigates whether tea consumption can enhance the survival of patients with epithelial ovarian cancer, a prospective cohort study was conducted in Hangzhou, China. The cohort comprised 254 patients recruited during 1999-2000 with histopathologically confirmed epithelial ovarian cancer and was followed up for a minimum of 3 years. Two hundred forty four (96.1%) of the cohort or their close relatives were traced. The variables examined included their survival time and the frequency and quantity of tea consumed post-diagnosis. The actual number of deaths was obtained and Cox proportional hazards models were used to obtain hazard ratios and associated 95% confidence intervals (CI), adjusting for age at diagnosis, locality, BMI, parity, FIGO stage, histologic grade of differentiation, cytology of ascites, residual tumour and chemotherapeutic status. The survival experience was different between tea drinkers and non-drinkers (p < 0.001). There were 81 (77.9%) of 104 tea-drinkers who survived to the time of interview, compared to only 67 women (47.9%) still alive among the 140 non-drinkers. Compared to non-drinkers, the adjusted hazard ratios were 0.55 (95% CI = 0.34-0.90) for tea-drinkers, 0.43 (95% CI = 0.20-0.92) for consuming at least 1 cup of green tea/day, 0.44 (95% CI = 0.22-0.90) for brewing 1 batch or more of green tea/day, 0.40 (95% CI = 0.18-0.90) for consuming more than 500 g of dried tea leaves/year, and 0.38 (95% CI = 0.15-0.97) for consuming at least 2 g of dried tea leaves/batch. The corresponding dose-response relationships were significant (p < 0.05). We conclude that increasing the consumption of green tea post-diagnosis may enhance epithelial ovarian cancer survival. Copyright 2004 Wiley-Liss, Inc.

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Gynecol Oncol. 2004 Oct;95(1):235-41.
Weekly topotecan for recurrent endometrial cancer: a case series and review of the literature.
Traina TA, Sabbatini P, Aghajanian C, Dupont J.
Developmental Chemotherapy Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

OBJECTIVE.: Topotecan, a topoisomerase 1 inhibitor, has demonstrated antitumor activity in ovarian and endometrial cancers when administered daily for 5 days every 3 weeks. Recently, topotecan has been studied on a weekly dosing schedule for the treatment of ovarian cancer and found to have efficacy with reduced toxicity. The aim of this study is to review the Memorial Sloan-Kettering Cancer Center (MSKCC) experience with weekly topotecan dosing in women with recurrent endometrial cancer. We have included a review of the literature of weekly topotecan in the treatment of patients with gynecologic cancer. METHODS.: After Institutional Review Board (IRB) approval, we identified all women with recurrent endometrial cancer treated with topotecan at MSKCC from May 1996 to February 2004. Patients treated on a weekly schedule were assessed for toxicity and response. A review of the literature pertaining to weekly topotecan in the treatment of endometrial cancer was also performed. RESULTS.: Eleven patients were treated with weekly topotecan during the study period, with doses ranging from 2.5-4.0 mg/m(2) on a 2- or 3-week schedule with 1 week off. The median age of the patients was 60 years old (range, 47-76 years), and the median Karnofsky performance status was 80%. Six of the 11 patients were previously treated with more than three chemotherapy regimens and eight had received prior pelvic radiation. Ninety-seven percent of treatment doses were delivered as scheduled, and only two patients required dose reductions. One patient achieved a prolonged partial response for 54 weeks, and two patients had stabilization of disease for 15 weeks each. CONCLUSIONS.: Weekly topotecan has antitumor activity and is well tolerated in patients with recurrent endometrial cancer, including those patients with multiple prior treatments. Topotecan on a weekly bolus schedule should be evaluated in prospective trials to better establish its role in the treatment of recurrent endometrial cancer.

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Gynecol Oncol. 2004 Oct;95(1):165-72.
Oxaliplatin plus high-dose leucovorin and 5-fluorouracil (FOLFOX 4) in platinum-resistant and taxane-pretreated ovarian cancer: A phase II study.
Pectasides D, Pectasides M, Farmakis D, Gaglia A, Koumarianou A, Nikolaou M, Koumpou M, Kountourakis P, Papaxoinis G, Mitrou P, Economopoulos T, Raptis SA.
Second Department of Internal Medicine-Propaedeutic, Athens University Medical School, Attikon University Hospital, Athens, Greece.

OBJECTIVE: A prospective phase II study was conducted to evaluate the efficacy and toxicity of oxaliplatin plus 5-fluoruracil (5-FU) and high-dose leucovorin (LV) (FOLFOX-4) in patients with platinum-resistant, taxane-pretreated recurrent ovarian cancer. PATIENTS AND METHODS: Thirty-eight patients, with a median age of 58 years (range 33-77), were treated with oxaliplatin 85 mg m(-2) as a 2-h infusion on day 1, LV 200 mg m(-2) day(-1) as a 2-h infusion followed by bolus 5-FU 400 mg m(-2) day(-1) and a 22-h infusion of 5-FU 600 mg m(-2) day(-1) for 2 consecutive days. Treatment was repeated every 3 weeks. Patients were evaluated for response every two cycles. RESULTS: The vast majority of patients had performance status 0 or 1 and 76.3% had >/= 2 metastatic sites. A median number of four cycles per patient (range, 1-8) were administered. Based on an intention-to-treat analysis, 3 patients (7.9%) achieved a complete response (CR) and 8 (21.1%) achieved a partial response (PR), for an overall response rate of 29%. Another 29% of patients had stable disease (SD). The median relapse-free survival was 5.2 months (range 2.5-17), the median time to tumor progression was 4.8 months (range 0.6-19), and the median overall survival was 10.1 months (range 0.2-36). Toxicity was mild to moderate. Grade 3/4 neutropenia and thrombocytopenia occurred in 29% and 21.1% of patients, respectively. Febrile neutropenia was encountered in 3 patients (7.9%), who were successfully treated. Grade 3/4 neurotoxicity developed in 15.8% of patients; neurotoxicity gradually declined after treatment discontinuation. Alopecia, nausea-vomiting, diarrhea, mucositis, and asthenia were not a serious problem. There were no treatment-related deaths. CONCLUSION: The combination of oxaliplatin and 5-FU/LV (FOLFOX-4) appears to be an effective regimen with a good toxicity profile for the treatment of platinum-resistant, taxane-pretreated ovarian cancer.

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Gynecol Oncol. 2004 Oct;95(1):109-13.
Phase 2 trial of prolonged administration of oral topotecan in platinum/taxane-refractory ovarian, fallopian tube, and primary peritoneal cancers.
Markman M, Webster K, Zanotti K, Kulp B, Peterson G, Belinson J.
Departments of Hematology/Medical Oncology and Gynecology/Obstetrics, The Cleveland Clinic Foundation, Cleveland, OH 44195, United States.

OBJECTIVES: Preclinical and clinical data have demonstrated the importance of schedule in optimizing the cytotoxic potential of topotecan, one of the most active agents in ovarian cancer. The availability of oral topotecan permits the exploration of the clinical utility of prolonged treatment programs employing this drug. METHODS: Patients with platinum/taxane resistant ovarian and primary peritoneal cancers were treated with oral topotecan at an initial fixed dose of 1.5 mg/day for 5 days, followed by a 2-day break, with treatment continued on this schedule until disease progression or unacceptable toxicities. RESULTS: Seven patients (median age 61) were entered into this phase 2 trial before further enrollment was discontinued due to the development of excessive side effects (grade 3: fatigue (n = 3); emesis (n = 1), thrombocytopenia with bleeding (n = 1). Two additional patients noted grade 2 fatigue. Four patients experienced reductions in hemoglobin concentrations >4.0 g/dl from baseline during treatment, with two patients requiring red cell transfusions and two receiving recombinant erythropoietin. Three patients developed grade 3 neutropenia, while there were no episodes of >/=grade 2 diarrhea. Three patients exhibited biological evidence of an anti-neoplastic effect of therapy (>50% declines in serum CA-125 levels). CONCLUSION: Despite the strong theoretical appeal (as well as limited biological evidence of activity in platinum/taxane-refractory disease) associated with prolonging exposure of cycling ovarian cancer cells to topotecan, the specific oral regimen employed in this trial was associated with excessive bone marrow suppression, especially treatment-induced anemia, resulting in an unacceptable incidence of severe fatigue.

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Gynecol Oncol. 2004 Oct;95(1):1-8.
Long-term survival advantage for women treated with pegylated liposomal doxorubicin compared with topotecan in a phase 3 randomized study of recurrent and refractory epithelial ovarian cancer.
Gordon AN, Tonda M, Sun S, Rackoff W; On behalf of the Doxil Study 30-49 Investigators.
Arizona Gynecologic Oncology, Phoenix, AZ 85006, United States.

OBJECTIVE: Provide long-term follow-up data for women treated in a randomized multicenter study of pegylated liposomal doxorubicin compared with topotecan. METHODS: Patients with epithelial ovarian cancer that recurred after or failed to respond to first-line platinum-based chemotherapy were randomized to receive pegylated liposomal doxorubicin 50 mg/m(2) every 28 days (n = 239) or topotecan 1.5 mg/m(2) per day for 5 days every 21 days (n = 235). Patients were stratified prospectively based on response to initial platinum-based chemotherapy as well as the presence or absence of bulky disease. Most patients had been previously treated with platinum and taxanes (74% in the pegylated liposomal doxorubicin group and 72% in the topotecan group). Survival data are mature: 87% of patients have died (n = 413). RESULTS: There was an 18% reduction in the risk of death for patients treated with pegylated liposomal doxorubicin (median survival 62.7 weeks for pegylated liposomal doxorubicin and 59.7 weeks for topotecan-treated patients; HR = 1.216; 95% confidence interval (CI) 1.000-1.478; P = 0.050). The hazard ratio for all randomized subjects (includes those randomized, but never treated; n = 481) was 1.23 (median survival 63.6 weeks for pegylated liposomal doxorubicin and 57.0 weeks for topotecan-treated patients; 95% CI 1.01-1.50; P = 0.038). For patients with platinum-sensitive disease, there was a 30% reduction in the risk of death for the pegylated liposomal doxorubicin-treated group (median survival 107.9 weeks for pegylated liposomal doxorubicin and 70.1 weeks for topotecan-treated patients; HR = 1.432; 95% CI 1.066-1.923; P = 0.017). In patients with platinum-refractory disease, survival was similar between treatment groups. CONCLUSION: Long-term follow-up demonstrates that treatment with pegylated liposomal doxorubicin significantly prolongs survival compared with topotecan in patients with recurrent and refractory epithelial ovarian cancer. The survival benefit is pronounced in patients with platinum-sensitive disease.

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Int J Gynecol Cancer. 2004 Sep-Oct;14(5):799-803.
Second-line therapy of advanced ovarian cancer with GnRH analogs.
Balbi G, Piano LD, Cardone A, Cirelli G.
Department of Obstetrics, Gynecology and Neonatology, Second University of Naples, Napoli, Italy.

Abstract. Balbi G, Piano LD, Cardone A, Cirelli G. Second-line therapy of advanced ovarian cancer with GnRH analogs.Ovarian cancer is still the first cause of death among female malignancies. The standard treatment adopted in ovarian cancer is a radical surgical treatment or cytoreduction, followed by six courses of platinum-based chemotherapy; second-line regimens are associated with severe side effects. GnRH analogs could represent an alternative therapeutical approach. The aim of our study was to evaluate the role of GnRH analogs in the management of platinum-resistant ovarian cancers. We enrolled 12 patients affected by advanced ovarian cancer, previously treated with six courses of platinum-paclitaxel. In second-line therapy, we used leuprolide on 1, 8, and 28 days of treatment. CA 125 levels were recorded for each patient. One case of clinical partial response was obtained (8.3%). Stable disease was diagnosed in three patients (25%). Progression was recorded in eight cases (66.7%). Progression-free survival was 6 months. The treatment was well tolerated by patients. The high tolerability and the results obtained with leuprolide versus platinum in second-line therapy might permit a better use of the analogs for advanced ovarian cancer.

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Int J Gynecol Cancer. 2004 Sep-Oct;14(5):772-8.
Long-term survival in 463 women treated with platinum analogs for advanced epithelial carcinoma of the ovary: life expectancy compared to women of an age-matched normal population.
Lambert HE, Gregory WM, Nelstrop AE, Rustin GJ.
Department of Clinical Oncology, Hammersmith Hospital, London, UK.

Abstract. Lambert HE, Gregory WM, Nelstrop AE, Rustin GJS. Long-term survival in 463 women treated with platinum analogs for advanced epithelial carcinoma of the ovary: life expectancy compared to women of an age-matched normal population.The objective was to assess the long-term survival (5-15 years) in 463 women, with stages IIb-IV epithelial carcinoma of the ovary and to compare their survival with that of a normal population matched for age and sex. Statistical analysis of 463 women, with stages IIb-IV epithelial cancer of the ovary, who were participants in two consecutive North Thames Ovary Group randomized trials, which took place between 1985 and 1994, was performed. The median follow-up period was 10.5 years. The women were treated with debulking surgery, where possible, and adjuvant platinum chemotherapy. One of the randomized groups in the first North Thames trial also received total abdominal radiotherapy. Survival rates at 5, 10, and 15 years were assessed. Prognostic factors for long-term survival were determined using a mathematical model to separate early effects from late effects. The ratio of observed to expected deaths compared to the normal population was calculated. Overall survival at 5 years was 21% (95% confidence intervals 17.5-25%), at 10 years was 13.5% (95% confidence intervals 10.5-17%), and at 15 years was 12% (95% confidence intervals 9-16%). The important prognostic factors for long-term survival were disease-free or minimal residual disease (a single remaining deposit <2 cm) at initial surgery with tumor grade 1 and good performance status. Compared with the normal population (1995 data), the ratio of observed to expected deaths after start of chemotherapy at 5 years was 14.1 (P < 0.001 Fisher's exact test), at 9-10 years 4.9 (P = 0.0033, Fisher's exact test), while in the 11- to 15-year period it had dropped to 2.75 (P = 0.090, Fisher's exact test), which was not significantly different. Patients with advanced cancer of the ovary, who survive 11 years or longer, have a life expectancy which is very similar to that of a normal population of women of the same age. Women with advanced ovarian cancer have an improved chance of long-term survival following treatment if they present with minimal residual disease after primary surgical debulking, grade 1 tumors, and good performance status.

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Springer Semin Immunopathol. 2004 Sep 11 [Epub ahead of print]
Stem-cell transplantation for the treatment of advanced solid tumors.
Nieto Y, Jones RB, Shpall EJ.
University of Colorado Health Sciences Center, 4200 East Ninth Avenue, B-190, 80262, Denver, CO, USA.

Over the past two decades, high-dose chemotherapy (HDC) with autologous stem-cell transplantation (ASCT) has been explored for a variety of solid tumors in adults, particularly breast cancer, ovarian cancer and non-seminomatous germ-cell tumors. The results of prospective phase II studies seemed superior in many cases to the outcome expected with standard-dose chemotherapy (SDC). The value of HDC for adult solid tumors remains, in most instances, a controversial issue, currently under the scrutiny of randomized phase III trial evaluation. ASCT pursuing an immune graft-versus-tumor effect has been evaluated in recent years for patients with advanced and refractory solid malignancies. This article reviews the results of the main phase II and III studies of HDC with ASCT, as well as the preliminary experience using allogeneic transplantation for solid tumors.

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Gynecol Oncol. 2004 Sep;94(3):655-60.
Diaphragm resection for ovarian cancer: technique and short-term complications.
Cliby W, Dowdy S, Feitoza SS, Gostout BS, Podratz KC.
Gynecologic Surgery, Mayo Clinic, Rochester, MN, 55905 United States.

OBJECTIVE.: Diaphragm resection (DR) is occasionally necessary to achieve optimal cytoreductive surgery in ovarian carcinoma (OC). In a recent survey of the SGO membership, bulky diaphragm disease was one of the most common justifications for suboptimal debulking (Gynecol. Oncol. 82 (2001) 489). The aim of this study was to assess postoperative complications of DR in OC. METHODS.: Retrospective chart review of all patients with OC who underwent DR from January 1988 through December 2001 at Mayo Clinic. RESULTS.: We identified 41 women who underwent DR for OC. DR was performed during debulking for recurrent disease in 85%. Most patients (95%) underwent associated radical debulking procedures including bowel resection (51%), hepatic resection (27%), and splenectomy (17%). Full-thickness diaphragmatic lesions were present in 85% of specimens. Residual disease was classified as no gross residual in 80% of cases and <1 cm in 10%. Postoperative complications requiring treatment occurred in eight cases: pneumothorax (two cases, definitely attributable to DR); symptomatic pleural effusion (four cases, possibly attributable to DR); one case each of subphrenic abscess and gastro-pleural fistula (most likely unrelated to DR). CONCLUSIONS.: (1) DR as part of cytoreductive surgery for ovarian cancer carries comparable risks to other radical debulking procedures. (2) The majority of complications are expected outcomes after entrance into the pleural cavity and generally manageable with chest tube. (3) DR is a useful adjunct to other radical debulking procedures and can eliminate isolated bulky diaphragmatic disease as an obstacle to optimal cytoreductive surgery for patients with ovarian cancer.

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J Clin Oncol. 2004 Sep 1;22(17):3517-23.
The activity of taxanes in the treatment of sex cord-stromal ovarian tumors.
Brown J, Shvartsman HS, Deavers MT, Burke TW, Munsell MF, Gershenson DM.
Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. jurobinso@mdanderson.org

PURPOSE: To determine the efficacy and side effects of taxanes, with or without platinum, for the treatment of sex cord-stromal tumors of the ovary. PATIENTS AND METHODS: We conducted a retrospective review of all patients seen from 1985 to 2002 at The University of Texas M.D. Anderson Cancer Center with ovarian sex cord-stromal tumors. Eligible patients underwent pathology confirmation and clinical evaluation at M.D. Anderson and received a taxane for initial or recurrent disease. RESULTS: Of 222 patients identified, 44 were eligible for analysis. For nine patients treated in the first-line adjuvant setting, median progression-free survival (PFS) was not reached at 51 months. Of two patients treated for measurable disease in the first-line setting, one had a complete response. Median PFS was 34.3 months; median overall survival (OS) was not reached. Median follow-up was 90.3 months (range, 39.4 to 140.5 months). Response rate for 30 patients treated with a taxane +/- platinum for recurrent, measurable disease was 42%. Median PFS was 19.6 months; median OS was not reached. Median follow-up was 100.7 months (range, 8.1 to 361.3 months). The presence of platinum correlated with response in the recurrent, measurable disease setting. The number of patients was insufficient to detect relative efficacy of paclitaxel and docetaxel. Adverse effects of paclitaxel included neutropenia (n = 6), anemia (n = 1), thrombocytopenia (n = 1), myelodysplasia (n = 1), and hypersensitivity (n = 1). CONCLUSION: Taxanes seem to be active agents in the treatment of patients with sex cord-stromal tumors of the ovary. The combination of taxanes with platinum in the treatment of this disease deserves additional investigation.

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J Clin Oncol. 2004 Sep 1;22(17):3507-16.
Randomized, placebo-controlled study of oregovomab for consolidation of clinical remission in patients with advanced ovarian cancer.
Berek JS, Taylor PT, Gordon A, Cunningham MJ, Finkler N, Orr J Jr, Rivkin S, Schultes BC, Whiteside TL, Nicodemus CF.
David Geffen School of Medicine at UCLA, Division of Gynecologic Oncology, University of California at Los Angeles, CA 90095-1740, USA. jberek@mednet.ucla.edu

PURPOSE: To assess oregovomab as consolidation treatment of advanced ovarian cancer and refine the immunotherapeutic strategy for subsequent study. PATIENTS AND METHODS: Patients with stage III/IV ovarian cancer who had a complete clinical response to primary treatment were randomly assigned to oregovomab or placebo administered at weeks 0, 4, and 8, and every 12 weeks up to 2 years or until recurrence. The primary end-point was time to relapse (TTR). RESULTS: One hundred forty-five patients were treated with oregovomab (n = 73) or placebo (n = 72). For the population overall, median TTR was not different between treatments at 13.3 months for oregovomab and 10.3 months for placebo (P =.71). Immune responses were induced in most actively treated patients. This was associated with prolonged TTR. Quality of life was not adversely impacted by treatment. Adverse events were reported with similar frequency in oregovomab and placebo groups, indicating a benign safety profile. A long-term survival follow-up is ongoing. Cox analysis of relapse data identified significant factors: performance status, CA-125 before third cycle, and baseline CA-125. Further evaluation identified a subpopulation with favorable prognostic indicators designated as the successful front-line therapy (SFLT) population. For the SFLT population, TTR was 24.0 months in the oregovomab group compared with 10.8 months for placebo (unadjusted hazard ratio of 0.543 [95% CI, 0.287 to 1.025]), a hypothesis-generating observation. CONCLUSION: Consolidation therapy with oregovomab did not significantly improve TTR overall. A set of confirmatory phase III studies has been initiated to determine whether the SFLT population derives benefit from oregovomab treatment.

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Oncology. 2004;66(5):343-6.
Phase 2 trial of interferon-beta as second-line treatment of ovarian cancer, fallopian tube cancer, or primary carcinoma of the peritoneum.
Markman M, Belinson J, Webster K, Zanotti K, Morrison B, Jacobs B, Borden E, Lindner D.
Cleveland Clinic Taussig Cancer Center, and the Departments of Hematology/Medical Oncology, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. markmam@ccf.org

OBJECTIVE: The protocol was designed to examine the biological effects and clinical activity of interferon-beta in patients with platinum/taxane-resistant ovarian cancer. METHODS: Patients with resistant ovarian and fallopian tube cancers and primary peritoneal carcinoma were treated with recombinant human interferon-beta (Rebif, Serono International) at doses ranging from 6 to 24 million international units (MIU)/day, based on their tolerance to therapy. Levels of IP-10, an interferon-inducible protein, were measured in the serum to evaluate the biological effects of the drug. Also, the peripheral blood mononuclear cells and serum were examined for the induction of previously described novel regulators of interferon-induced death. RESULTS: Eighteen patients were treated, of whom 9 (50%) could be treated at the highest dose level (24 MIU). The major toxicities were fever, chills and fatigue. The median duration of therapy was 6 weeks (range 1-22). No objective responses were observed. IP-10 levels were significantly increased, compared with baseline, at 2, 4, and 6 weeks after initiation of therapy (p < 0.01). CONCLUSIONS: Recombinant human interferon-beta produced a definite biological effect in the serum of treated patients, but this outcome was not translated into any clinically observable or meaningful impact on the disease process.

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Am J Clin Oncol. 2004 Feb;27(1):46-50.
Paclitaxel and carboplatin as second-line therapy in women with platinum-sensitive ovarian carcinoma treated with platinum and paclitaxel as first-line therapy.
Eltabbakh GH, Yildirim Z, Adamowicz R.
Department of Obstetrics and Gynecology, University of Vermont/Fletcher Allen Health Care, Burlington, Vermont, USA.

The study was performed to assess response rate, progression-free interval (PFI), and side effects of the combination paclitaxel and carboplatin as second-line therapy among women with platinum-sensitive epithelial ovarian carcinoma (EOC). Thirty women who achieved partial surgical response at second-look surgery (n = 8) or who had recurrence (n = 22) more than 6 months after treatment with platinum-based chemotherapy were treated with paclitaxel (135 mg/m2 for 3 hours) and carboplatin (area under the concentration-time curve 5) every 3 weeks. Response rate, PFI, and side effects of treatment were recorded. One hundred sixty-seven cycles of treatment (median = 6, range = 2-11) were administered. Among 22 patients with measurable or assessable disease, 14 had complete response and 3 had partial response. Five patients had progressive disease. The overall response rate was 77%. The median PFI was 10 months (range = 1-29). Among 22 patients in whom recurrence or progression developed after second-line therapy, the median interval was 9 months (range = 1-26). The incidence of grade III or IV neutropenia, leukopenia, and thrombocytopenia was 48%, 27%, and 3%, respectively. One patient discontinued treatment secondary to persistent thrombocytopenia. Eight patients died secondary to their disease. It was concluded that the combination paclitaxel and carboplatin has a high success rate, long duration of response, and is well tolerated as a second-line therapy among patients with platinum-sensitive EOC.

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Am J Clin Oncol. 2004 Feb;27(1):14-8.
Docetaxel versus paclitaxel for adjuvant treatment of ovarian cancer: case-control analysis of toxicity.
Hsu Y, Sood AK, Sorosky JI.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA.

The objective of this study was to evaluate the toxicity profile of docetaxel/carboplatin versus paclitaxel/carboplatin. All patients with primary ovarian, fallopian tube, or peritoneal malignancies treated with docetaxel and platinum at the University of Iowa between January 1996 and June 1999 were identified. Controls, treated with paclitaxel and platinum, were matched for age, date of diagnosis, type of cancer, stage, and residual disease. Toxicity was evaluated prior to each cycle and was graded according to the Gynecologic Oncology Group criteria. Twenty patients were identified in each group and evaluated. In the docetaxel/carboplatin group, sixteen (80%) patients experienced hematologic toxicity. Nine (45%) had grade III or IV neutropenia and fever developed in two of these patients. Grade III or IV thrombocytopenia developed in two patients. In contrast, among the paclitaxel/carboplatin group, grade III or IV neutropenia developed in only three patients (p < 0.05) and grade III or IV thrombocytopenia developed in two patients. There were no significant differences between the two groups with regard to gastrointestinal or renal toxicity. In the paclitaxel/carboplatin group, 13 patients developed neuropathy compared to only 2 patients (10%) in the docetaxel/carboplatin group (p < 0.05). There was no difference in the clinical response between the two treatment groups. In conclusion, neutropenia was more common with the docetaxel/carboplatin regimen, whereas neuropathy was more common in the paclitaxel-based regimen. The therapeutic efficacy was equivalent between the two groups.

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Gan To Kagaku Ryoho 2003 Feb;30(2):243-9
[Paclitaxel and carboplatin with or without pirarubicin (THP-ADR) as first line chemotherapy
in elderly patients]
[Article in Japanese]
Nagao S, Okimoto N, Hongo A, Mizutani Y, Kodama J, Yoshinouchi M, Hiramatsu Y, Kudo T.
Dept. of Obstetrics and Gynecology, Okayama University Medical School.

To evaluate the validity of administration of paclitaxel and carboplatin with or without pirarubicin (THP-ADR) as first line chemotherapy in elderly patients with gynecologic cancer, we explored the efficacy and safety of these regimens. From October 1, 1998 to September 30, 2001, we administered paclitaxel and carboplatin with or without THP-ADR pursuant to the chart we prepared originally as first line chemotherapy in patients with gynecologic cancer. Eleven elderly patients (age > 70 years) and 62 younger patients (age < 70 years) were entered into the present study. Paclitaxel was administered as a 3-hour intravenous (i.v.) infusion at dosages of 135 to 180 mg/m2 immediately followed by carboplatin over 60 minutes at dosages of area under the curve (AUC) 3 to 5, administered intravenously or intraperitoneally. We observed grade 3/4 anemia more frequently in elderly patients receiving the regimen including paclitaxel and carboplatin without THP-ADR (9% v.s. 47%, p < 0.0001). Grade 3/4 anemia (10% v.s. 22%, p = 0.02) and grade 3/4 thrombocytopenia (7% v.s. 22%, p = 0.007), febrile neutropenia (14% v.s. 44%, p = 0.02) also occurred more frequently in elderly patients receiving the regimen including paclitaxel and carboplatin with THP-ADR. The overall response rates were equivalent among elderly and younger patients (69% and 78%), respectively. The regimen consisting of paclitaxel and carboplatin without THP-ADR was applied safely to elderly patients.

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J Clin Oncol 2003 Mar 1;21(5):799-806
Comment on: J Clin Oncol. 2003 Mar 1;21(5):762-4.
Surgery combined with peritonectomy procedures and intraperitoneal chemohyperthermia in abdominal cancers with peritoneal carcinomatosis: a phase II study.
Glehen O, Mithieux F, Osinsky D, Beaujard AC, Freyer G, Guertsch P, Francois Y, Peyrat P, Panteix G, Vignal J, Gilly FN.
Surgical Department, Anesthesiology and Intensive Care Unit, Medical Oncology Department, Centre Hospitalo-Universitaire Lyon Sud, Pierre Benite, France.

PURPOSE: To evaluate the tolerance of peritonectomy procedures (PP) combined with intraperitoneal chemohyperthermia (IPCH) in patients with peritoneal carcinomatosis (PC), a phase II study was carried out from January 1998 to September 2001. PATIENTS AND METHODS: Fifty-six patients (35 females, mean age 49.3) were included for PC from colorectal cancer (26 patients), ovarian cancer (seven patients), gastric cancer (six patients), peritoneal mesothelioma (five patients), pseudomyxoma peritonei (seven patients), and miscellaneous reasons (five patients). Surgeries were performed mainly on advanced patients (40 patients stages 3 and 4 and 16 patients stages 2 and 1) and were synchronous in 36 patients. All patients underwent surgical resection of their primary tumor with PP and IPCH (with mitomycin C, cisplatinum, or both) with a closed sterile circuit and inflow temperatures ranging from 46 degrees to 48 degrees C. Three patients were included twice. RESULTS: A macroscopic complete resection was performed in 27 cases. The mortality and morbidity rates were one of 56 and 16 of 56, respectively. The 2-year survival rate was 79.0% for patients with macroscopic complete resection and 44.7% for patients without macroscopic complete resection (P =.001). For the patients included twice, two are alive without evidence of disease, 54 and 47 months after the first procedure. CONCLUSION: IPCH and PP are able to achieve unexpected long-term survival in patients with bulky PC. However, one must be careful when selecting the patients for such an aggressive treatment, as morbidity rate remains high even for an experienced team.

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Gynecol Oncol 2003 Feb;88(2):136-40
Three-consecutive-day topotecan is an active regimen for recurrent epithelial ovarian cancer.
Brown JV 3rd, Peters WA 3rd, Rettenmaier MA, Graham CL, Smith MR, Drescher CW, Micha JP.
Gynecologic Oncology Associates, Hoag Memorial Hospital Cancer Center, Newport Beach, CA 92663, USA. iebbrown@cox.net

OBJECTIVE: The aim was to determine the response rate and toxicity of topotecan administered Days 1-3 every 21 days for recurrent epithelial cancers of the ovary, peritoneum, or fallopian tube. A 3-day regimen may be more convenient and less expensive than a 5-day schedule. METHODS: Patients with recurrent epithelial cancer of the ovary, peritoneum, or fallopian tube who had adequate hepatic, renal, and hematologic function were eligible for participation. Topotecan (2 mg/m(2)) was administered for 3 consecutive days every 21 days. Response was measured clinically and serologically. Granulocyte colony stimulating factors (GCSF) were not utilized prophylactically, but could be added under specific conditions. RESULTS: Thirty-one patients with recurrent ovarian cancer whose median age was 63 (range 32-84) received 165 cycles of topotecan (median = 6; range 2-8) and are evaluable for toxicity. The median number of prior regimens was 1. Topotecan was administered on schedule in 96.6% of cycles. Grade 3/4 neutropenia was seen in 29.1 and 23.6% of courses, respectively; but only 3.4% of cycles required GCSF support (6 cycles for 2 patients). Grade 4 thrombocytopenia was rare (1% of cycles). Nonhematologic toxicity was mild. The response rate for 28 evaluable patients was 32.1% (10.7% complete response (CR) and 21.4% partial response (PR)); stable disease was seen in 17.9% of patients. The median progression-free interval (PFI) for all patients was 15.5 weeks (range 5-40). Eighteen platinum-sensitive patients demonstrated a 43.4% response rate (12.5% CR and 31.3% PR); stable disease was documented in 18.8%. The median PFI for platinum-sensitive patients was 18.5 weeks (range 5-40). CONCLUSION: Topotecan is an effective regimen with acceptable toxicity for recurrent ovarian cancer when administered for 3 consecutive days (2 mg/m(2)) every 21 days. It can be delivered on schedule without GCSF support in the vast majority of patients.

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Gynecol Oncol 2003 Feb;88(2):130-5
A phase II study of docetaxel in paclitaxel-resistant ovarian and peritoneal carcinoma: a Gynecologic Oncology Group study.
Rose PG, Blessing JA, Ball HG, Hoffman J, Warshal D, DeGeest K, Moore DH.
Case Western Reserve University, Division of Gynecologic Oncology, University Hospitals of Cleveland, Cleveland, OH 44106, USA. prose@metrohealth.org

OBJECTIVES: Docetaxel is an inhibitor of microtubule depolymerization and has demonstrated activity in paclitaxel-resistant breast cancer and gynecologic cancer. The Gynecologic Oncology Group (GOG) conducted a study of docetaxel in paclitaxel-resistant ovarian and peritoneal carcinoma to determine its activity, and nature and degree of toxicity, in this cohort of patients. METHODS: Patients with platinum- and paclitaxel-resistant ovarian or peritoneal carcinoma, defined as progression while on or within 6 months of therapy, were eligible if they had measurable disease and had not received more than one chemotherapy regimen. Docetaxel at a dose of 100 mg/m(2) was administered iv over 1 h every 21 days. A prophylactic regimen of oral dexamethasone 8 mg bid was begun 24 h before docetaxel administration and continued for 48 h thereafter. Hepatic function was strictly monitored. RESULTS: Sixty patients were entered and treated with a total of 256 courses, with all 60 evaluable for toxicity and 58 evaluable for response. Responses were observed in 22.4% of patients, with 5.2% achieving complete response and 17.2% achieving partial response (95% CI, 12.5-35.3%). The median duration of response was 2.5 months. The likelihood of observing a response did not appear to be related to the length of the prior paclitaxel-free interval or duration of prior paclitaxel infusions. The principal adverse effect of grade 4 neutropenia occurred in 75% of patients. There was one treatment-related death. Dose reductions were required in 36% of patients. CONCLUSIONS: Docetaxel is active in paclitaxel-resistant ovarian and peritoneal cancer but, in view of significant hematologic toxicity, further study is warranted to ascertain its optimal dose and schedule.

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Gynecol Oncol 2003 Feb;88(2):118-22
Altretamine (hexamethylmelamine) in the treatment of platinum-resistant ovarian cancer: a phase II study.
Keldsen N, Havsteen H, Vergote I, Bertelsen K, Jakobsen A.
Department of Oncology, Herning Hospital, Herning, Denmark. hecnk@ringamt.dk

OBJECTIVE: To evaluate the activity of oral Altretamine in women with epithelial ovarian carcinoma who responded (PR or CR) to first line chemotherapy but relapsed within 6 months. The protocol was later amended to include patients with relapse within 12 months. METHODS: A multicentric phase II trial. The patients had to have measurable disease. No more than one prior chemotherapy regiment was allowed. The patients were treated with 260 mg/m(2)/day of Altretamine in four divided doses for 2 weeks, repeated every 4 weeks. The response was evaluated after every two courses. RESULTS: Thirty-one eligible patients were treated with a median of 3 courses of Altretamine (range 1-12). Hematological toxicity was minimal. Gastrointestinal toxicity was common. Response evaluation was possible for 26 patients. Three patients (9.7% intent-to-treat) achieved a partial response. Eight patients had stable disease, and 15 patients had progressive disease after two treatment courses. The median time to progression was 10 weeks (range, 5-51 weeks). Medial survival was 34 weeks (range, 7-112+). CONCLUSION: Altretamine should not be chosen as standard treatment in patients with platinum-resistant recurrent ovarian cancer. However, Altretamine represents a useful alternative in patients who prefer oral treatment or when socioeconomic considerations are an important issue.

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Obstet Gynecol 2003 Feb;101(2):251-7
Reproductive function after conservative surgery and chemotherapy for malignant germ cell tumors
of the ovary.
Tangir J, Zelterman D, Ma W, Schwartz PE.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut 06520-8063, USA.

OBJECTIVE: To analyze the long-term effects on reproductive function of fertility-preserving treatment for malignant germ cell tumors of the ovary. METHODS: A case series analysis was performed on patients with malignant germ cell tumors of the ovary seen or consulted on at our institution between 1975 and 1995. Follow-up information regarding reproductive function was obtained by a mailed or telephone questionnaire. RESULTS: A total of 106 patients with malignant germ cell tumors of the ovary were included in the study. Twenty patients were excluded because of loss of follow-up or death. For the remaining 86 patients, the median follow-up was 122 months (24-384 months). Fertility-preserving surgery was performed in 64 patients. Thirty-eight have attempted conception and 29 have achieved at least one pregnancy (76%). Among the patients who conceived, 20 were International Federation of Gynecology and Obstetrics (FIGO) stage I, one was stage II, and eight were stage III. Sixteen received vincristine, actinomycin D, and cyclophosphamide; three received cisplatin, vinblastine, and bleomycin; three received bleomycin, etoposide, and cisplatin; one received etoposide and cisplatin; four did not receive any chemotherapy; and two were treated with other combinations. Among the nine patients who could not conceive, seven were FIGO stage I and two were stage III. Four of these patients received vincristine, actinomycin D, and cyclophosphamide; three received etoposide and cisplatin; one received cisplatin, vinblastine, and bleomycin; and one patient received no chemotherapy. A total of 38 children were born to these women. Follow-up was available for 16 of these children, who have no evidence of congenital anomalies. CONCLUSION: Fertility-preserving surgery followed by chemotherapy, even in advanced-stage malignant germ cell tumors of the ovary, is effective in conserving the reproductive function of women with malignant germ cell tumors of the ovary.

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Int J Radiat Oncol Biol Phys 2003 Mar 1;55(3):707-12
Comment in: Int J Radiat Oncol Biol Phys. 2003 Mar 1;55(3):563-4.
Poly(L-glutamic acid)-paclitaxel conjugate is a potent enhancer of tumor radiocurability.
Milas L, Mason KA, Hunter N, Li C, Wallace S.
Department of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030-4095, USA. lmilas@mdanderson.org

PURPOSE: Conjugating drugs with polymeric carriers is one way to improve selective delivery to tumors. Poly (L-glutamic acid)-paclitaxel (PG-TXL) is one such conjugate. Compared with paclitaxel, its uptake, tumor retention, and antitumor efficacy are increased. Initial studies showed that PG-TXL given 24 h before or after radiotherapy enhanced tumor growth delay significantly more than paclitaxel. To determine if PG-TXL-induced enhancement is obtained in a more clinically relevant setting, we investigated PG-TXL effects on tumor cure. METHODS AND MATERIALS: Mice bearing 7-mm-diameter ovarian carcinomas were treated with PG-TXL at an equivalent paclitaxel dose of 80 mg/kg, single dose or 5 daily fractions of radiation or both PG-TXL and radiation. Treatment endpoint was TCD(50) (radiation dose yielding tumor control in 50% of mice). Acute radioresponse of jejunum, skin, and hair was determined for all treatments. RESULTS: PG-TXL dramatically improved tumor radioresponse, reducing TCD(50) of single-dose irradiation from 53.9 (52.2-55.5) Gy to 7.5 (4.5-10.7) Gy, an enhancement factor (EF) of 7.2. The drug improved the efficacy of fractionated irradiation even more, reducing the TCD(50) of 66.6 (62.8-90.4) Gy total fractionated dose to only 7.9 (4.3-11.5) Gy, for an EF of 8.4. PG-TXL did not affect normal tissue radioresponse resulting from either single or fractionated irradiation. CONCLUSION: PG-TXL dramatically potentiated tumor radiocurability after single-dose or fractionated irradiation without affecting acute normal tissue injury. To our knowledge, PG-TXL increased the therapeutic ratio of radiotherapy more than that previously reported for other taxanes, thus, PG-TXL has a high potential to improve clinical radiotherapy.

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Gan To Kagaku Ryoho 2003 Jan;30(1):151-4
[Weekly paclitaxel infusion in patients with recurrent ovarian cancer--a pilot study]
[Article in Japanese]
Kawagoe H, Kawata T, Nishio S, Shimomura T, Fujiyoshi K, Ishimatsu J, Tsunawaki A.
Dept. of Obstetrics and Gynecology, Kumamoto City Hospital.

This preliminary study was performed to evaluate the safety and efficacy of weekly paclitaxel administration by 1-hour infusion. A total of 7 patients with recurrent ovarian cancer were treated with weekly paclitaxel (TXL). TXL was given at a dose of 70 mg/m2 in 1-hour infusions every week for at least 20 consecutive weeks unless lesions became progressive. Premedication was administered 30 min before TXL infusion. The 7 patients received a total 110 cycles of therapy. Hypersensitivity reactions were not observed. Grade 3 or 4 neutropenia occurred in only 0.9% of the cycles. Neurotoxicity was commonly observed, but that of grade 3 or greater severity was not recorded. No other severe non-hematologic toxicities were observed. Partial responses were seen in three of 7 patients. Weekly 1-hour TXL is considered to be safe and effective as a salvage therapy in patients with recurrent ovarian cancer.

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Gan To Kagaku Ryoho 2003 Jan;30(1):141-4
[Two cases of complete response to combination chemotherapy of gemcitabine and docetaxel for recurrent ovarian cancer]
[Article in Japanese]
Ito K, Adachi S, Iijima T, Nakatsuji Y, Kimura T, Nobunaga T.
Dept. of Obstetrics and Gynecology, Kansai Rosai Hospital.

The established standard treatment for advanced ovarian cancer is carboplatin and paclitaxel. However, more than 70% of patients have recurrent disease. The standard therapy for recurrent ovarian cancer has not been confirmed. It was reported that docetaxel had a 30-40% of response rate in patients with recurrent ovarian cancer, and that gemcitabine had a 13-22% response rate. The combination chemotherapy of gemcitabine and docetaxel is also applied to non-small cell lung cancer. We use a regimen of 800 mg/m2 of gemcitabine on day 1 and day 8 in combination with 70 mg/m2 of docetaxel on day 8 with a 3-week interval. We treated 2 patients with recurrent ovarian cancer who responded completely to combination chemotherapy with gemcitabine and docetaxel.

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J Obstet Gynaecol 2002 Nov;22(6):666-8
The effect of platinum-based combination chemotherapy on the lymph nodes in advanced-stage epithelial ovarian cancer: does it decrease the incidence of lymph node involvement?
Simsek T, Simsek M, Pesterelli E, Karaveli S, Trak B.
Department of Obstetrics and Gynaecology, Akdeniz University School of Medicine, Antalya, Turkey. Simsek@med.akdeniz.edu.tr

This paper aims to determine the impact of platinum-based combination chemotherapy on the lymph nodes in advanced-stage epithelial ovarian carcinoma. From 1997 to 2000, the patients in whom we performed lymphadenectomy before (group A) or after chemotherapy (group B) in the Department of Obstetrics and Gynecology, Akdeniz University School of Medicine were enrolled in this study. A total of 47 cases were included in the study. Twenty five cases had lymphadenectomy during the initial laparatomy and 22 cases during second-look procedures. Lymph node metastasis was detected in 14 (56%) patients in group A and in 10 (45.4%) cases in group B (P > 0.05). Platinum-based combination chemotherapy does not decrease significantly the incidence of involved lymph nodes in advanced-stage epithelial ovarian carcinoma.

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Anticancer Res 2002 Nov-Dec;22(6B):3669-71
Tissue polypeptide specific antigen (TPS) and carbohydrate antigen 125 (CA-125) in the early prediction of recurrent ovarian cancer.
Yeh LS, Hung YC, Kao A, Lin CC, Lee CC.
Department of OBS/GYN, China Medical College Hospital, No. 2, Yuh-Der Road, Taichung 404, Taiwan.

It is very important to establish a tumor marker combination with strong lead-time effects in early detection of recurrent ovarian cancer. This retrospective study included 32 patients with recurrent epithelial ovarian cancer after primary therapy. The serum levels of tissue polypeptide specific antigen (TPS) and carbohydrate antigen 125 (CA-125) were followed-up. Normal upper limits of serum levels of 78.5 U/l for TPS and 35 U/ml for CA-125 were selected according to the 95th percentile of serum concentrations measured in healthy control patients. When compared with other follow-up modalities, TPS and CA-125 appeared lead-time effective with early diagnosis of recurrent ovarian cancer in 18 and 16 patients, respectively. This difference was not statistically significant. The combination of TPS and CA-125 provided lead-time effects in 24 patients. Our data indicate that the combination of TPS and CA-125 is a potential tool in the early prediction of recurrent ovarian cancer.

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Anticancer Res 2002 Sep-Oct;22(5):2923-32
Treosulfan in the treatment of advanced ovarian cancer: a randomised co-operative
multicentre phase III-study.
Breitbach GP, Meden H, Schmid H, Kuhn W, Sass G, Schach S, Schmidt-Rohde P, Bastert G; GTOC Study Group.
Department of Gynecology and Obstetrics, Hospital Neunkirchen gGmbH, Brunnenstr. 20, 66538 Neunkirchen, Germany.

BACKGROUND: In August 1988 a randomised phase III multicenter trial was started in order to compare cisplatinum/treosulfan (PT) with standard cisplatinum/cyclophosphamide (PC) in advanced ovarian carcinoma, aiming at lower toxicity and maintained efficiency. PATIENTS AND METHODS: Five hundred and nineteen patients were enrolled into the protocol. Final evaluation after a median observation time of more than five years was made in July 1996 and included 398 eligible patients, of whom 366 were evaluable regarding efficiency and 290 in respect of toxicity. The tumour stages were classified as FIGO II in 53, FIGO III in 244 and FIGO IV in 68 patients. The patients were stratified regarding post-operative tumour burden. RESULTS: Hematological and gastrointestinal toxicity WHO > = 3 were comparable between the two study arms though a significant difference could be demonstrated regarding alopecia (PT 8% vs. PC 47% after six cycles). The median time to progression as the main efficiency item was in favour of the study schedule (PT 20.6 vs. PC 15.1 months) while significant differences were neither observed in the whole study group nor in the analysed subgroups (R0, < 2 cm, > = 2 cm). The same held true for overall survival. CONCLUSION: PT may be recommended as a less toxic substitute for the former standard PC. After the acceptance of paclitaxel/cisplatin as a new standard, the role of treosulfan should be investigated regarding adjuvant therapy in patients without residual tumor, as a potential partner in triple or sequential treatment and in second-line treatment.

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J Natl Cancer Inst 2003 Jan 15;95(2):125-32
Comment in: J Natl Cancer Inst. 2003 Jan 15;95(2):94-5.
International Collaborative Ovarian Neoplasm trial 1: a randomized trial of adjuvant chemotherapy in women with early-stage ovarian cancer.
Colombo N, Guthrie D, Chiari S, Parmar M, Qian W, Swart AM, Torri V, Williams C, Lissoni A, Bonazzi C; International Collaborative Ovarian Neoplasm (ICON) collaborators.
European Institute of Oncology, Milan, Italy.

BACKGROUND: The question of whether platinum-based adjuvant chemotherapy can improve outcomes in patients with early-stage epithelial ovarian cancer is an important one. We carried out a multicenter, open randomized trial to determine whether adjuvant chemotherapy would improve overall survival and prolong recurrence-free survival in women with early-stage epithelial ovarian cancer. METHODS: Between August 1991 and January 2000, 477 patients in 84 centers in five countries were randomly assigned to receive either adjuvant chemotherapy immediately following surgery (n = 241) or no adjuvant chemotherapy until clinically indicated (n = 236). Kaplan-Meier curves of overall survival and recurrence-free survival were compared using the Mantel-Cox version of the log-rank test. All statistical tests were two-sided. RESULTS: Women who received adjuvant chemotherapy had better overall survival than women who did not (hazard ratio [HR] of 0.66, 95% confidence interval [CI] = 0.45 to 0.97; P =.03). These results translate into 5-year survival figures of 70% for women who did not receive adjuvant chemotherapy and 79% for women who did receive adjuvant chemotherapy, a difference of 9% (95% CI = 1% to 15%). Adjuvant chemotherapy also improved recurrence-free survival (HR = 0.65; 95% CI = 0.46 to 0.91; P =.01). These results translate into 5-year recurrence-free survival figures of 62% for women who did not receive adjuvant chemotherapy and 73% for women who did receive adjuvant chemotherapy, a difference of 11% (95% CI = 3% to 18%). CONCLUSION: These results suggest that platinum-based adjuvant chemotherapy improves survival and delays recurrence in patients with early-stage ovarian cancer.

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J Clin Oncol 2003 Jan 15;21(2):291-7
Phase II trial of irinotecan in patients with metastatic epithelial ovarian cancer or peritoneal cancer.
Bodurka DC, Levenback C, Wolf JK, Gano J, Wharton JT, Kavanagh JJ, Gershenson DM.
Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. dcbourka@mdanderson.org

PURPOSE: To evaluate the efficacy and toxicity of irinotecan in patients with metastatic platinum-resistant or platinum-refractory epithelial ovarian cancer or primary peritoneal cancer. PATIENTS AND METHODS: Thirty-one patients with measurable disease were enrolled in our study at The University of Texas M.D. Anderson Cancer Center. Twenty-five of these patients were treated with irinotecan at a dose of 300 mg/m2 intravenously for 90 minutes every 3 weeks; the remaining six patients were treated with 250 mg/m2 because their age was greater than 65 years. Median age was 57 years (range, 38 to 74 years). The majority (84%) had a Zubrod performance status of 0. All patients were evaluated for irinotecan toxicity, and 29 (94%) were evaluable for response. RESULTS: The overall response rate was 17.2%. One patient (3%) had a complete response, four (14%) had partial responses, 14 (48%) had stable disease, and 10 had (35%) disease progression. Median progression-free survival was 2.8 months (range, 1.1 to 16 months), median duration of response was 1.4 months (range, 0.7 to 10.1 months); median survival from primary diagnosis was 24.3 months (range, 6.5 to 85.7 months); and median survival from initiation of irinotecan was 10.1 months (range, 2.3 to 34 months). Major toxicities included fatigue (16 patients), neutropenia (11 patients), diarrhea (nine patients), nausea (10 patients), and anorexia (seven patients). Eleven patients required dose reductions because of these toxicities. No treatment-related deaths occurred. CONCLUSION: Irinotecan has moderate efficacy and substantial toxicity in patients with metastatic platinum-resistant or platinum-refractory epithelial ovarian or primary peritoneal cancer.

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J Clin Oncol 2003 Jan 15;21(2):283-90
Evaluation of monoclonal humanized anti-HER2 antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2: a phase II trial of the Gynecologic Oncology Group.
Bookman MA, Darcy KM, Clarke-Pearson D, Boothby RA, Horowitz IR.
Division of Medical Science, Fox Chase Cancer Center, Rockledge, PA, USA. ma_bookman@fccc.edu

PURPOSE: To evaluate the feasibility, toxicity, and efficacy of single-agent monoclonal antibody therapy targeting the human epidermal growth factor receptor 2 (HER2)/neu receptor in ovarian and primary peritoneal carcinoma. PATIENTS AND METHODS: Eligible patients had measurable persistent or recurrent epithelial ovarian or primary peritoneal carcinoma with 2+ or 3+ HER2 overexpression documented by immunohistochemistry. Intravenous trastuzumab was administered initially at a dose of 4 mg/kg, then weekly at 2 mg/kg. Patients without progressive disease or excessive toxicity could continue treatment indefinitely. Those with stable or responding disease at 8 weeks were offered treatment at a higher weekly dose (4 mg/kg) at time of progression. Patient sera were analyzed for the presence of the soluble extracellular domain of HER2, host antibodies against trastuzumab, and trastuzumab pharmacokinetics. RESULTS: A total of 837 tumor samples were screened for HER2 expression, and 95 patients (11.4%) exhibited the requisite 2+/3+ expression level. Forty-five patients, all of whom received prior chemotherapy, were entered, and 41 were deemed eligible and assessable. There were only mild expected toxicities and no treatment-related deaths. Although an elevated level of the soluble extracellular domain of HER2 was detected in eight of 24 patients, serum HER2 was not associated with clinical outcome. There was no evidence of host antitrastuzumab antibody formation. Serum concentrations of trastuzumab gradually increased with continued therapy. An overall response rate of 7.3% included one complete and two partial responses. Median treatment duration was 8 weeks (range, 2 to 104 weeks), and median progression-free interval was 2.0 months. CONCLUSION: The clinical value of single-agent trastuzumab in recurrent ovarian cancer is limited by the low frequency of HER2 overexpression and low rate of objective response among patients with HER2 overexpression.

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Bull Cancer 2002 Dec;89(12):1019-26
[Conservative management of malignant and borderline ovarian tumor]
[Article in French]
Morice P, Camatte S, Wickart-Poque F, Rouzier R, Pautier P, Pomel C, Lhomme C, Haie-Meder C, Duvillard P, Castaigne D.
Service de chirurgie oncologique gynecologique, Institut Gustave-Roussy, 39, rue Camille-Desmoulins, 94805 Villejuif, France.

Conservative management of at least a part of one ovary and the uterus, in order to preserve fertility-potential, could be propose in most of patients with nonepithelial and borderline ovarian tumor. This conservative management could be performed even in patients with borderline ovarian tumor associated with noninvasive peritoneal implants (if complete resection of peritoneal disease). A removal of the preserved ovary after completion of the pregnancy(ies) is not necessary if patients agree to a careful follow-up procedure. In patient with epithelial ovarian cancer, conservative management could be performed only in case of young patients who desire to preserve fertility function with: unilateral tumor (stage IA), grade 1 (and 2?), who underwent an adequate staging surgery (including peritoneal washings, omentectomy, multiple peritoneal biopsies, uterine curettage and complete pelvic and paraaortic lymphadenectomy) and with a careful follow-up. A conservative management should not be performed in patients with tumor stage > IA and/or grade 3. Removal of preserved ovary should be performed after completion of pregnancy(ies) in order to reduce the risk of ovarian recurrence.

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Hua Xi Yi Ke Da Xue Xue Bao 2000 Jun;31(2):188-90
[The effect of intraperitoneal chemotherapy on retroperitoneal lymph node metastasis of ovarian cancer]
[Article in Chinese]
Niu X, Peng Z, Ding S, Yang K.
Department of Gynecology and Obstetrics, Second Affiliated Hospital, WCUMS, Chengdu 610041.

The objective of this study was to investigate the effect of intraperitoneal chemotherapy(repeated injections of cisplatin in small doses during a short time) on retroperitoneal lymph node metastasis of ovarian cancer. Thirty patients with ovarian cancer were selected and divided into two groups. The patients in the first group received intraperitoneal chemotherapy only once (48 hours before operation); the patients in the second group received intraperitoneal chemotherapy twice (96 hours and 48 hours before operation). After the intraperitoneal chemotherapy, according to the predicted time, the Pt concentrations of the tissues were measured by flameless atomic absorption spectrometry; the pathologic examinations of the lymph nodes were carried out. The results showed that the drug concentrations of the aortic, obturator and iliac lymph nodes of the first group were not significantly different, neither were the drug concentrations of the lymph nodes of the second group. The drug concentrations of the lymph nodes of the first and the second groups were 2.06 and 1.91 times that of the surrounding tissues respectively. Also, the drug concentrations of peritoneum of the first and the second groups were 4.14 and 2.50 times that of the lymph nodes. The drug concentrations of the iliac, obturator and aortic lymph nodes of the second group were 2.27, 2.75 and 2.54 times that of the first group (P < 0.005). Under light microscope, the metastatic cancer tissues in lymph nodes showed liquefaction necrosis in the second group. The results indicate that small doses of cisplatin given by repeated injections during a short time can lead to drug accumulation and consequently high efficacy with low toxicity, suggesting that this method may be used for the treatment of lymphatic metastasis of ovarian cancer.

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Gynecol Oncol 2003 Jan;88(1):51-7
Weekly low-dose carboplatin and paclitaxel in the treatment of recurrent ovarian and peritoneal cancer.
Havrilesky LJ, Alvarez AA, Sayer RA, Lancaster JM, Soper JT, Berchuck A, Clarke-Pearson DL, Rodriguez GC, Carney ME.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina 27710, USA. havri001@mc.duke.edu

OBJECTIVES: Weekly paclitaxel alone has moderate activity in the salvage treatment of recurrent ovarian cancer and is associated with a favorable toxicity profile. Combination paclitaxel and carboplatin is a well-established first-line regimen for ovarian cancer. The purpose of this study was to evaluate weekly low-dose paclitaxel and carboplatin in recurrent ovarian or peritoneal cancer. METHODS: Patients with recurrent ovarian or peritoneal cancer previously treated with between one and four chemotherapeutic regimens were eligible. Patients had measurable or assessable disease defined by clinical exam, radiographic studies, or serum CA-125 greater than 75 U/ml. One cycle of treatment consisted of carboplatin at an area under the curve of 2 and paclitaxel at 80 mg/m(2) on days 1, 8, and 15 on a 28-day cycle. Clinical responses were defined by established criteria. RESULTS: Twenty-nine patients were included in this intent-to-treat study. The median number of prior treatment regimens was 2 (range 1 to 4). The overall response rate was 82.8% (16 complete clinical responses, 8 partial responses). Among 8 platinum-refractory patients, the response rate was 37.5%, while 21 platinum-sensitive patients had a 100% response rate. Median time to progression was 13.7 months among platinum-sensitive patients and 3.2 months among platinum-refractory patients. Overall median time to progression was 11.5 months and median-duration of response was 9.9 months. Hematologic toxicity was common (32% grade 3 neutropenia, no grade 4 neutropenia, 14.2% grade 3 or 4 thrombocytopenia) and managed by treatment delay, dose reduction of paclitaxel, or discontinuation of carboplatin. CONCLUSION: Weekly low-dose carboplatin and paclitaxel has significant activity in both platinum-sensitive and platinum-resistant recurrent ovarian cancer with acceptable toxicity that is easily managed by dose adjustment.

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Gynecol Oncol 2003 Jan;88(1):35-9
Phase II trial of gemcitabine plus cisplatin repeating doublet therapy in previously treated, relapsed
ovarian cancer patients.
Nagourney RA, Brewer CA, Radecki S, Kidder WA, Sommers BL, Evans SS, Minor DR, DiSaia PJ.
Rational Therapeutics, Inc., Long Beach, California 90806, USA. Robert.Nagourney@RationalTherapeutics.com

OBJECTIVES: The aim was to determine the safety and efficacy of gemcitabine plus cisplatin for patients with relapsed ovarian carcinoma and to compare ex vivo drug sensitivity profiles with clinical outcomes. PATIENTS AND METHODS: Previously treated patients with ovarian carcinoma received cisplatin (30 mg/m(2)) plus gemcitabine (600-750 mg/m(2)) on Days 1 and 8 of each 21-day cycle. Seventeen of the 27 patients underwent ex vivo analyses for correlation with clinical response. RESULTS: Of 27 patients, there were 7 (26%) complete and 12 (44%) partial responses, for an overall response rate of 70% (95% CI: 53-87%). Toxicities included neutropenia Grade III in 51.9%, Grade IV in 29.6%; anemia Grade III in 18.5 %; thrombocytopenia Grade III in 66.7 %, Grade IV in 29.6%; nausea and vomiting Grade III in 14.8 %; peripheral neuropathy Grade III in 3.7%; and alopecia Grade IV in 11.1% of patients. The median time to progression for objective responders was 7.9 months with a range of 2.1 to 13.2 months. There were no treatment-related deaths. Ex vivo results correlated with response, time to progression, and survival, remaining significant when adjusted for platin-resistance and number of prior therapies. Adjustment for platin-free interval decreased the significance but did not, in and of itself, predict significantly for progression-free survival. CONCLUSIONS: Cisplatin plus gemcitabine is active for patients with relapsed ovarian cancer. Toxicities, primarily hematologic, are manageable with dose modifications. Responses observed in heavily pretreated and platin-resistant patients indicate activity in drug-refractory patients. The results of the ex vivo analyses correlate with clinical outcomes.

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Gynecol Oncol 2003 Jan;88(1):17-21
Gemcitabine reverses cisplatin resistance: demonstration of activity in platinum- and multidrug-resistant ovarian and peritoneal carcinoma.
Rose PG, Mossbruger K, Fusco N, Smrekar M, Eaton S, Rodriguez M.
Case Western Reserve University and Ireland Cancer Center, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University Hospitals of Cleveland, Ohio 44106, USA.

OBJECTIVE: Preclinical models in an ovarian cancer cell line (A2780) demonstrate synergistic activity with the combination of gemcitabine and cisplatin compared to either single agent alone. Platinum resistance is related to expression of excision repair proteins, one of which (ERCC-1) has been identified as playing a critical role in the synergy of gemcitabine and cisplatin. We evaluated the cisplatin and gemcitabine regimen in patients with platinum refractory and multidrug refractory ovarian and peritoneal carcinoma. METHODS: Gemcitabine (750 mg/m(2)) was administered intravenously over 30 min followed by cisplatin (30 mg/m(2)) on Days 1 and 8 every 21 days. Day 8 therapy was canceled for an absolute neutrophil count <1000/mm(3) or platelet count <75,000/mm(3). Sequential dose reductions of gemcitabine to 600, 400, and 300 mg/m(2) were prescribed in the event of canceled therapy, neutropenic sepsis, or severe thrombocytopenia (platelets <20,000/m(3)). RESULTS: Thirty-six platinum- and paclitaxel-resistant patients were studied. Thirty-five were evaluable for response, of which 6 had progressed on gemcitabine as a single agent. Fifteen of the patients responded (42.9%, 95% CI 28.0-59.1%). Eleven were partial clinical responses and 4 were complete clinical responses, with 4 of the 6 patients who had failed gemcitabine as a single agent responding. Among the responding patients the median response duration was 11 months (range 4-14 months). For all patients the progression-free interval was 6 months (range 1-14 months). The median survival was 12 months. CONCLUSION: The combination of gemcitabine and cisplatin is active in patients who are platinum resistant. Additionally, activity is demonstrated even in patients who have previously been resistant to gemcitabine.

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Gynecol Oncol 2003 Jan;88(1):9-16
Quality of life in women treated with neoadjuvant chemotherapy for advanced ovarian cancer: a prospective longitudinal study.
Chan YM, Ng TY, Ngan HY, Wong LC.
Department of Obstetrics and Gynecology, Queen Mary Hospital, University of Hong Kong, China. chanymjoe@hotmail.com

OBJECTIVE: The purpose was to examine the outcomes of patients with advanced ovarian cancer treated with neoadjuvant chemotherapy, with a special emphasis on the patients' quality of life (QOL). METHODS: Seventeen patients with advanced ovarian cancer were treated with neoadjuvant chemotherapy based on the extent of disease on computer tomography. All patients received combined platinum/paclitaxel chemotherapy. Debulking surgery was performed after three cycles or six cycles of chemotherapy, depending on the response to the chemotherapy. Patients' QOL was studied over time using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 and was then compared with that of patients treated with conventional treatment in the previous cohort. RESULTS: The response rate to chemotherapy assessed at three cycles was 82.4%. The rate of optimum debulking to residual disease less than 2 cm after chemotherapy was 76.9%, and 38.5% had no gross residual disease after surgery. The median overall survival was 22.9 months. The median disease-free interval was 13.3 months. The overall QOL improved after chemotherapy and this continued to improve up to 12 months. The other functional scales also showed improvements over time, apart from the initial transient deterioration in the role functioning and cognitive functioning at 3 months after chemotherapy. Patients treated with neoadjuvant chemotherapy seem to have better but statistically insignificant difference in QOL parameters than patients treated conventionally. CONCLUSION: Neoadjuvant chemotherapy is an alternative treatment for patients with advanced ovarian cancer in whom the chance of optimal cytoreduction is low. The patients' overall quality of life and functional status improve after neoadjuvant chemotherapy.

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Gynecol Oncol 2003 Jan;88(1):3-8
Comment in: Gynecol Oncol. 2003 Jan;88(1):1-2.
Pilot evaluation of high-dose carboplatin and paclitaxel followed by high-dose melphalan supported by peripheral blood stem cells in previously untreated advanced ovarian cancer: a gynecologic oncology group study.
Schilder RJ, Brady MF, Spriggs D, Shea T.
Department of Medical Oncology, Fox Chase Center, Philadelphia, Pennsylvania 19111, USA. rj_schilder@fccc.edu

OBJECTIVES: To evaluate the efficacy and safety of multiple cycles of high-dose carboplatin and paclitaxel and one consolidation cycle of high-dose melphalan with all cycles supported by hematopoietic stem cells and cytokine, in previously untreated patients with optimally debulked stage III epithelial ovarian cancer. PATIENTS AND METHOD: Patients had histologically documented epithelial ovarian cancer and optimal initial cytoreductive surgery. No prior chemotherapy was permitted. Adequate performance status, bone marrow, hepatic, and renal function was required. After being mobilized with cyclophosphamide 3 g/m(2), paclitaxel 300 mg/m(2), and filgrastim 5 microg/kg/day, peripheral blood stem cells (PBSC) were collected by leukapheresis. Patients received three cycles of carboplatin AUC 15 mg. min/ml iv, paclitaxel 250 mg/m(2), and PBSC with filgrastim every 28 days, followed by one cycle of melphalan 140 mg/m(2) and hematopoietic support. RESULTS: Nine patients entered the trial and received all planned cycles of chemotherapy. Of the eight patients who consented to surgical reassessment upon completing therapy, four had residual small-volume macroscopic disease, three had microscopic residual disease, and one had pathologic complete response. The estimated probability of a pathologic complete response was 12.5% (95% confidence interval: 0.3-52.7%). Hematologic toxicity was severe but manageable. Eleven of 45 cycles (24.4%) resulted in hospital admission for neutropenic fever, dehydration +/- diarrhea, syncope, or shortness of breath and pain secondary to tense ascites. CONCLUSIONS: The low pathological complete response rate did not justify toxicity; thus, the study was closed. High-dose chemotherapy as first-line treatment for epithelial ovarian cancer remains experimental and should be restricted to clinical trials.

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Gan To Kagaku Ryoho 2002 Nov;29(12):2336-8
[A case of ovarian cancer in which a remarkable effect was seen with low-dose CDDP intratumoral injection of CPT-11]
[Article in Japanese]
Inoue S, Kagawa M, Watanabe Y, Kusanishi H.
Dept. of Obstetrics and Gynecology, Akashi Municipal Hospital, Hyogo.

We treated an ovarian cancer patient in whom low-dose CDDP intratumoral injection with CPT-11 therapy was very effective. The patient was a 63-year-old woman. She showed symptoms of peritonitis. Carcinomatous peritonitis was suspected on abdominal CT scan and tumor markers were at high levels (CA125 10,827 U/ml, SLX 82 U/ml). At laparotomy, massive ascites (3,000 ml), omental cakes and disseminated peritoneal tumors were revealed. Her uterus and adnexa were not enlarged. The omental tumor and ovaries were biopsied and revealed serous adenocarcinoma. The patient was treated with combined chemotherapy of CDDP and CPT-11. CDDP (20 mg/day) was administered by intraperitoneally for 3 days, and CDDP (10 mg/day) was administered by intratumoral injection (percutaneous for omental tumor) for 5 days. CPT-11 (40 mg/day) was administered twice a week. As a result, marked shrinkage of the tumors was confirmed. This low-dose CDDP intratumoral injection with CPT-11 may be effective for such omental tumors with carcinomatous peritonitis.

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Ai Zheng 2002 Aug;21(8):863-7
[Impact of arsenic trioxide on proliferation and metastasis of drug-resistant human ovarian
carcinoma cell line]
[Article in Chinese]
Huang SG, Kong BH, Ma YY, Jiang S.
Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan 250012, P. R. China. shouguohuang@21cn.com

BACKGROUND & OBJECTIVE: The drug-resistance and metastasis in early stages of human malignant ovarian neoplasm have significant effect on chemotherapy of human ovarian carcinoma. The objective of this study was to explore the impact of arsenic trioxide(As2O3) on proliferation and metastasis of drug-resistant human epithelial ovarian carcinoma cell line 3AO/cDDP, in order to treat human ovarian carcinoma thoroughly. METHODS: The growing inhibiting rates of drug-resistant human ovarian carcinoma cell line 3AO/cDDP by various concentrations of As2O3 in different time course were studied by methyl thiazolyl tetrazolium (MTT) method; Apoptosis percentage, cell cycle phase distribution and expressions of Fas, N-myc, nm23H1 and MTA1 gene were estimated by flow cytometry (FCM); 3AO/cDDP cells apoptosis phenotype was observed by transmissional electron microscopy. RESULTS: 3AO/cDDP cell growing inhibiting rates by As2O3 were significantly different in dose-dependent and time-dependent manners(P < 0.05); Within a certain concentration range, 3AO/cDDP apoptosis inducing rates by As2O3 were dose- and time-dependent, and the most appropriate concentration was 3.0 mumol/L. Lower concentrations of As2O3 perturbed cell progressing through S/G2 phase, while higher concentrations selectively induced S phase cells apoptosis; As2O3 up-regulated Fas and nm23H1 gene expressions, but down-regulated N-myc and MTA1 gene expressions. Morphological observation indicated that As2O3 inducing 3AO/cDDP death characterized by apoptotic phenotype. CONCLUSION: As2O3 could influence the capacity of growth and proliferation of drug-resistant human ovarian carcinoma cell line and its mechanism could be positively and negatively related with Fas, nm23H1 gene and N-Myc, MTA1 gene expressions.

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Gynecol Oncol 2002 Nov;87(2):171-7
A phase I study of weekly topotecan and Paclitaxel in previously treated epithelial ovarian
carcinoma patients.
Homesley H, Benigno B, Williams J, Vaccarello L.
Brookview Research Inc. Nashville, Tennessee 37203, USA. hdh7173@aol.com

OBJECTIVE: We have previously reported on the feasibility of weekly topotecan as single-agent therapy in previously treated patients with ovarian cancer. The objective of this study was to assess the maximum tolerated dose (MTD) of weekly bolus intravenous (IV) topotecan combined with weekly paclitaxel in a comparable patient population. METHODS: Previously treated ovarian cancer patients with measurable disease and/or elevated cancer antigen 125 (CA-125) received (as second-line or third-line therapy) weekly 30-min bolus IV topotecan starting at 2 mg/m(2) combined with weekly paclitaxel starting at a dose of 60 mg/m(2). In this intrapatient dose-escalation study, topotecan and paclitaxel were escalated in parallel until the MTD was reached, defined as the first dose level at which >or= 2 of 6 patients experienced dose-limiting toxicity. RESULTS: Twenty-one of 26 patients were evaluable for toxicity and received a total of 306 weeks of therapy (median, 13 weeks; range, 5 to 33 weeks). No significant dose-limiting toxicity was observed up to a weekly bolus IV topotecan dose of 3 mg/m(2) and a concurrent paclitaxel dose of 80 mg/m(2). The MTD was topotecan 3.5 mg/m(2) plus 90 mg/m(2) paclitaxel. The dose-limiting toxicities included anemia and fatigue, with 10 of 21 patients receiving epoetin alfa for grade 3 or 4 anemia; only 1 patient required a blood transfusion. Two patients had a treatment delay of at least 1 week and only 1 patient required a dose reduction to maintain the weekly schedule. CONCLUSIONS: Based on the results of this study, the recommended initial dose for this novel regimen is topotecan 3 mg/m(2) and paclitaxel 80 mg/m(2). Further investigation of the efficacy of weekly topotecan plus paclitaxel in less heavily pretreated patients is warranted.

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Zhonghua Yi Xue Za Zhi 2002 Sep 10;82(17):1207-10
[Anti-tumor effect of lentivirus-mediated MUCI antibody-targeted gene therapy with VP22-TK system on MUC1(+) human ovarian cancer transplanted intraperitoneally in nude mice]
[Article in Chinese]
Kong B, Wang W, Liu C, Ma D, Qu X, Jiang J, Yang X, Zhang Y, Jiang S.
Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan 250012, China.

OBJECTIVE: To investigate the anti-tumor effect of anti-MUCI single-chain variable fragment (ScFv)-targeted and lentivirus-mediated herpes simplex virus structural protein VP22 and thymidinre kinase (TK) therapy on MUC1(+) human ovarian epithelial carcinoma tumor in mice transplanted intraperitoneally. METHODS: Lentiviruses scFv-VP22-TK and VP22-TK were constorted Ten female BABL/c mice were injected intraperitoneally with MUC1+ human ovarian epithelial carcinoma cells line 3AO and then pathological examination was done to those mice that died of tumor. A human ovarian epithelial carcinoma model was established in another 30 female mice and they were randomly divided into 6 groups of 5 mice: NS (normal saline) + NS group (injected intraperitoneally with NS once per day for 3 days and then with NS 24 h after once a day for 5 days), VP22-TK + NS group (injected with herpes simplex virus structural protein VP22 and TK once a day for three days and then with NS 24 h after once a day for 5 days), scFv-VP22-TK + NS group (injected with scFv-VP22-TK and then NS in the same way), NS + ganciclovir (GCV) group (injected with NS and then with GCV), VP22-TK + GCV group (injected with VP22-TK and then GCV), and scFv-VP22-TK + GCV group (injected with scFv-VP22-TK and then GCV). The survival time was observed. Ten female nude mice without injection of tumor cells were injected with scFv-VP22-TK or VP22-TK, each for 5 mice; 3 weeks later their abdominal organs were examined to observe the effects of lentivirus on organs. RESULTS: All of the first ten mice injected with human ovarian epithelial carcinoma cells died of tumor. The mean survival times of the six experimental groups were 18.4 d +/- 2.9 d, 18.8 d +/- 1.5 d, 17.6 d +/- 1.1 d, 18.5 d +/- 1.6 d, 24 d +/- 5 d, and 46 d +/- 22 d respectively with significant differences between the VP22-TK + GCV group and NS + GCV group (chi(2) = 6.71, P = 0.009), between the scFv-VP22-TK + GCV group and NS + GCV group (chi(2) = 9.7, P = 0.002), and between the scFv-VP22-TK + GCV group and the VP22-TK + GCV group (chi(2) = 7.43, P = 0.006). Necrosis and apoptosis could be seen in the tumors in the VP22-TK + GCV group and scFV-VP22-TK + GCV group. No toxicity was observed in the mice injected with only scFv-VP22-TK or VP22-TK. CONCLUSION: The anti-MUCI ScFv-targeted and lentivirus-mediated herpes simplex virus VP22 and thymidinre kinase (TK) gene therapy has a significant anti-tumor effect on MUC1+ human ovarian epithelial carcinoma.

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Gan To Kagaku Ryoho 2002 Nov;29(11):1943-9
[Combination chemotherapy of paclitaxel followed by nedaplatin for human ovarian cancer]
[Article in Japanese]
Uchida N, Yamada H, Maekawa R, Yoshioka T.
Discovery Research Laboratory, Shionogi & Co., Ltd.

The antitumor activity of a combination of paclitaxel (TXL) followed by nedaplatin (NDP) against SK-OV-3 human ovarian cancer was evaluated. We also compared the antitumor activity of TXL plus NDP with that of TXL plus carboplatin (CBDCA) or TXL plus cisplatin (CDDP). TXL was injected i.v. daily for four days and either NDP, CBDCA or CDDP was injected i.v. once after the TXL treatment, into tumor-bearing mice. The sequential administration of TXL prior to NDP resulted in enhanced inhibition of tumor growth in comparison with either TXL or NDP monotherapy. The combination in TXL plus NDP was synergistic and superior to that of TXL plus CDDP or TXL plus CBDCA therapy. Histological tests demonstrated that the fraction of BrdU-incorporated cells in tumor tissue was significantly inhibited by the combination of TXL with NDP. These results demonstrated the antitumor efficacy of TXL with NDP against human ovarian cancer and suggest the clinical effectiveness of combination of TXL with NDP.

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Eur J Cancer 2002 Dec;38(18):2416-20
A phase II trial of ZD0473 in platinum-pretreated ovarian cancer.
Gore ME, Atkinson RJ, Thomas H, Cure H, Rischin D, Beale P, Bougnoux P, Dirix L, Smit WM.
Medical Oncology, Royal Marsden Hospital NHS Trust, London, UK. martin.gore@rmh.nthames.nhs.uk

The primary aim of this phase II trial was to assess the antitumour activity of ZD0473 in ovarian cancer patients who had failed initial platinum-based therapy. Patients (n=94) were classified as either platinum-sensitive (n=35) or platinum-resistant (n=59) depending on whether they had relapsed or progressed within 26 weeks of completing first-line platinum-based chemotherapy. Patients initially received 120 mg/m(2) ZD0473 as a 1-h intravenous (i.v.) infusion on day 1 of a 3-week cycle. If well tolerated, the dose could be escalated to 150 mg/m(2). Few patients (9%) withdrew because of treatment-related adverse events and no clinically significant oto-, nephro- or neurotoxicity was observed. Objective response rates for platinum-resistant and sensitive patients were 8.3 and 32.4%, respectively, and clinical benefit was observed in 76.5% of the sensitive patients. Median time to progression was 57 and 180 days, and median time to death was 242 and 402 days, for resistant and sensitive patients, respectively. In conclusion, ZD0473 has a manageable toxicity profile and encouraging activity in platinum-sensitive ovarian cancer patients.

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Oncology 2003;64(1):46-53
Combination therapy with granisetron, methylprednisolone and droperidol as an antiemetic prophylaxis in CDDP-induced delayed emesis for gynecologic cancer.
Sagae S, Ishioka S, Fukunaka N, Terasawa K, Kobayashi K, Sugimura M, Nishioka Y, Kudo R, Minami M.
Department of Obstetrics and Gynecology, Sapporo Medical University, School of Medicine, Sapporo, Japan. sagaes@sapmed.ac.jp

OBJECTIVE: To better control both acute and delayed emesis resulting from cisplatin(CDDP)-based chemotherapy for gynecological malignancies, we designed a 'cocktail therapy' (CCT) using granisetron (GRN) in combination with methylprednisolone (MPD) plus droperidol (DRP). METHODS: Two crossover clinical trials were carried out to compare the efficacy and safety of (a) GRN alone (3 mg/patient) with that of GRN, MPD (250 mg/patient) and DRP (0.5 ml/patient) in 42 patients (CCT group) and (b) GRN and MPD (CMB group) with that of the CCT group in 27 patients during the first 7 days of chemotherapy, independent of the weight/body surface of the patients. One of these regimens was administered intravenously for the first 3 days of chemotherapy, in case of failure for a maximum of 5 days. RESULTS: For acute emesis, complete protection from nausea and vomiting by the end of the 1st day was achieved in 64.3% receiving GRN and in 92.9% receiving CCT (p < 0.01). For delayed emesis, complete protection was best achieved in CCT on days 2-3, showing statistical significance compared to GRN treatment (p < 0.01). Comparing the three kinds of treatment during 7 days, the lowest protection was 38.1% in the GRN group, 51.9% in the CMB group and 72.5% in the CCT group, especially on days 2 or 3. CONCLUSIONS: The CCT combination is useful for the control of delayed and/or anticipatory emesis resulting from CDDP-based chemotherapy for women with gynecological malignancies. Copyright 2003 S. Karger AG, Basel

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Ai Zheng 2002 Apr;21(4):416-20
[Phase II clinical study of topotecan hydrochloride in patients with recurrent advanced ovarian cancer]
[Article in Chinese]
Li JD, Guan ZZ, Liu JH, Xin XY, Cui Y, Huang CJ, Liu FY, Song L, Bian ML, Zhou QH.
Cancer Center, Sun Yat-sen University, Guangzhou 510060, P. R. China.

BACKGROUND AND OBJECTIVE: Clinical studies showed there was no satisfying treatment of the patients with recurrent advanced ovarian cancer by using chemotherapy of combining platinum, and it is very important for oncologist to seek the second-line drugs to treat the patients with recurrent ovarian cancer. The current study was designed to evaluate the efficacy and toxicity of single agent Topotecan hydrochloride in the patients with recurrent advanced ovarian cancer. MATERIAL AND METHOD: A total of 31 patients with recurrent ovarian cancer in a multiple centers clinical trial were treated with Topotecan 1.25 mg/m2 qd, i.v. inf. for 5 consecutive days every three weeks. RESULT: Among 21 evaluable cases, overall response rate was 33.33%. Among 29 ITT population the response rate was 24.14%, including 3 CR and 4 PR. Main side effects were hematologic toxicities, 31.0% patients and 37.5% courses developed Grade III-IV leukocytopenia, 20.7% patients and 14.3% courses developed Grade III-IV thrombocytopemia. Non-hematologic toxicities were mild. CONCLUSION: Topotecan is effective for treating the patients with recurrent ovarian cancer who failed with platinum-based regimes.

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