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Latest Research on Ovarian Cancer
     
Int J Gynecol Cancer. 2008 Mar-Apr;18(2):363-8.
Role of diaphragmatic surgery in 69 patients with ovarian carcinoma.
Devolder K, Amant F, Neven P, van Gorp T, Leunen K, Vergote I.
Department of Obstetrics & Gynaecology, Division of Gynaecological Oncology, University Hospitals Leuven, Katholieke Universiteit Leuven, Leuven, Belgium.

Diaphragmatic stripping or coagulation is a technique aiming to optimally cytoreduce ovarian cancer. We investigated the complications, the overall survival, and the relapse rate following this procedure. Records of 69 patients with diaphragmatic involvement who underwent debulking surgery between September 1993 and December 2001 were reviewed. A total of 69 patients underwent diaphragmatic surgery as part of cytoreductive surgery for epithelial ovarian cancer. In 17 cases, the diaphragmatic tumors were stripped from the muscle, in 22 cases coagulated, and in 30 cases stripped and coagulated. Postoperative complications were pleural effusion (41 cases, 3 needed a chest drain, 7 needed a pleural puncture, 1 needed both) and pneumothorax (4 cases, 1 needed a chest drain). In one case of bilateral pleural effusion, the patient developed pneumonia. In one case of pleural effusion on the right side, the patient needed a pleural puncture and developed a partial atelectasis of the middle lobe of the right lung. The median overall survival was 66 months in the stripping group compared with 49 months in the coagulation group. In 56 cases (81%), the patient developed a relapse, and the first site of relapse was the diaphragm in 11 cases (20%). We conclude that diaphragmatic resection is an important part of optimal debulking surgery with an acceptable morbidity.

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Int J Gynecol Cancer. 2008 Mar-Apr;18(2):249-54.
A phase II, multicenter trial of weekly topotecan in patients with recurrent platinum-sensitive epithelial cancers of the ovary and peritoneum.
Brown JV 3rd, Rettenmaier MA, Lopez KL, Graham C, Micha JP, Goldstein B.
Gynecologic Oncology Associates, Hoag Cancer Center, Newport Beach, California 92663, USA. bram@gynoncology.com

The purpose of this study was to evaluate the response rate and toxicity of weekly topotecan in patients with recurrent platinum-sensitive epithelial cancers of the ovary and peritoneum. Thirty-nine platinum-sensitive recurrent ovarian cancer patients received topotecan (4 mg/m(2)) intravenously day 1, day 8, day 15, every 28 days. Colony-stimulating factors were excluded from the study. Clinical response was assessed by clinical, serologic, and radiographic measures at the conclusion of cycle four. Patients received 136 cycles of topotecan (median = 3; range 1-6) and were evaluated for response and toxicity. Median number of prior regimens was one. Grade 3/4 neutropenia developed in 3 (7.7%) patients. Grade 3 thrombocytopenia was seen in one (2.6%) patient, with no incidence of grade 4 thrombocytopenia. There was no evidence of grade 3 anemia, but one patient (2.6%) was associated with grade 4 anemia. There was no grade 3 or 4 neuropathy. We encountered 18 dose reductions following less than or equal to grade 2 myelosuppression, necessitating the removal of eight (20.5%) patients prior to cycle four. Twenty-one (53.8%) patients were removed from the study due to disease progression. Following the completion of cycle four, four (10.3%) patients demonstrated stable disease and four (10.3%) patients exhibited a partial response. There were no complete responses. Median disease-free survival was 12 weeks. Weekly topotecan (4 mg/m(2)) demonstrated modest activity and was moderately well tolerated. However, the significant number of dose reductions and high incidence of patients who demonstrated disease progression suggests additional modifications with this specific regimen are necessary.

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Gynecol Oncol. 2008 Feb 29 [Epub ahead of print]
Randomized phase 3 trial of interferon gamma-1b plus standard carboplatin/paclitaxel versus carboplatin/paclitaxel alone for first-line treatment of advanced ovarian and primary peritoneal carcinomas: Results from a prospectively designed analysis of progression-free survival.
Alberts DS, Marth C, Alvarez RD, Johnson G, Bidzinski M, Kardatzke DR, Bradford WZ, Loutit J, Kirn DH, Clouser MC, Markman M; GRACES Clinical Trial Consortium.
Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.

OBJECTIVES: Interferon gamma (IFN-gamma) is a pleiotropic cytokine with antiproliferative, immunostimulatory, and chemosensitization properties. This trial was designed to evaluate IFN-gamma 1b plus carboplatin and paclitaxel in treatment-naive ovarian cancer (OC) and primary peritoneal carcinoma (PPC) patients. METHODS: Eligible patients were randomized to 6 cycles of carboplatin/paclitaxel every 3 weeks or the same in combination with IFN-gamma 1b (100 microg 3x/wk subcutaneously). The primary endpoint was overall survival (OS) time (target hazard ratio (HR)=0.77). Secondary endpoints included progression-free survival (target HR=0.7), based on blinded review of serial imaging scans, physical exams, and CA-125 levels. RESULTS: 847 patients were enrolled (OC 774, PPC 73) in Europe (n=539) and North/South America (n=308) from January 29, 2002 to March 31, 2004 and stratified according to: optimal debulking (n=271) versus suboptimal debulking with plans for interval debulking
(PID) (n=238) or no PID (n=338). The study stopped early following a protocol-defined second interim analysis which revealed significantly shorter OS time in patients receiving IFN-gamma 1b plus chemotherapy compared to chemotherapy alone (1138 days vs. not estimable, HR=1.45, 95% CI=1.15-1.83). At the time of the analysis, 169 of 426 (39.7%) patients in the IFN-gamma 1b plus chemotherapy group had died compared to 128 of 421 (30.4%) in the chemotherapy alone group. Serious adverse events were more common in the IFN-gamma 1b plus chemotherapy group (48.5% vs. 35.4%), primarily due to a higher incidence of serious hematological toxicities (34.5% vs. 22.7%). CONCLUSIONS: Treatment with IFN-gamma 1b in combination with carboplatin/paclitaxel does not have a role in the first-line treatment of advanced ovarian cancer.

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Cancer Biother Radiopharm. 2008 Feb;23(1):92-107.
Review: intracavitary radioimmunotherapy to treat solid tumors.
Aarts F, Bleichrodt RP, Oyen WJ, Boerman OC.
Department of Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Radioimmunotherapy (RIT) potentially is an attractive treatment for radiosensitive early-stage solid tumors and as an adjuvant to cytoreductive surgery. Topical administration of RIT may improve the efficacy because higher local concentrations are achieved. We reviewed the results of locally applied radiolabeled monoclonal antibodies for the treatment of solid tumors. Intracavitary RIT in patients with ovarian cancer and glioma showed improved targeting after local administration, as compared to the intravenous administration. In addition, various studies showed the feasibility of locally applied RIT in these patients. In studies that included patients with small-volume disease, adjuvant RIT in ovarian cancer and glioma showed to be at least as effective as standard therapy. The information about RIT for peritoneal carcinomatosis of colorectal origin is scarce, while results from preclinical data are promising. RIT may be applied for other, relatively unexplored indications. Studies on the application of radiolabeled antibodies in early urothelial cell cancer have been performed, showing that intracavitary RIT may hold a promise. Moreover, in patients with malignant pleural mesothelioma or malignant pleural effusion, RIT may play a role in the palliative treatment. Intracavitary RIT limits toxicity and improves tumor targeting. RIT is more effective in patients with small-volume disease of solid cancers. RIT may have potential for palliation in patients with malignant pleural mesothelioma or malignant pleural effusion. The future of RIT may, therefore, not only be in the inclusion in contemporary multimodality treatment, but also in the expansion to palliative treatment.

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Eur J Surg Oncol. 2008 Feb 18 [Epub ahead of print]
Aggressive surgical strategies in advanced ovarian cancer: A monocentric study of 203 stage IIIC and IV patients.
Colombo PE, Mourregot A, Fabbro M, Gutowski M, Saint-Aubert B, Quenet F, Gourgou S, Rouanet P.
Department of Surgical Oncology, CRLC Val d'Aurelle, 208 rue des Apothicaires, 34298 Montpellier Cedex 5, France.

AIMS: The standard treatment for advanced ovarian cancer consists of cytoreductive surgery associated with a platinum/paclitaxel-based chemotherapy. Nevertheless, there is still the question as to the extent and timing of the surgical debulking. The aim of this study was to evaluate the place of surgery in the therapeutic sequence. PATIENTS AND METHODS: We reviewed data from all consecutive patients with stage IIIC and IV epithelial ovarian cancer, operated on at our institution between 1990 and 2005. Patients were divided into 2 groups, according to the position of surgery in the therapeutic sequence. Patients in group 1 received initial debulking surgery. Group 2 consisted of patients having received their first debulking after initial chemotherapy. RESULTS: Two hundred and three patients were identified and frequently underwent aggressive surgery, in particular, digestive surgery with bowel resections. Perioperative mortality and morbidity rates were low (2% and 14%, respectively) and there was no difference between the groups. Overall survival in group 1 for patients with complete cytoreduction (residual disease (RD)=0), optimal surgery (RD<1cm) or sub-optimal surgery (RD>1cm) was 50%, 30% and 14%, respectively. In group 2, overall survival following complete surgery was 30%, and no long-term survival was observed when surgery was not complete at the time of interval surgery. Survival was worse for patients who had received more than 4 cycles of neoadjuvant chemotherapy. CONCLUSION: This study confirms the importance of surgery in the prognosis of advanced ovarian cancer. Only the patient subgroup that underwent complete initial or interval surgery was associated with a prolonged remission. Optimal surgery with a controlled morbidity can be achieved in many cases, even if bowel resection is needed, at the time of primary debulking. In the interval cytoreductive surgery subgroup, the response to initial chemotherapy and surgery was found to be essential for prognosis.

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J Clin Oncol. 2008 Feb 20;26(6):890-6.
Phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in progressive or recurrent ovarian cancer.
Ferrandina G, Ludovisi M, Lorusso D, Pignata S, Breda E, Savarese A, Del Medico P, Scaltriti L, Katsaros D, Priolo D, Scambia G.
Department of Oncology, Catholic University, Campobasso, Italy. gabriella.ferrandina@libero.it

PURPOSE: We aimed at investigating the efficacy, tolerability, and quality of life (QOL) of gemcitabine (GEM) compared with pegylated liposomal doxorubicin (PLD) in the salvage treatment of recurrent ovarian cancer. PATIENTS AND METHODS: A phase III randomized multicenter trial was planned to compare GEM (1,000 mg/m(2) on days 1, 8, and 15 every 28 days) with PLD (40 mg/m(2) every 28 days) in ovarian cancer patients who experienced treatment failure with only one platinum/paclitaxel regimen and who experienced recurrence or progression within 12 months after completion of primary treatment. RESULTS: One hundred fifty-three patients were randomly assigned to PLD (n = 76) or GEM (n = 77). Treatment arms were well balanced for clinicopathologic characteristics. Grade 3 or 4 neutropenia was more frequent in GEM-treated patients versus PLD-treated patients (P = .007). Grade 3 or 4 palmar-plantar erythrodysesthesia was documented in a higher proportion of PLD patients (6%) versus GEM patients (0%; P = .061). The overall response rate was 16% in the PLD arm compared with 29% in the GEM arm (P = .056). No statistically significant difference in time to progression (TTP) curves according to treatment allocation was documented (P = .411). However, a trend for more favorable overall survival was documented in the PLD arm compared with the GEM arm, although the P value was of borderline statistical significance (P = .048). Statistically significantly higher global QOL scores were found in PLD-treated patients at the first and second postbaseline QOL assessments. CONCLUSION: GEM does not provide an advantage compared with PLD in terms of TTP in ovarian cancer patients who experience recurrence within 12 months after primary treatment but should be considered in the spectrum of drugs to be possibly used in the salvage setting.

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Cancer Causes Control. 2008 Feb 9 [Epub ahead of print]
Hormone therapy and ovarian cancer: incidence and survival.
Wernli KJ, Newcomb PA, Hampton JM, Trentham-Dietz A, Egan KM.
Cancer Prevention Program, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, M4-B402, Seattle, WA, 98109, USA, kwernli@fhcrc.org.

OBJECTIVE: We conducted a population-based case-control study to investigate the association between hormone therapy (HT) and ovarian cancer incidence, and followed all these cancer cases to determine the association of HT use with ovarian cancer mortality. METHODS: Seven hundred fifty-one incident cases of invasive epithelial ovarian cancer aged 40-79 years were diagnosed in Massachusetts and Wisconsin between 1993-1995 and 1998-2001 and matched to similarly aged controls (n = 5,808). Study subjects were interviewed by telephone, which ascertained information on HT use and specific preparation, estrogen alone (E-alone) or estrogen plus progestin (EP). Ovarian cancer cases were followed-up for mortality through December 2005. Multivariate logistic regression was used to estimate odds ratios and 95% confidence intervals (CI) for ovarian cancer incidence, and Cox proportional hazards modeling was used to estimate hazard ratios and corresponding confidence intervals for ovarian
cancer mortality. RESULTS: Ever use of HT was significantly associated with an increased risk of ovarian cancer (odds ratio 1.57, 95% CI 1.31-1.87). The excess risk was confined to women who used E-alone preparations (OR 2.33, 95% CI 1.85-2.95). No significant associations were detected between pre-diagnosis HT use and ovarian cancer survival. CONCLUSIONS: Hormone therapy increases risk of ovarian cancer among E-alone users, but there is no substantial impact on survival after diagnosis.

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Gynecol Oncol. 2008 Feb 6 [Epub ahead of print]
Improved tolerance of primary chemotherapy with reduced-dose carboplatin and paclitaxel in elderly ovarian cancer patients.
Fader AN, Gruenigen VV, Gibbons H, Abushahin F, Starks D, Markman M, Belinson J, Rose P.
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Cleveland Clinic Foundation, Cleveland, Ohio, USA.

OBJECTIVE: Elderly cancer patients are less likely to tolerate chemotherapy. We sought to compare the toxicity profiles and outcomes of elderly ovarian cancer patients treated with standard versus reduced-dose IV carboplatin/paclitaxel. METHODS: A retrospective, multi-center analysis of women >/=70 years with papillary serous ovarian/primary peritoneal cancers diagnosed from 1994-2005 was performed. Reduced-dose (RD) patients received carboplatin AUC 4-5 and paclitaxel 135 mg/m(2); standard-dose (SD) patients received carboplatin AUC 5-6 and paclitaxel 175 mg/m(2). Patient variables collected included age, stage, performance status (PS), cytoreductive status, Charlson comorbidity scores, and growth factor administration. RESULTS: One-hundred patients met the study criteria. RD patients (n=26) were significantly older than SD patients (n=74; median age 77.0 versus 74.7, respectively, p=0.014). No differences were noted in stage, comorbidity scores, cytoreductive status or growth factor administration between cohorts. Incidence of grade 3-4 neutropenia was higher in the SD group (54.1% versus 19.2%; p=0.002). SD patients were more likely to experience cumulative toxicity (p=0.003) and required delays in therapy (p=0.05). Although PS was poorer in SD patients (p=0.02), on multivariate analysis, only the administration of the SD regimen predicted toxicity (p=0.008). There were no differences in progression-free or overall survival between cohorts (median follow-up: 34 months). On multivariate analysis, age (p=0.004) and PS (p=0.008) had a significant impact on survival. CONCLUSION(S): This preliminary data suggests that reduced-dose carboplatin/paclitaxel may be better tolerated but equally effective as the standard regimen in elderly ovarian cancer patients. Age, performance status and other geriatric parameters should be considered when dosing chemotherapy in the elderly.

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BMC Cancer. 2007 Dec 19;7(1):227 [Epub ahead of print]
Adjuvant whole abdominal intensity modulated radiotherapy (IMRT) for high risk stage FIGO III patients with ovarian cancer (OVAR-IMRT-01) - Pilot trial of a phase I/II study: study protocol.
Rochet N, Jensen AD, Sterzing F, Munter MW, Eichbaum MH, Schneeweiss A, Sohn C, Debus J, Harms W.

ABSTRACT: BACKGROUND: The prognosis for patients with advanced epithelial ovarian cancer remains poor despite aggressive surgical resection and platinum-based chemotherapy. More than 60% of patients will develop recurrent disease, principally intraperitoneal, and die within 5 years. The use of whole abdominal irradiation (WAI) as consolidation therapy would appear to be a logical strategy given its ability to sterilize small tumour volumes. Despite the clinically proven efficacy of whole abdominal irradiation, the use of radiotherapy in ovarian cancer has profoundly decreased mainly due to high treatment-related toxicity. Modern intensity-modulated radiation therapy (IMRT) could allow to spare kidneys, liver, and bone marrow while still adequately covering the peritoneal cavity with a homogenous dose. Methods / design: The OVAR-IMRT-01 study is a single center pilot trial of a phase I/II study. Patients with advanced ovarian cancer stage FIGO III (R1 or R2< 1cm) after surgical resection and platinum-based chemotherapy will be treated with whole abdomen irradiation as consolidation therapy using intensity modulated radiation therapy (IMRT) to a total dose of 30 Gy in 1.5 Gy fractions. A total of 8 patients will be included in this trial. For treatment planning bone marrow, kidneys, liver, spinal cord, vertebral bodies and pelvic bones are defined as organs at risk. The planning target volume includes the entire peritoneal cavity plus pelvic and para-aortic node regions. DISCUSSION: The primary endpoint of the study is the evaluation of the feasibility of intensity-modulated WAI and the evaluation of the study protocol. Secondary endpoint is evaluation of the toxicity of intensity modulated WAI before continuing with the phase I/II study. The aim is to explore the potential of IMRT as a new method for WAI to decrease the dose to kidneys, liver, bone marrow while covering the peritoneal cavity with a homogenous dose, and to implement whole abdominal intensity-modulated radiotherapy into the adjuvant multimodal treatment concept of advanced ovarian cancer FIGO stage III.

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Minerva Chir. 2007 Dec;62(6):459-476.
Updated treatment of peritoneal carcinomas: a review.
Deraco M, Laterza B, Kusamura S, Baratti D.
Dipartimento di Chirurgia, Unità Tumori Peritoneali, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milano marcello.deraco@istitutotumori.mi.it.

Peritoneal surface malignancy (PSM) is a clinical entity with an unfavourable prognosis, which characterizes the evolution of neoplastic diseases from the abdominal and/or pelvic organs and could also be the terminal stage of extra-abdominal tumors. Examples of diseases that can spread mainly within the peritoneal cavity are appendiceal tumors, ovarian cancer, colorectal cancer, abdominal sarcomatosis, gastric cancer and peritoneal mesothelioma. The locoregional therapy is defined as the combination of cytoreductive surgery (CRS) and intraperitoneal hyperthermic perfusion (IPHP). The rationale of this combined therapy for PSM is based on the natural history of this clinical entity that remains confined in the peritoneal cavity for most of its natural history. This pattern of spread would seem to indicate the potential usefulness of selectively increasing drug concentration in the tumour-bearing area by direct intraperitoneal chemotherapy instillation. This approach led to these outcomes: the median survival of colorectal carcinoma and ovarian cancer was 32 months; patients with peritoneal mesothelioma showed 57% survival at 5 years, while in patients with appendiceal mucinous tumors and pseudomyxoma peritonei (PMP) the 10 years overall survival was 78%. A significant improvement in survival was associated with hyperthermic intra-peritoneal chemotherapy (HIPEC) in patients with gastric cancer. Considering the constant increasing of diseases treatable with this procedure, more centres should be activated. The establishment of a clear policy and scientific guidelines is mandatory, in order to perform the CRS+HIPEC safely, minimizing treatment-related morbidity and mortality and maximizing the results in terms of survival and quality of life.

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Cancer Imaging. 2007 Dec 17;7:210-5.
Cytoreductive surgery in ovarian cancer.
Pomel C, Jeyarajah A, Oram D, Shepherd J, Milliken D, Dauplat J, Reynolds K.
Department of Gynaecological Oncology, St Bartholomew's Hospital, London, UK; Department of Surgical Oncology, Jean Perrin Comprehensive Cancer Centre, Clermont-Ferrand, France.

As the overall prognosis for patients with ovarian cancer is poor, the management of this condition should be restricted to expert multi-disciplinary teams in gynaecological oncology. Apparent early stage ovarian cancer requires accurate and complete staging so that potential sites for metastases are not missed. Omitting adequate staging may have significant consequences including a negative impact on survival rates in young patients. The challenge with advanced ovarian cancer is to obtain a detailed appreciation of the extent of disease. This information allows treatment with primary chemotherapy if the cancer is considered to be inoperable and/or the general condition of the patient renders her unfit for appropriate surgery. Available data would suggest that a 5-year survival rate of 50% is only possible for those patients who have had complete cytoreduction of all tumour. Therefore, the best surgical option for patients with advanced ovarian cancer is a 'complete' primary surgical procedure that achieves complete clearance of the abdominal cavity rather than 'optimal' surgery that leaves tumour nodules up to 1 cm in diameter in situ in the patient.

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J Transl Med. 2007 Dec 12;5(1):66 [Epub ahead of print]
Phase II study of intraperitoneal recombinant interleukin-12 (rhIL-12) in patients with peritoneal carcinomatosis (residual disease <1cm) associated with ovarian cancer or primary peritoneal carcinoma.
Lenzi R, Edwards R, June C, Seiden MV, Garcia ME, Rosenblum M, Freedman RS.

ABSTRACT: BACKGROUND: Pharmacokinetic advantages of intraperitoneal (IP) rhIL-12, tumor response to IP delivery of other cytokines as well as its potential anti-angiogenic effect provided the rationale for further evaluation of IPrhIL-12 in patients with persistent ovarian or peritoneal carcinoma. METHODS: A phase 2 multi-institutional trial (NCI Study #2251) of IP rIL-12 (300 nanogram/Kg weekly) was conducted in patients with ovarian carcinoma or primary peritoneal carcinoma. Patients treated with primary therapy for ovarian cancer who had no extraabdominal/parenchymal disease or bulky peritoneal disease were eligible. Four to 8 weeks from last chemotherapy, eligible patients underwent a laparotomy/laparoscopy. Patients with residual disease [less than or equal to] 1 cm were registered for the treatment phase 2-5 weeks post surgery. The effect of IP rIL-12 on the expression of TNF-alpha, INF-alpha, IL-10, IP-10, IL-8, FGF, VEGF was also studied. RESULTS: Thirty-four patients were registered for the first screening phase of the study. Median age was 56.6 years (range: 31-71) 12 completed the second phase and were evaluable for response and toxicity. Performance scores of IL-12 treated patients were 0 (11 pts) and 1 (1 pt). There were no treatment related deaths, peritonitis or significant catheter related complications. Toxicities included grade 4 neutropenia (1), grade 3 fatigue (4), headache (2), myalgia (2), non-neutropenic fever (1), drug fever (1), back pain (1), and dizziness (1). The best response observed was SD. Two patients had SD and 9 had PD, and 1 was evaluable for toxicity only. Peritoneal fluid cytokine measurements demonstrated a [greater than or equal to]3 fold relative increase post-rhIL-12: IFN-gamma, 5/5 pts; TNF-alpha, 1/5; IL-10, 4/5; IL-8, 5/5; and VEGF, 3/5. IP10 levels were increased in 5/5 patients. Cytokine response profiles suggest either NK or T-cell mediated effects of IP rhIL-12. Cytokine/chemokine results also suggest a pleiotropic response since proteins with potential for either anti-tumor (IFN-gamma, IP-10) or pro-tumor growth effects (VEGF, IL-8) were detected. CONCLUSIONS: IP IL-12 can safely be administered at this dose and schedule to patients after first line chemotherapy for ovarian/peritoneal carcinoma. The maximum response was stable disease. Future IP therapies with rhIL-12 will require better understanding and control of pleiotropic effects of IL-12.

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Isr Med Assoc J. 2007 Nov;9(11):787-90.
Cytoreductive surgery and intraperitoneal hyperthermic chemotherapy in peritoneal carcinomatosis.
Nesher E, Greenberg R, Avital S, Skornick Y, Schneebaum S.
Department of Surgery A, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. e_nesher@bezeqint.net

BACKGROUND: Peritoneal carcinomatosis is an advanced form of cancer with poor prognosis that in the past was treated mainly palliatively. Today, the definitive approach to peritoneal surface malignancy involves peritonectomy, visceral resection and perioperative intra-abdominal hyperthermic chemotherapy. The anticipated results range from at least palliative to as far as intent to cure. Proper patient selection is mandatory. OBJECTIVES: To determine whether cytoreductive surgery and intraperitoneal hyperthermic chemotherapy can extend survival, and with minor complications only, in patients with peritoneal carcinomatosis. METHODS: Twenty-two IPHP procedures were performed in 17 patients with peritoneal carcinomatosis in our institution between 1998 and 2007: 6 had pseudomyxoma peritonei, 5 had colorectal carcinoma, 3 had ovarian cancer and 3 had mesotheliomas. All patients underwent cytoreductive surgery, leaving only residual metastasis < 1 cm in size. Intraperitoneal chemotherapy was administered through four large catheters (2F) using a closed system of two pumps, a heat exchanger and two filters. After the patient's abdominal temperature reached 41 degrees C, 30-60 mg mitomycin C was circulated intraperitoneally for 1 hour. RESULTS: The patients had a variety of anastomoses. None demonstrated anastomotic leak and none experienced major complications. Six patients had minor complications (pleural effusion, leukopenia, fever, prolonged paralytic ileus, sepsis), two of which may be attributed to chemotherapy toxicity (leukopenia). There was no perioperative mortality. Some patients have survived more than 5 years. CONCLUSIONS: IPHP is a safe treatment modality for patients with peritoneal carcinomatosis. It has an acceptable complications rate and ensures a marked improvement in survival and in the quality of life in selected patients.

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Arzneimittelforschung. 2007;57(10):665-78.
Prospective controlled cohort studies on long-term therapy of ovairian cancer patients with mistletoe (Viscum album L.) extracts iscador.
Grossarth-Maticek R, Ziegler R.
Institut für Präventive Medizin, Europäisches Zentrum für Frieden und Entwickl]ung, Heidelberg, Germany.

BACKGROUND: Mistletoe extracts such as Iscador are commonly used as complementary/anthroposophic medications for many cancer indications, particularly for solid cancers. The efficacy of this complementary therapy is still controversial. OBJECTIVE: Does long-term therapy with mistletoe extracts Iscador show any effect on survival and psychosomatic self-regulation of patients with ovarian cancer? Patients and methods: Prospective recruitment and long-term follow-up in controlled cohort studies. (1) Two randomized matched-pair studies: OvarRand (ovarian cancer patients without distant metastases; 21 pairs) and OvarMetRand (ovarian cancer patients with distant metastases; 20 pairs); patients having no mistletoe therapy were matched for prognostic factors. By paired random allocation, one of the patients of each pair was suggested therapy with mistletoe extracts Iscador to be applied by her attending physician. (2) Two non-randomized matched-pair studies: Ovar (ovarian cancer patients without distant metastases; 75 pairs) and OvarRand (ovarian cancer patients with distant metastases; 62 pairs); patients that already received therapy with mistletoe extracts Iscador were matched by the same criteria to control patients without therapy with mistletoe extracts Iscador. RESULTS: For overall survival in the randomized studies, the effect in favor of therapy with mistletoe extracts Iscador was significant in OvarMetRand but not in OvarRand; hazard ratio estimate and 95% confidence interval: 0.40 (0.15, 1.03) and 0.33 (0.12, 0.92), respectively. In the non-randomized studies Ovar and OvarMet, the results adjusted for relevant prognostic variables were 0.47 (0.31, 0.69) and 0.62 (0.37, 1.05). Psychosomatic self-regulation in the Iscador group increases significantly within 12 months on a scale from 1 to 6 compared with the control group in the randomized study OvarRand as well as in the non-randomized study Ovar on patients with ovarian cancer without distant metastases; estimate of the median difference and 95% confidence interval: 0.58 (0.30, 0.90) and 0.30 (0.05, 0.65), respectively. CONCLUSION: Mistletoe extracts Iscador might have the effect of prolonging overall survival of ovarian cancer patients. In the short term, psychosomatic self-regulation increases more markedly under Iscador therapy than under conventional therapy alone.

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J Chemother. 2007 Oct;19(5):577-81.
Gemcitabine combined with oxaliplatin (GEMOX) as salvage treatment in elderly patients with advanced ovarian cancer refractory or resistant to platinum: a single institution experience.
Germano D, Rosati G, Manzione L.
domgerm@libero.it

Both oxaliplatin (OXA) and gemcitabine (GEM) have shown single agent activity in patients with recurrent ovarian cancer. Response rates to second-line therapies remain low and there is a need to develop more effective regimens. In view of the synergistic effect of using GEM followed by OXA, we studied these agents in elderly patients with recurrent ovarian cancer refractory or resistant to first-line chemotherapy using platinum with or without paclitaxel. The aim of the study was to evaluate the efficacy and toxicity of combination GEM 1000 mg/m(2) Day 1 i.v. and OXA 100 mg/m(2) in 2h infusion Day 2; treatment was repeated every 2 weeks for 6 courses or until progression of disease or intolerable toxicity. The study was monoinstitutional and started in November 2002. 21 patients, median age 68.6 years (range 65-82) have been treated. Median Performance Status was 0-1, all had at least 1 prior platinum based chemotherapy and 11 had received also a taxane. Patients received a median of 6 cycles of treatment (range 4-11). There were 2 patient (9%) with complete response, 3 patients (14%) achieved a partial response. Low profile toxicity (grade 1-2, WHO criteria) was observed: nausea/vomiting 52%, thrombocytopenia 13%, neuropathy 28%. The GEMOX combination is well tolerated and even in this small group of patients, encouraging responses were documented.

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Int J Gynecol Cancer. 2007 Jul 21; [Epub ahead of print]
A multi-institutional evaluation of factors predictive of toxicity and efficacy of bevacizumab for recurrent ovarian cancer.
Wright JD, Secord AA, Numnum TM, Rocconi RP, Powell MA, Berchuck A, Alvarez RD, Gibb RK, Trinkaus K, Rader JS, Mutch DG.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, New York, New York, USA.

While bevacizumab has shown activity in recurrent ovarian cancer, a higher than expected incidence of bowel perforations has been reported in recent trials. We sought to determine factors associated with toxicity and tumor response in patients with relapsed ovarian cancer treated with bevacizumab. A retrospective review of patients with recurrent ovarian cancer treated with bevacizumab was undertaken. Response was determined radiographically and through CA125 measurements. Statistical analysis to determine factors associated with toxicity and response was performed. Sixty-two eligible patients were identified. The cohort had received a median of 5 prior chemotherapy regimens. Single-agent bevacizumab was administered to 12 (19%), while 50 (81%) received the drug in combination with a cytotoxic agent. Grade 3-5 toxicities occurred in 15 (24%) patients, including grade 3-4 hypertension in 4 (7%), gastrointestinal perforations in 7%, and chylous ascites in 5%. Development of chylous ascites and gastrointestinal perforations appeared to correlate with tumor response. The overall response rate was 36% (4 complete response, 17 partial response), with stable disease in 40%. A higher objective response rate was seen in the bevacizumab combination group compared to single-agent treatment (43% vs 10%) (P = 0.07). However, 29 grade 3-5 toxic episodes were seen in the combination group vs only 1 in the single-agent bevacizumab cohort (P = 0.071). We conclude that bevacizumab demonstrates promising activity in recurrent ovarian cancer. The addition of a cytotoxic agent to bevacizumab improved response rates at the cost of increased toxicity. Gastrointestinal perforations occurred in 7%. The perforations occurred in heavily pretreated patients who were responding to therapy.

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Int J Gynecol Cancer. 2007 Jul 21; [Epub ahead of print]
The influence of reproductive and hormonal factors on ovarian cancer survival.
Nagle CM, Bain CJ, Green AC, Webb PM.
Cancer and Population Studies Group, Queensland Institute of Medical Research, Brisbane, Australia.

Reproductive and hormonal exposures are known to influence ovarian carcinogenesis, but little is known about the effect of these factors on survival. We have studied survival according to hormonal and reproductive history in a population-based cohort of 676 Australian women aged 18-79, newly diagnosed with invasive epithelial ovarian cancer in the early 1990s. In order to place our findings in context, we have also undertaken a systematic review of the pertinent literature. Detailed information about each woman's reproductive and contraceptive history was obtained from pregnancy and contraceptive calendars at the time of diagnosis. Cox regression was used to obtain multivariate adjusted hazard ratios (HR) and 95% confidence intervals (CI). A total of 419 (62%) of the 676 women died during the follow-up (giving a 5-year survival proportion of 44%). Apart from better survival for women who had ever breastfed (multivariate HR 0.74, 95% CI 0.55-0.98), we found no association between survival from invasive ovarian cancer and a range of hormonal and gynecological factors including parity, use of oral contraceptives, and histories of tubal sterilization or hysterectomy. Systematic review of the literature generally supported the lack of influence of these factors on survival from ovarian cancer. We conclude that, except for a possible survival advantage among women with a history of breastfeeding, reproductive and hormonal exposures prior to diagnosis do not influence survival from invasive ovarian cancer, in contrast to their substantial effects on etiology of this disease.

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World J Surg. 2007 Jul 15; [Epub ahead of print]
Cytoreductive Surgery and Intraperitoneal Chemohyperthermia for Chemoresistant and Recurrent Advanced Epithelial Ovarian Cancer: Prospective Study of 81 Patients.
Cotte E, Glehen O, Mohamed F, Lamy F, Falandry C, Golfier F, Gilly FN.
Department of Oncologic Surgery, Centre Hospitalo-Universitaire Lyon Sud, 69495, Pierre Bénite, Cedex, France.

PURPOSE: There is no standardized treatment for patients with chemoresistant or recurrent advanced ovarian cancer. Locoregional treatments combining cytoreductive surgery and intraperitoneal chemohyperthermia (HIPEC) may improve survival for locoregional disease. PATIENTS AND METHODS: A prospective single center study of 81 patients with recurrent or chemoresistant peritoneal carcinomatosis from ovarian cancer was performed. Patients were treated by maximal cytoreductive surgery combined with HIPEC (with cisplatinum at 20 mg/m(2)/L). A total of 47 patients were included for their third, fourth, fifth, sixth, or seventh surgical look. Altogether, 54 patients presented with extensive carcinomatosis (malignant nodules of >5 mm). RESULTS: Complete macroscopic resection (CCR-0) was achieved in 45 patients. Mortality and morbidity rates were 2.5% and 13.6%, respectively. With a median follow-up of 47.1 months, the overall and disease-free median survivals were 28.4 and 19.2 months, respectively. Carcinomatosis extent and completeness of cytoreduction (p = 0.02 and p <0.001, respectively) were identified as independent prognostic factors. For CCR-0 patients, overall and disease-free survivals were 54.9 and 26.9 months, respectively. CONCLUSION: Salvage therapy combining optimal cytoreductive surgery and HIPEC may achieve long-term survival in selected patients with recurrent or chemoresistant ovarian cancer. This strategy may be most effective in patients with limited carcinomatosis or when cytoreductive surgery provides sufficient downstaging.

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Int J Gynecol Cancer. 2007 Jul 11; [Epub ahead of print]
Mucinous ovarian cancer.
Harrison ML, Jameson C, Gore ME.
Department of Medicine, Royal Marsden Hospital, London, United Kingdom.

Mucinous epithelial ovarian cancer (mEOC) accounts for approximately 10% of EOCs. Patients presenting with early-stage disease have an excellent prognosis, however, those with advanced disease have a poor outcome with relative resistance to standard ovarian cancer chemotherapy. Molecular and genetic studies demonstrate differences between mucinous and serous EOC supporting the concept that these tumors develop along separate pathways. Together with the observed differences in clinical behavior and outcome for mEOC, there is a need to develop specific therapeutic strategies for this histologic subtype. The relative rarity of advanced mEOC has resulted in few patients enrolled in major ovarian cancer trials. The results of such trials may not necessarily reflect those specific to mEOC. Separate trials testing alternative chemotherapeutics are required. Metastatic mucinous tumors from other sites such as the gastrointestinal tract may present with ovarian involvement. For all mucinous tumors of the ovary, establishing primary as opposed to metastatic cancers is important. Clinical presentation, tumor markers, histologic, and immunohistochemical features are helpful in distinguishing most cases.

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J Clin Oncol. 2007 Jul 10;25(20):2944-51.
Management of ovarian stromal cell tumors.
Colombo N, Parma G, Zanagnolo V, Insinga A.
University of Milan Bicocca, Milan, Italy. nicoletta.colombo@ieo.it

PURPOSE: To describe the clinical management of ovarian stromal cell tumors, which are a heterogeneous group of neoplasms that develop from the sex cords and the ovarian stroma. DESIGN: We reviewed the current evidence on the clinical management of these relatively rare ovarian malignancies, which are typically detected at an early stage and may recur as late as 30 years following the initial treatment. The overall prognosis is favorable with a long-term survival ranging from 75% to 90% for all stages. Adult granulosa cell tumor (GCT) is the most common malignancy among these tumors. RESULTS: Surgery is the cornerstone of initial treatment. In women of childbearing age and with disease limited to one ovary, a fertility-sparing surgery can be a reasonable approach. Tumor stage represents the most important clinical parameter of prognostic relevance. The value of postoperative adjuvant therapy for high-risk patients has not been proven by prospective randomized studies. Platinum-based chemotherapy is used currently for patients with advanced stages or recurrent disease, with an overall response rate of 63% to 80%. Taxane and platinum combination chemotherapy seems to be a reasonable candidate for future trials. Little evidence exists for the use of radiation or hormonal therapy, and these modalities should be restricted to selected cases. Given the propensity of GCT for late relapse, prolonged follow-up is required. CONCLUSION: Surgery remains the most effective treatment for ovarian stromal tumors and, whenever feasible, for relapsing disease. Platinum-based chemotherapy is currently used in metastatic or recurrent tumors.

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J Clin Oncol. 2007 Jul 10;25(20):2938-43.
Management of ovarian germ cell tumors.
Gershenson DM.
Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77230-1439, USA. dgershen@mdanderson.org

PURPOSE: To review contemporary management of malignant ovarian germ cell tumors (MOGCT). DESIGN: The literature on the topic of MOGCT is reviewed, including pathology, prognostic factors, surgical strategies, postoperative therapy, late effects of therapy, and treatment of recurrence. RESULTS: Prognostic factors for MOGCT include the International Federation of Gynecology and Obstetrics staging system's stage, residual disease, histologic type, and elevation of serum tumor markers. Fertility-sparing surgery is possible in a large proportion of patients. The importance of comprehensive surgical staging is somewhat controversial. For patients with advanced-stage disease, maximum cytoreductive surgery appears to be beneficial. Although second-look surgery is not recommended routinely, selected patients may benefit from secondary cytoreduction. For those patients who require postoperative chemotherapy, standard therapy consists of the combination of bleomycin, etoposide, and cisplatin. However, there is a growing trend toward surveillance; this strategy continues to be studied. Although premature menopause may occur in a small proportion of patients, at least 80% of those who undergo fertility-sparing surgery and chemotherapy may expect to preserve reproductive function. For patients with early-stage disease, cure rates approach 100%. For those with advanced-stage disease, cure rates are reportedly at least 75%. CONCLUSION: MOGCT is a rare malignancy that principally affects girls and young women. With optimal therapy, the prognosis is excellent, and most patients may retain reproductive function.

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J Clin Oncol. 2007 Jul 10;25(20):2928-37.
Management of borderline ovarian neoplasms.
Cadron I, Leunen K, Van Gorp T, Amant F, Neven P, Vergote I.
Division of Gynecological Oncology, Department of Obstetrics and Gynecology, University Hospitals Leuven, Katholieke Universiteit Leuven, Leuven, Belgium.

Over the last decades, the management of borderline ovarian tumors (BOTs) has changed from radical surgery to more conservative therapy as a result of the need for fertility-sparing surgery and the increasing use of laparoscopy. The question is whether this is good clinical practice from an oncologic point of view. Here, recent literature regarding management of borderline ovarian neoplasms is reviewed, and oncologic concerns are discussed with emphasis on the mode of surgery and the possibility of fertility-sparing surgery and its consequences. Proper staging is defined as an exploration of the entire abdominal cavity with peritoneal washings, infracolic omentectomy, and multiple peritoneal biopsies as the cornerstone of a successful treatment, and this is only possible through a midline incision. For stage I disease, conservative surgery consisting of unilateral salpingo-oophorectomy or cystectomy in case of bilateral ovarian involvement or when the disease develops in the only remaining ovary is a valuable alternative in a number of young patients who want to preserve their fertility. Patients with advanced-stage disease or who are finished childbearing are treated with radical surgery consisting of peritoneal washings, total abdominal hysterectomy, bilateral salpingo-oophorectomy, infracolic omentectomy, complete peritoneal resection of macroscopic lesions, or multiple peritoneal biopsies; in case of mucinous BOTs, patients also are treated with an appendectomy.

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J Clin Oncol. 2007 Jul 10;25(20):2909-20.
Adjuvant chemotherapy for early-stage ovarian cancer: review of the literature.
Tropé C, Kaern J.
Department of Gynecologic Oncology, The Norwegian Radium Hospital, Montebello, Oslo, Norway. c.g.trope@medisin.uio.no

PURPOSE: This overview summarizes studies with acceptable quality and validity and presents a synthesis of the effectiveness on adjuvant therapy after surgery for early ovarian cancer (EOC) patients. METHODS: The literature published between 1970 and 2006 was identified systematically by computer-based searches in MEDLINE and Cochrane library. RESULTS: Twenty-two prospective randomized studies were analyzed, which included 4,626 patients. No difference between adjuvant chemotherapy (AC) and radiotherapy was found. There is agreement on that patients with stage IA, grade 1 tumors have excellent survival and do not need postsurgical therapy. The International Collaborative Ovarian Neoplasm 1/Adjuvant Chemotherapy in Ovarian Neoplasm trials were the first to show an effect on survival of AC, but in patients with adequate surgical staging, there was no additional effect of AC. For patients who are staged incompletely at the time of initial surgery, completion of the staging procedure with either laparoscopy or laparotomy is a reasonable approach before a final decision is made regarding the need for AC. If full staging cannot be performed due to medical contraindication or patient refusal, consideration of AC is reasonable in selected patients. Using prognostic variables such as grade, International Federation of Gynecology and Obstetrics substage, pretreatment of CA-125 < or = 30 U/mL, and DNA ploidy, it is possible to divide patients into risk groups to avoid overtreatment. Gynecologic Oncology Group study 157 suggests that it may be possible to minimize chemotherapy-induced toxicity by using three instead of six cycles of AC, although it is not known fully whether this will compromise effectiveness. CONCLUSION: Future randomized studies in EOC will include the investigation of new targeted therapies and new prognostic factors in adequately staged patients.

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J Clin Oncol. 2007 Jul 10;25(20):2873-83.
Role of surgery in ovarian carcinoma.
Fader AN, Rose PG.
Cleveland Clinic Foundation, Cleveland, OH 44195, USA.

Surgery plays a critical role in the optimal management of all stages of ovarian carcinoma. In apparent early-stage ovarian cancer, a comprehensive surgical evaluation allows stratification of patients into low- and high-risk categories. Low-risk patients may be candidates for fertility-sparing surgery and can safely avoid chemotherapy and be observed. Treatment of patients with high-risk early- or advanced-stage ovarian cancer usually requires a combined modality approach. Although it is well known that epithelial ovarian cancer is moderately chemosensitive, what distinguishes it most from other metastatic solid tumors is that surgical cytoreduction of tumor volume is highly correlated with prolongation of patient survival. Procedures such as radical pelvic surgery, bowel resection, and aggressive upper abdominal surgery are commonly required to achieve optimal cytoreduction. Women who develop recurrent disease may be eligible for a secondary cytoreductive surgery or may require a surgical intervention to palliate disease-related symptoms. For women at high risk of ovarian cancer, prophylactic bilateral salpingo-oophorectomy significantly reduces the incidence of this disease. The purpose of this article is to provide a comprehensive review of the surgical management of ovarian carcinoma. The roles of primary, interval, and secondary cytoreductive surgeries; second-look procedures; and palliative surgery are reviewed. The indications for fertility-sparing and minimally invasive surgery as well as the current guidelines for prophylactic surgery in high-risk mutation carriers are also discussed.

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J Clin Oncol. 2007 Jul 10;25(20):2867-72.
Intraperitoneal chemotherapy for ovarian cancer: overview and perspective.
Rao G, Crispens M, Rothenberg ML.
Division of Hematology/Oncology, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN 37232-6307, USA.

Intraperitoneal (IP) chemotherapy has theoretical, pharmacologic, and clinical advantages over intravenous (IV) chemotherapy in women with optimally debulked epithelial ovarian cancer confined to the abdominal cavity. Consistent, statistically significant improvements in both progression-free and overall survival have been demonstrated in three large phase III trials conducted in the United States during the past 10 years. Nevertheless, concerns over IP drug distribution and systemic absorption, technical challenges of IP catheter placement and the incidence of IP catheter-related complications, and the clinical relevance of these studies have limited the adoption of IP therapy in ovarian cancer. Current interest in the evaluation of molecularly targeted therapies should build on the progress that has been made through the use of IP chemotherapy in women with optimally debulked ovarian cancer.

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Int J Gynecol Cancer. 2007 Apr 8; [Epub ahead of print]
Survival and prognostic factors in early-stage epithelial ovarian carcinoma treated with taxane-based adjuvant chemotherapy.
Skirnisdottir I, Sorbe B.
Department of Women's and Children's Health, Obstetrics and Gynecology, University Hospital, Uppsala, Sweden.

The present study was undertaken with the question about the outcome (recurrence-free survival, [RFS]) after adjuvant chemotherapy with taxane and carboplatin in the early stages of epithelial ovarian cancer after primary surgery. Treatment-related toxicity was also evaluated. A total of 113 patients were included in this study. The 5-year RFS rate for all 113 patients treated with adjuvant chemotherapy including taxane and carboplatin after primary surgery was 79%. The 5-year RFS rate for 85 patients in FIGO stage I was 85% and for 18 patients in FIGO stage II, it was 44%. For clear-cell carcinomas, the RFS was 87%. In univariate analysis, recurrent disease was associated with both FIGO stage and tumor grade, but in multivariate logistic regression analysis of prognostic factors for tumor recurrences, only FIGO stage (stage I versus stage II) was a significant and independent prognostic factor. However, an odds ratio (OR) of 1.9 for tumor grade (grade 3 versus grades 1-2) demonstrated two times increased risk for recurrence in a patient with a grade 3 tumor compared with grade 1-2 tumors. Furthermore, an OR of 0.39 for lymph node sampling versus no sampling meant 61% reduced risk for recurrence for a patient who had undergone lymph node sampling at surgical staging laparotomy. The major toxicities in the present study were myelosuppression (46%) and neurotoxicity (34%). Despite the use of prophylaxis, severe paclitaxel-related hypersensitivity occurred in three patients (3%).

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Int J Gynecol Cancer. 2007 Apr 8; [Epub ahead of print]
Bulky lymph node resection in patients with recurrent epithelial ovarian cancer: impact of surgery.
Benedetti Panici P, Perniola G, Angioli R, Zullo MA, Manci N, Palaia I, Bellati F, Plotti F, Calcagno M, Basile S.
Department of Obstetrics and Gynecology, University "La Sapienza" of Rome, Rome, Italy.

The aim of this study was to evaluate the role of systematic lymphadenectomy, feasibility, complications rate, and outcome in epithelial ovarian cancer (EOC) patients with recurrent bulky lymph node disease. A prospective observational study of EOC patients with pelvic/aortic lymph node relapse was conducted between January 1995 and June 2005. After a clinical and laparoscopic staging, secondary cytoreduction, including systematic lymphadenectomy, were performed. The eligibility criteria were as follows: disease-free interval >/=6 months, radiographic finding suggestive of bulky lymph node recurrence, and patients' consent to be treated with chemotherapy. Forty-eight EOC patients with lymph node relapse were recruited. Twenty-nine patients were amenable to cytoreductive surgery. Postoperatively, all patients received adjuvant treatment. The median numbers of resected aortic and pelvic nodes were 15 (2-32) and 17 (8-47), respectively. The median numbers of resected aortic and pelvic positive lymph nodes were 4 (1-18) and 3 (1-17), respectively. The mean size of bulky nodes was 3.3 cm. Four patients (14%) experienced one severe complication. No treatment-related deaths were observed. After a median follow-up of 26 months, among cytoreduced patients, 18 women were alive with no evidence of disease, nine were alive with disease. Among the 11 patients not amenable to surgery, five women were alive with persistent disease, six patients died of disease, at a median follow-up of 18 months. Estimated 5-year overall survival and disease-free interval for operated women were 87% and 31%, respectively. In conclusion, patients with bulky lymph node relapse can benefit from systematic lymphadenectomy in terms of survival. The procedure is feasible with an acceptable morbidity rate.

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Cancer. 2007 Apr 9; [Epub ahead of print]
Predictors of comprehensive surgical treatment in patients with ovarian cancer.
Goff BA, Matthews BJ, Larson EH, Andrilla CH, Wynn M, Lishner DM, Baldwin LM.
Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington.

BACKGROUND.: Providing appropriate surgical treatment for women with ovarian cancer is one of the most effective ways to improve ovarian cancer outcomes. In this study, the authors identified factors that were associated with a measure of comprehensive surgery, so that interventions may be targeted appropriately to improve surgical care. METHODS.: Using Healthcare Cost and Utilization Project hospital discharge data from 1999 to 2002 for 9 states, the authors identified 10,432 admissions of women who had an International Classification of Disease, 9th Revision (ICD-9) primary diagnosis of ovarian cancer and who had undergone oophorectomy. Based on National Institutes of Health Consensus Panel recommendations, surgeries were categorized as comprehensive by using ICD-9 diagnosis and procedure codes. Logistic regression analysis using data from 5 states with a full set of variables (n = 6854 patients)was used to identify factors that were associated with the receipt of comprehensive surgical care. RESULTS.: Overall, 66.9% of admissions (range, 46.3-80.8% of admissions) received comprehensive surgery. Factors that were associated independently with comprehensive surgical care included age (ages 21-50 years vs ages 71-80 years or >/=81 years), race (Caucasian vs African American or Hispanic), payer (private insurance vs Medicaid), cancer stage (advanced vs early), annual surgeon volume (low/medium [2-9 surgeries per year] or high [>10 surgeries per year] vs very low [1 surgery per year]), and surgeon specialty (gynecologic oncologists vs obstetrician gynecologists or general surgeons). Among nonteaching hospitals, medium-volume hospitals (10-19 ovarian cancer surgeries per year) and high-volume hospitals (>/=20 surgeries per year) had significantly higher comprehensive surgery rates than low-volume facilities (1-9 surgeries per year). Volume did not influence comprehensive surgery rates in teaching hospitals. CONCLUSIONS.: Many women with ovarian cancer, especially those in poor, elderly, or minority groups, are not receiving recommended comprehensive surgery. Efforts should be made to ensure that all women with ovarian cancer, especially those in vulnerable populations, have the opportunity to receive care from centers or surgeons with higher comprehensive surgery rates. Cancer 2007. (c) 2007 American Cancer Society.

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J Clin Oncol. 2007 Apr 1;25(10):1169-75.
Does ovarian cancer treatment and survival differ by the specialty providing chemotherapy?
Silber JH, Rosenbaum PR, Polsky D, Ross RN, Even-Shoshan O, Schwartz JS, Armstrong KA, Randall TC.
The Center for Outcomes Research, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. silber@email.chop.edu

PURPOSE: Chemotherapy for ovarian cancer is usually administered by medical oncologists (MOs) or gynecologic oncologists (GOs). GOs perform a broad spectrum of surgical and medical activities while managing a limited number of diseases; MOs specialize in the administration of chemotherapy but manage a broad array of diseases. We asked whether survival, treatment, and toxicity differed according to the type of specialist providing the chemotherapy after surgery. PATIENTS AND METHODS: Using Surveillance, Epidemiology, and End Results (SEER)--Medicare data for patients 65 years old from 1991 through 2001 from eight SEER sites, we identified 344 patients with ovarian cancer who were treated with chemotherapy by a GO after surgery. Using optimal matching and propensity scores based on 36 characteristics, we matched these patients to 344 similar patients who were operated on and staged by the same type of surgeon but who received chemotherapy from an MO. RESULTS: MOs administered chemotherapy over more weeks than did the GOs (16.5 v 12.1 weeks, respectively; P < .0023), and MO patients had substantially more weeks that included chemotherapy-associated adverse events than GO patients (16.2 v 8.9 weeks, respectively; P < .0001). However, there was no difference in 5-year survival rate between the GO and MO groups (35% v 34%, respectively; P = .45). CONCLUSION: GO- and MO-treated patients who were closely matched on prognostic characteristics experienced very different rates of chemotherapy-associated adverse events and very different chemotherapy treatment styles by specialty type; however, their survival was virtually identical.

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Gynecol Oncol. 2007 Mar 28; [Epub ahead of print]
Prognostic factors for complete debulking in advanced ovarian cancer and its impact on survival. An exploratory analysis of a prospectively randomized phase III study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group (AGO-OVAR).
Wimberger P, Lehmann N, Kimmig R, Burges A, Meier W, Du Bois A; for the AGO-OVAR.
Department of Gynecology and Obstetrics, University of Essen, Hufelandstr. 55, D-45122 Essen, Germany.

BACKGROUND.: No residual tumor as result of primary surgery in advanced ovarian cancer is known as one of the most important prognostic factors. PURPOSE.: To evaluate the impact of different prognostic factors for surgical outcome and to evaluate the impact of surgical outcome on survival. METHODS.: Surgical data as well as survival data were documented throughout the multi-center prospective randomized phase III trial (OVAR-3) of the AGO-OVAR and were used for this exploratory analysis. In this study 798 patients with FIGO IIB-IV were first operated then randomized and homogenously treated with cisplatin/paclitaxel or carboplatin/paclitaxel. Only patients with complete surgical data (n=761) entered this analysis. RESULTS.: Multivariable logistic regression analysis showed a significant decrease of probability for complete debulking without any macroscopic residual tumor for higher pre-operative tumor load (OR 0.32; 95% CI 0.17-0.61), higher FIGO stage (OR 0.22; 95% CI 0.13-0.39), worse performance status (OR 0.57; 95% CI 0.38-0.86), advanced age (OR 0.78; 95% CI 0.65-0.94) and presence of peritoneal carcinomatosis (OR 0.17; 95% CI 0.10-0.28). Surgery in centers with surgeons who performed comprehensive surgical debulking including retroperitoneal lymphadenectomy and peritoneal stripping was associated with higher rates of complete debulking compared to surgery in other centers (32.8% vs. 22.9%, p=0.007). This resulted in a markedly improved overall survival (p=0.045). This effect was held true after adjustment for prognostic factors (HR 0.77, 95% CI 0.63-0.94, p=0.012). CONCLUSION.: Post-operative residual tumor is one of the most important independent prognostic factor for survival. Our results suggest an advantage for aggressive primary surgery and complete debulking. This surgical goal was achieved more often in experienced centers.

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Int J Gynecol Cancer. 2007 Mar 15; [Epub ahead of print]
Treatment of FIGO stage IV ovarian carcinoma: results of primary surgery or interval surgery after neoadjuvant chemotherapy: a retrospective study.
Rafii A, Deval B, Geay JF, Chopin N, Paoletti X, Paraiso D, Pujade-Lauraine E.
Service de Chirurgie, Institut Claudius Regaud, Toulouse, France.

The objective of the study is to determine whether surgery influences the outcome of stage IV ovarian cancer. The study design is as follows: From May 1995 to December 2000, 129 patients with FIGO stage IV ovarian cancer, recruited in 42 centers, were prospectively included in GINECO first-line randomized studies of platinum-based regimens with paclitaxel administered simultaneously or sequentially. In all, 109 were eligible for this study. Standard peritoneal cytoreductive surgery was defined as a procedure including at least total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and peritoneal debulking. Surgery was considered optimal if residual lesions were smaller than 1 cm. The Kaplan-Meier method was used to compare survival. Initial abdominopelvic cytoreductive surgery was considered standard in 55 (54%) patients. Abdominopelvic surgery was optimal in 29 patients and nonoptimal in 26. Twenty-two (22%) patients had a simple biopsy, and 25 (24%) patients underwent substandard surgery. Twenty-two of these 47 patients without initial standard surgery underwent a second surgical procedure, and 17 of the 22 patients completed standard surgery. The median overall survival time in the entire population was 24.3 months (95% confidence interval [CI], 19.5-29.1 months). Patients treated without a cytoreductive surgical procedure had significantly worse median survival (15.1 months; 95% CI, 5.4-24.9 months) than patients who had optimal primary surgery (22.9 months; 95% CI, 15.6-30.1 months), nonoptimal primary surgery (27.1 months; 95% CI, 21.2-32.9 months), or neoadjuvant chemotherapy followed by surgery (45.5 months; 95% CI, 23.5-67.5 months) (P= .001). In conclusion, this study shows a significant benefit of debulking surgery in stage IV ovarian cancer patients who responded to neoadjuvant chemotherapy. Neoadjuvant chemotherapy can help to select patients for surgery.

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Cancer Chemother Pharmacol. 2007 Mar 29; [Epub ahead of print]
Weekly paclitaxel and carboplatin (PC-W) for patients with primary advanced ovarian cancer: results of a multicenter phase-II study of the NOGGO.
Sehouli J, Stengel D, Mustea A, Camara O, Keil E, Elling D, Ledwon P, Christiansen B, Klare P, Gebauer G, Schwarz M, Lichtenegger W; on behalf of the Ovarian Cancer Study Group of the Nord-Ostdeutsche Gesellschaft fur Gynakologische Onkologie (NOGGO).
Department of Gynaecology and Gynaecologic Oncology, Charite Virchow University Hospital, Augustenburger Platz 1, 13353, Berlin, Germany, Sehouli@aol.com.

OBJECTIVES: To study the toxicity and efficacy of weekly paclitaxel and carboplatin (PC-W) in women with primary ovarian cancer METHODS: This investigation extended a phase-I dose finding study and was approved by the institutional review boards of all participating institutions. Between 1999 and 2003, women with radically resected ovarian cancer of FIGO stages II B to IV were enrolled at 17 German centres. Patients received weekly paclitaxel at a dose of 100 mg/m(2), followed by carboplatin AUC 2. After a first treatment block consisting of six cycles of chemotherapy, patients had a treatment-free interval of 14 days, followed by a second block of six cycles. Treatment was completed by a 28-days break and a final block of six cycles. RESULTS: Altogether, 129 women with a mean age of 59 +/- standard deviation 11 years entered the study. Most patients (82.9%) had serous papillary carcinoma of FIGO stage III (72.9%) and IV (20.9%). Participants received 1,851 cycles of chemotherapy; averaging 14.3 +/- 4.3 cycles each patient. PC-W produced low rates of peripheral neuropathy (grade 3: 2.3%, 95% confidence interval [CI] 0.5-6.6%), with rapid recovery after 3 months. However, 72 patients had grade III/IV anaemia (55.8%, 95% CI 46.8-64.5%). There were 36 events of grade III/IV leukopenia (27.9%, 95% CI 20.4-36.5%). One patient sustained neutropenic fever. CA-125- and objective response was noted in 73.9% (95% CI 64.7-81.8%) and 55.6% (95% CI 41.4-69.1%) of patients. Median progression free and overall survival was 21 and 43 months, respectively. CONCLUSIONS: PC-W is feasible; a randomized study is warranted to compare this new regimen with conventional 3-weekly treatment.

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Gynecol Oncol. 2007 Mar 16; [Epub ahead of print]
Intraperitoneal chemotherapy for patients with advanced ovarian cancer: A review of the evidence and standards for the delivery of care.
Fung-Kee-Fung M, Provencher D, Rosen B, Hoskins P, Rambout L, Oliver T, Gotlieb W, Covens A; IP Chemotherapy Working Group on behalf of the Society of Gynecologic Oncologists of Canada.
Division of Gynecologic Oncology, University of Ottawa, Ottawa, Ontario, Canada.

OBJECTIVES.: To evaluate the role of intraperitoneal (IP) chemotherapy as part of primary treatment in patients with advanced ovarian cancer and to develop standards of care within the context of current clinical practice. METHODS.: A multidisciplinary expert panel, convened to develop standards on the use of IP chemotherapy, searched the MEDLINE, EMBASE, and Cochrane Library databases up to December 2006 for randomized trials or published standards on the efficacy and/or delivery of IP chemotherapy. RESULTS.: Eight randomized trials comparing IP chemotherapy versus intravenous (IV) chemotherapy were identified. Three trials reported statistically significant improvements in median survival of 8.0, 11.0, and 15.9 months with cisplatin-based IP chemotherapy. In one trial, the 15.9-month improvement in median overall survival (RR=0.75, 95% CI=0.58-0.97) represented a 25% reduction in the risk of death with IP chemotherapy. Severe adverse events and catheter-related complications were often dose limiting with IP chemotherapy. Using a consensus-based approach with a nationally representative panel, multidisciplinary care standards were developed to review medical and surgical criteria, the practice setting, volume requirements, and the institutional criteria required to safely deliver IP chemotherapy. CONCLUSION.: The survival benefits with cisplatin-based IP chemotherapy may represent a significant improvement in the outlook for select patients with advanced ovarian cancer. The delivery of IP chemotherapy is more challenging than the IV route; however, severe adverse events and catheter-related complications may be offset through research defining the optimum treatment regimen, and the standardization of care. System-wide standards for the delivery of IP chemotherapy in Canada for patients with optimally debulked stage III ovarian cancer are offered.

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Oncology (Williston Park). 2007 Feb;21(2):227-32; discussion 232, 235, 239-42.
The role of intraperitoneal therapy in advanced ovarian cancer.
Hess LM, Alberts DS.
Arizona Cancer Center Tucson, Arizona, USA.

Intraperitoneal (i.p.) chemotherapy is a preferred treatment option that should be offered to all women for front-line treatment of stage III optimally debulked ovarian cancer. Patients should be provided with information on the survival and toxicity for both i.p. and intravenous (i.v.) therapies, as well as practical information about the administration of each regimen, so that they may play an active role in the decision-making process. When making a decision between i.p. and i.v. therapeutic options, the experience and preference of the oncologist are critical factors in determining appropriate therapy for each woman.

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Cancer. 2007 Jan 11; [Epub ahead of print]
Secondary cytoreductive surgery for localized, recurrent epithelial ovarian cancer: analysis of prognostic factors and survival outcome.
Salani R, Santillan A, Zahurak ML, Giuntoli RL 2nd, Gardner GJ, Armstrong DK, Bristow RE.
The Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, Maryland.

BACKGROUND.: The objective of this study was to evaluate the role of secondary cytoreductive surgery in the outcome of patients who had recurrent epithelial ovarian carcinoma that was limited to </=5 recurrence sites within the abdomen or pelvis on preoperative imaging studies and attempt to define selection criteria associated with improved survival, with specific attention to the number of lesions suspicious for recurrent disease. METHODS.: Patients who underwent secondary surgical cytoreduction for recurrent epithelial ovarian cancer between September 1997 and March 2005 were identified retrospectively from tumor registry databases. Study inclusion criteria required a complete clinical response to primary therapy, >/=12 months between initial diagnosis and recurrence, and </=5 recurrence sites on preoperative imaging studies. Univariate and multivariate logistic regression analyses were used to evaluate the effect of clinicopathologic variables on overall postrecurrence survival. RESULTS.: Fifty-five patients met the study inclusion criteria. The median patient age at recurrence was 57.7 years, and the median diagnosis-to-recurrence interval was 32 months (range, 12-164 months). Complete cytoreduction was achieved in 41 patients (74.5%). On multivariate analysis, the statistically significant and independent predictors of overall survival were a diagnosis-to-recurrence interval >/=18 months (median survival, 49 months vs 3 months; P < .01), the number of radiographic recurrence sites (median survival, 50 months for patients with 1 or 2 sites vs 12 months for patients with 3 to 5 sites; P < .03), and residual disease (median survival, 50 months for patients with no macroscopic residual disease vs 7.2 months for patients with macroscopic residual disease; P < .01). Age, tumor grade, histology, CA-125 level, ascites, and tumor size were not associated significantly with survival. CONCLUSIONS.: The current data supported the definition of localized recurrent ovarian cancer as patients with 1 or 2 radiographic recurrence sites. In this select population, a diagnosis-to-recurrence interval >/=18 months and complete secondary surgical cytoreduction, which was achievable in the majority of patients, were associated with a median postrecurrence survival of approximately 50 months. Cancer 2007. (c) 2007 American Cancer Society.

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Obstet Gynecol. 2007 Jan;109(1):12-9.
Association of lymphadenectomy and survival in stage I ovarian cancer patients.
Chan JK, Munro EG, Cheung MK, Husain A, Teng NN, Berek JS, Osann K.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA 94305, USA. johnchan@stanford.edu

OBJECTIVE: To estimate the survival impact of lymphadenectomy in women diagnosed with clinical stage I ovarian cancer. METHODS: Demographic and clinicopathologic information were obtained from the Surveillance, Epidemiology and End Results Program between 1988 and 2001. Data were analyzed using Kaplan-Meier methods and Cox proportional hazards regression. RESULTS: A total of 6,686 women had clinical stage I ovarian cancer (median age 54 years, range 1-99). Of this total, 75.9% of patients were Caucasian, 8.3% were Hispanic, 5.8% were African American, and 7.3% were Asian. Epithelial tumors were present in 85.8% of the women, and 2,862 (42.8%) patients underwent lymphadenectomy. Patients aged 50 years or more were less likely to undergo lymphadenectomy compared with their younger cohorts (39.8% compared with 60.2%, P<.001). Only 32.7% of African-American women had lymphadenectomy compared with 42.7% of Caucasian women, 47.2% of Hispanics, and 48.8% of Asians (P<.001). Lymphadenectomy was associated with improved 5-year disease-specific survival of all patients from 87.0% to 92.6% (P<.001). More specifically, lymphadenectomy improved the survival in those with non-clear cell epithelial ovarian cancer (85.9% to 93.3%, P<.001) but not in those with clear cell carcinoma, germ cell tumors, sex cord stromal tumors, and sarcomas. Moreover, the extent of lymphadenectomy (0 nodes, less than 10 nodes, and 10 or more nodes) increased the survival rates from 87.0% to 91.9% to 93.8%, respectively (P<.001). On multivariable analysis, the extent of lymphadenectomy was a significant prognostic factor for improved survival, independently of other factors such as age, stage, histology, and grade of disease. CONCLUSION: Our data suggest that women with stage I non-clear cell ovarian cancers who underwent lymphadenectomy had a significant improvement in survival. LEVEL OF EVIDENCE: II.

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Expert Opin Drug Saf. 2007 Jan;6(1):53-62.
Safety of topotecan in the treatment of recurrent small-cell lung cancer and ovarian cancer.
Garst J.
Duke University Medical Center, Box 3198, 25176 Morris Building, Durham, NC 27710, USA. garst001@mc.duke.edu

The topoisomerase I inhibitor, topotecan, is approved for the treatment of recurrent small-cell lung cancer (SCLC) and ovarian cancer (OC). Patients with recurrent SCLC and OC typically experience multiple relapses and receive multiple rounds of chemotherapy. In these settings, disease stabilisation is considered a treatment benefit, and quality-of-life effects and cumulative toxicities of treatments should be considered. Many patients with recurrent cancer may be predisposed to treatment-related adverse events because of advanced age, renal impairment or extensive prior therapy. The standard regimen of topotecan, 1.5 mg/m(2) on days 1-5 of a 21-day cycle, has generally mild nonhaematological toxicity and a well-defined haematological toxicity profile characterised by reversible and noncumulative neutropenia. Alternative regimens may lower the incidence of haematological toxicities and maintain antitumour efficacy. Topotecan may provide physicians with a versatile therapeutic option for the treatment of patients with relapsed SCLC or OC.

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Expert Opin Biol Ther. 2007 Jan;7(1):103-12.
Ovarian cancer vaccine trials and tribulations.
Buckanovich RJ.
University of Michigan Comprehensive Cancer Center, Division of Hematology-Oncology and Division of Gynecologic Oncology, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109, USA. ronaldbu@umich.edu

Solid tumor vaccine therapy is coming of age. After years of failures, setbacks and negative trials, the first positive trials of antitumor vaccines in humans are being seen. Antitumor vaccine trials have reported an improvement in progression-free survival in breast cancer and an overall survival advantage in prostate cancer. Although, to date no positive Phase III antitumor vaccines trials in ovarian cancer have been reported, recent great strides have been made in improving tumor vaccine target antigens, improving antigen presentation and understanding the mechanisms of immunosuppression associated with tumors. In addition, biological therapies are now being identified that may enhance the efficacy of tumor vaccines. This review summarizes recent trials of ovarian cancer vaccines and addresses future directions to improve vaccine efficacy.

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Semin Oncol. 2006 Dec;33(6 Suppl 12):18-24.
New and Emerging Intraperitoneal (IP) Drugs for Ovarian Cancer Treatment.
Muggia FM.
Division of Medical Oncology, New York University Medical Center, New York, NY.

Chemotherapy after surgical debulking represents an essential component of treatment for patients with advanced ovarian cancer. Three quarters of patients respond very well to initial treatment with platinum-containing drugs used either alone or in combination with a taxane, usually paclitaxel. With relapse rates exceeding 50% and median survival time of 2 years for patients after relapse, efforts are focused on treatment approaches to achieve and extend clinical complete remissions. These approaches include consolidation and maintenance therapy, intraperitoneal (IP) administration of cytotoxic agents, new combination chemotherapy regimens, development of new cytotoxic agents, and molecular-targeted therapies (beyond tumor DNA, the classical target of cytotoxic drugs). IP chemotherapy, which involves direct instillation of chemotherapy into the tumor site in the peritoneal cavity, is the focus of this review article. This article discusses studies involving new and emerging IP drugs for both first-line chemotherapy treatment of advanced ovarian cancer and recurrent platinum-sensitive ovarian cancer.

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Semin Oncol. 2006 Dec;33(6 Suppl 12):8-17.
Maximizing the delivery of intraperitoneal therapy while minimizing drug toxicity and maintaining quality of life.
Alberts DS, Delforge A.
Arizona Cancer Center, Tucson, AZ.

This decade has witnessed three large randomized trials (SWOG 8501/GOG 104, GOG 114, and GOG 172) clearly showing the advantages of intraperitoneal (IP) chemotherapy over systemic/intravenous therapy in treating selected patients with advanced stage ovarian cancer. Despite showing an impressive increase in median progression-free survival and median overall survival, complications in IP chemotherapy delivery and drug-related toxicities reported in these studies have hindered widespread acceptance and implementation of first-line IP therapy. Some of these complications and drug-related toxicities are treatment-limiting and need special attention. Success of IP therapy as a first-line choice of treatment is dependent upon ideal patient selection, effective delivery of appropriate doses of chemotherapy agents to the tumor site, and efficient management of complications. With proper orientation and instruction in IP catheter placement and patient management, these obstacles can be overcome, allowing for successful administration of IP therapies. This review article discusses clinical approaches to maximize the delivery of IP therapy while minimizing catheter complications. Mitigating drug toxicities with the use of cytoprotectants such as amifostine and preventing infection with the use of agents, such as amifostine and pegfilgrastim, are discussed in detail.

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Am J Prev Med. 2006 Dec;31(6):512-4.
Role of ultraviolet B irradiance and vitamin D in prevention of ovarian cancer.
Garland CF, Mohr SB, Gorham ED, Grant WB, Garland FC.
Department of Family and Preventive Medicine, University of California-San Diego, La Jolla, California 92093-0631, USA. garlandc@nhrc.navy.mil

BACKGROUND: There is a north-south gradient in age-adjusted mortality rates of ovarian cancer in the United States, with the highest rates in the Northeast and the lowest in the South through Southwest. This suggests that lower levels of solar irradiance might be associated with higher risk of ovarian cancer. Laboratory findings also suggest that low levels of vitamin D metabolites could play a role in the etiology of ovarian cancer. METHODS: The association of solar ultraviolet B (UVB) irradiance, stratospheric column ozone, and fertility rates at ages 15 to 19 years with incidence rates of ovarian cancer in 175 countries in 2002 were examined using multiple linear regression in 2006. RESULTS: Age-adjusted ovarian cancer incidence rates generally were highest in countries located at higher latitudes (R(2)=0.45, p< or =0.01). According to multivariate analysis, UVB irradiance (p< or =0.002) and fertility rates at ages 15 to 19 (p=0.01) were inversely associated with incidence rates, while stratospheric ozone (p< or =0.0008), which reduces transmission of UVB, was positively associated with incidence (R(2)=0.49, p<0.0001). CONCLUSIONS: Solar UVB irradiance was inversely associated with incidence rates of ovarian cancer in this study, adding new evidence to the theory that vitamin D might play a role in the prevention of ovarian cancer. Cohort studies are needed to confirm this possible association.
 

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