Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240).

BACKGROUND: On Aug 14, 2014, the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial. In this study, we report the prespecified final analysis of the primary objectives, OS and adverse events. METHODS: In this randomised, controlled, open-label, phase 3 trial, we recruited patients with metastatic, persistent, or recurrent cervical carcinoma from 81 centres in the USA, Canada, and Spain. Inclusion criteria included a GOG performance status score of 0 or 1; adequate renal, hepatic, and bone marrow function; adequately anticoagulated thromboembolism; a urine protein to creatinine ratio of less than 1; and measurable disease. Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible. We randomly allocated patients 1:1:1:1 (blocking used; block size of four) to intravenous chemotherapy of either cisplatin (50 mg/m2 on day 1 or 2) plus paclitaxel (135 mg/m2 or 175 mg/m2 on day 1) or topotecan (0·75 mg/m2 on days 1-3) plus paclitaxel (175 mg/m2 on day 1) with or without intravenous bevacizumab (15 mg/kg on day 1) in 21 day cycles until disease progression, unacceptable toxic effects, voluntary withdrawal by the patient, or complete response. We stratified randomisation by GOG performance status (0 vs 1), previous radiosensitising platinum-based chemotherapy, and disease status (recurrent or persistent vs metastatic). We gave treatment open label. Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information), assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board. The cutoff for final analysis was 450 patients with 346 deaths. This trial is registered with ClinicalTrials.gov, number NCT00803062. FINDINGS: Between April 6, 2009, and Jan 3, 2012, we enrolled 452 patients (225 [50%] in the two chemotherapy-alone groups and 227 [50%] in the two chemotherapy plus bevacizumab groups). By March 7, 2014, 348 deaths had occurred, meeting the prespecified cutoff for final analysis. The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups: 16·8 months in the chemotherapy plus bevacizumab groups versus 13·3 months in the chemotherapy-alone groups (hazard ratio 0·77 [95% CI 0·62-0·95]; p=0·007). Final OS among patients not receiving previous pelvic radiotherapy was 24·5 months versus 16·8 months (0·64 [0·37-1·10]; p=0·11). Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8·4 months) and chemotherapy-alone groups (7·1 months; 0·83 [0·66-1·05]; p=0·06). Fistula (any grade) occurred in 32 (15%) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1%) of 220 in the chemotherapy-alone groups (all previously irradiated). Grade 3 fistula developed in 13 (6%) versus one (<1%). No fistulas resulted in surgical emergencies, sepsis, or death. INTERPRETATION: The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated. After progression while receiving bevacizumab, we did not observe a negative rebound effect (ie, shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped). These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer. FUNDING: National Cancer Institute.

Phase III Randomized Trial of Maintenance Taxanes Versus Surveillance in Women With Advanced Ovarian/Tubal/Peritoneal Cancer: A Gynecologic Oncology Group 0212:NRG Oncology Study.

PURPOSE: To compare taxane maintenance chemotherapy, paclitaxel (P) and paclitaxel poliglumex (PP), with surveillance (S) in women with ovarian, peritoneal, or fallopian tube (O/PC/FT) cancer who attained clinical complete response after first-line platinum-taxane therapy. METHODS: Women diagnosed with O/PC/FT cancer who attained clinical complete response after first-line platinum-taxane-based chemotherapy were randomly allocated 1:1:1 to S or maintenance, P 135 mg/m2 once every 28 days for 12 cycles, or PP at the same dose and schedule. Overall survival (OS) was the primary efficacy end point. RESULTS: Between March 2005 and January 2014, 1,157 individuals were enrolled. Grade 2 or worse GI adverse events were more frequent among those treated with taxane (PP: 20%, P: 27% v S: 11%). Grade 2 or worse neurologic adverse events occurred more often with taxane treatment (PP: 46%, P: 36% v S: 14%). At the fourth scheduled interim analysis, both taxane regimens passed the OS futility boundary and the Data Monitoring Committee approved an early release of results. With a median follow-up of 8.1 years, 653 deaths were reported; none were attributed to the study treatment. Median survival durations were 58.3, 56.8, and 60.0 months for S, P, and PP, respectively. Relative to S, the hazard of death for P was 1.091 (95% CI, 0.911 to 1.31; P = .343) and for PP, it was 1.033 (95% CI, 0.862 to 1.24; P = .725). The median times to first progression or death (PFS) were 13.4, 18.9, and 16.3 months for S, P, and PP, respectively. Hazard ratio = 0.801; 95% CI, 0.684 to 0.938; P = .006 for P and hazard ratio = 0.854; 95% CI, 0.729 to 1.00; P = .055 for PP. CONCLUSION: Maintenance therapy with P and PP did not improve OS among patients with newly diagnosed O/tubal/peritoneal cancer, but may modestly increase PFS. GI and neurologic toxicities were more frequent in the taxane treatment arms.

Fertility preserving options in patients with gynecologic malignancies.

A proportion of reproductive age women are affected by gynecologic malignancies. This patient population is faced with difficult decisions, related to their cancer care and treatment, as well as future childbearing potential. Therefore, it is important for gynecologists to be familiar with fertility sparing management options in patients with cervical, ovarian, and endometrial cancer. In addition to understanding the surgical approaches available, providers should be able to counsel patients regarding their eligibility for and the indications and limitations of fertility sparing therapy for gynecologic cancer, allowing for appropriate referrals. A comprehensive PUBMED literature search was conducted using the key words "fertility preservation," "cervical cancer," "endometrial cancer," "ovarian cancer," "borderline tumor of the ovary," "germ cell tumor," "obstetrical outcomes," "chemotherapy," and "radiation." The following review summarizes fertility sparing options for patients with cervical, ovarian and endometrial cancer, with an emphasis on appropriate patient selection, oncologic, and obstetric outcomes.

First-line therapy in ovarian cancer trials.

At the 4th Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup (GCIG) held in Vancouver, Canada, in June 2010, representatives of 23 cooperative research groups studying gynecologic cancers gathered to establish international consensus on issues critical to the conduct of large randomized trials. The process focused on 13 predetermined questions. Group A, 1 of the 3 discussion groups, addressed the first 5 questions, examining first-line therapies in newly diagnosed ovarian cancer patients. A1: What are the appropriate end points for different trials (maintenance, upfront chemotherapy trials including molecular drugs)? A2: Are there any subgroups defined by tumor biology who need specific treatment options/trials? A3: Is the 2004 GCIG-recommended standard comparator arm still valid? A4: What is the role of modifying dose, schedule, and delivery of chemotherapy? A5: What role does surgery play today?

Recurrent endometrial stromal sarcoma: treatment with a progestin and gonadotropin releasing hormone agonist.

Endometrial stromal sarcoma (ESS) formerly classified as low-grade endometrial stromal sarcoma is a rare uterine malignancy with a good prognosis despite a tendency to recur. Primary surgical management for ESS includes total abdominal hysterectomy and bilateral salpingo-oophorectomy. Patients with ESS have long disease-free survival rates when treated with primary surgical therapy, but nearly fifty percent of these patients will recur. We present the case of a patient with recurrent ESS who had an excellent response to combined therapy with megestrol and leuprolide.

Node count and groin recurrence in early vulvar cancer: A Gynecologic Oncology Group study.

OBJECTIVE: To determine if low node count from superficial groin dissection correlated with first recurrence in the groin for patients with early vulvar cancer. METHODS: The Gynecologic Oncology Group (GOG) conducted a trial for patients with early stage squamous vulvar cancer, lesions <2 cm in size and <5 mm in depth. All fatty tissue below the inguinal ligament, medial to the sartorious and lateral to the adductor longus was removed. Incision of the fascia and skeletonizing the femoral vessels were not required. For this secondary analysis, we reviewed the records of all patients to assess node counts. RESULTS: Of the 113 patients eligible for the study, 104 patients (with 117 dissected groins) did not have a first recurrence in the groin. The median number of negative nodes was 9 (range: 1-26). Nine patients (with 9 dissected groins) suffered a first recurrence in the groin. The median number of negative nodes removed per groin was 7 (range: 4-22). There were no significant differences between patients with first recurrence in the groin and those without (p value=0.7475). There was a broad overlap of the confidence intervals. CONCLUSIONS: We were unable to show that groin failure after superficial lymphadenectomy was a result of low lymph node count. The small number of recurrences made firm conclusions impossible. Variations in anatomy and other factors may make node counting an unreliable measure of surgical quality.

Colposcopy to evaluate abnormal cervical cytology in 2008.

The rates of cervical cancer in the United States are low in comparison with developing nations. Whereas the Papanicolaou smear has performed well in terms of detecting both precursors of squamous cell carcinoma and squamous cell carcinoma of the cervix, this test has been less successful at identifying those women with the highest-risk premalignant disease. The use of human papillomavirus testing has also contributed to the improved sensitivity of screening for cervical cancer. In light of this, the colposcopy clinic retains high referral rates yet has poor diagnostic accuracy. Unfortunately, patients are triaged to follow-up for abnormal Papanicolaou smears based on algorithms that rely on the less evidence-based techniques of colposcopy. Therefore, the need to improve the specificity of colposcopic-guided biopsy remains. The colposcopic procedure is highlighted in this review and evaluated in terms of current literature on technique, the colposcopic impression, cervical biopsy, and methods proposed to enhance appreciation of the highest-risk lesions. By outlining certain flaws in technique and discussing the proposal of new tests to supplement the current standard of care, this review aimed to highlight the need for future research to maintain sensitivity but improve the specificity of colposcopy.

Final Overall Survival of a Randomized Trial of Bevacizumab for Primary Treatment of Ovarian Cancer.

PURPOSE: We report the final, protocol-specified analysis of overall survival (OS) in GOG-0218, a phase III, randomized trial of bevacizumab in women with newly diagnosed ovarian, fallopian tube, or primary peritoneal carcinoma. METHODS: A total of 1,873 women with incompletely resected stage III to IV disease were randomly assigned 1:1:1 to six 21-day cycles of intravenous carboplatin (area under the concentration v time curve 6) and paclitaxel (175 mg/m2) versus chemotherapy plus concurrent bevacizumab (15 mg/kg, cycles 2 to 6) versus chemotherapy plus concurrent and maintenance bevacizumab (cycles 2 to 22). Inclusion criteria included a Gynecologic Oncology Group performance status of 0 to 2 and no history of clinically significant vascular events or evidence of intestinal obstruction. OS was analyzed in the intention-to-treat population. A total of 1,195 serum and/or tumor specimens were sequenced for BRCA1/2 and damaging mutations in homologous recombination repair (HRR) genes. Intratumoral microvessel density was studied using CD31 immunohistochemistry. RESULTS: Median follow-up was 102.9 months. Relative to control (n = 625), for patients receiving bevacizumab-concurrent (n = 625), the hazard ratio (HR) of death was 1.06 (95% CI, 0.94 to 1.20); for bevacizumab-concurrent plus maintenance (n = 623), the HR was 0.96 (95% CI, 0.85 to 1.09). Disease-specific survival was not improved in any arm. No survival advantage was observed after censoring patients who received bevacizumab at crossover or as second line. Median OS for stage IV bevacizumab-concurrent plus maintenance was 42.8 v 32.6 months for stage IV control (HR, 0.75; 95% CI, 0.59 to 0.95). Relative to wild type, the HR for death for BRCA1/2 mutated carcinomas was 0.62 (95% CI, 0.52 to 0.73), and for non-BRCA1/2 HRR, the HR was 0.65 (95% CI, 0.51 to 0.85). BRCA1/2, HRR, and CD31 were not predictive of bevacizumab activity. CONCLUSION: No survival differences were observed for patients who received bevacizumab compared with chemotherapy alone. Testing for BRCA1/2 mutations and homologous recombination deficiency is essential.

Suppression of ovarian cancer cell tumorigenicity and evasion of Cisplatin resistance using a truncated epidermal growth factor receptor in a rat model.

The overexpression of the epidermal growth factor receptor (EGFR) is associated with a poor prognosis in ovarian cancer. The dominant-negative EGFR (EGFR-DNR) is a truncated receptor that lacks the tyrosine kinase domain and is devoid of signaling capability. This study tested the effects of a EGFR-DNR approach in ovarian cancer cells. NuTu-19, a rat ovarian cancer cell line was rendered resistant to cisplatin. Both NuTu-19 and resistant cells were infected with a retroviral vector containing the EGFR-DNR. NuTu-19 and NuTu-DNR (NuTu-19 cells expressing the EGFR-DNR) were injected into Fisher 344 immunocompetent rats. Western blot analyses were used to assess signal transduction pathways. All rats injected with NuTu-DNR cells remained healthy following tumor injection. In contrast, 100% of the rats injected with the NuTu-19 and NuTu-Sham (NuTu-19 cells expressing an empty vector) died of disease progression at the end of 15 weeks (P = 0.00009). On Western blot analysis, both NuTu-19 and NuTu-Sham cells showed a strong activation of mitogen-activated protein kinase (MAPK) after exposure to EGF. Cisplatin-resistant cell lines showed an enhanced EGF stimulatory effect via the MAPK pathway compared with parental cells. The EGFR-DNR significantly reduced the ability of EGF to induce cell signaling through the MAPK pathway. Lastly, the EGFR-DNR can partially reverse cisplatin resistance in drug-resistant cells. The EGFR-DNR approach suggests that EGFR confers a growth advantage to NuTu-19 cells in vivo. Thus, EGFR blockade may ultimately prove to be a useful therapeutic tool in the treatment of cisplatin-sensitive and cisplatin-resistant ovarian cancers.

Differences in prognostic molecular markers between women over and under 45 years of age with advanced ovarian cancer.

PURPOSE: The purpose of this study was to determine whether differences in molecular markers might explain the better prognosis of women < or =45 years of age versus women >45 years of age diagnosed with ovarian cancers. EXPERIMENTAL DESIGN: Tissue sections from women with stage III-IV ovarian cancers were examined for expression of CD34, p53, and HER2. The Kaplan-Meier method and Cox Proportional Hazard analyses were used to identify predictors for outcome. RESULTS: Fifty-two women < or =45 years of age were matched with 52 women who were >45 years old. Of the 46 available tissue sections, 24 were from the younger age group (mean age, 41 years), and 22 were from the older age group (mean age, 61 years). Based on CD34 expression, tumors from women >45 years of age had lower microvessel density (MVD) compared with tumors of younger women (10.3 versus 16.1 microvessels per x400 field; P = 0.03). Lower MVD (< or =11 microvessels per x400 field) predicted for a worse prognosis than higher MVD (>11 microvessels per x400 field) in the overall study group (P = 0.001) and within the older subgroup (P = 0.03). The expressions of p53 (P = 0.13) and HER2 (P = 0.49) did not vary between the two age groups. The median survivals of those with tumors that overexpressed p53 and HER2 were 28.6 and 23.9 months compared with 51.7 and 38.6 months in those with cancers that underexpressed these markers, respectively (P = 0.09 for p53, P = 0.15 for HER2). CONCLUSIONS: Ovarian cancers in women >45 years of age had lower MVD compared with those in women < or =45 years of age. Lower MVD was an independent prognostic factor for decreased survival. Lower frequency of neovascularization in these cancers may contribute to the decreased survival observed in women >45 years of age.

Long-term results of low-dose-rate interstitial-intracavitary brachytherapy in the treatment of carcinoma of the cervix.

PURPOSE: Brachytherapy plays a major role in the treatment of patients with carcinoma of the cervix. However, routine intracavitary brachytherapy may not be feasible or adequate to treat locally advanced disease. The purpose of this retrospective study (spanning a 20-year period) was to determine the outcome of interstitial low-dose-rate brachytherapy in the treatment of bulky or locally advanced cervical cancer. The long-term survival and safety of this technique were evaluated, along with its impact on local and locoregional control, disease-free survival, and complications. METHODS AND MATERIALS: A total of 185 previously untreated patients with cervical cancer were treated between 1977 and 1997. According to the International Federation of Gynecology and Obstetrics classification, 21 patients had Stage IB (barrel), 77 Stage II, 77 Stage III, and 10 Stage IV disease. All patients were treated by a combination of external megavoltage irradiation to the pelvis to a dose of 5040 cGy followed by interstitial-intracavitary implants to a dose of 40-50 Gy to the implanted volume in two applications. RESULTS: Clinical local control was achieved in 152 (82%) of the 185 patients. A 5-year disease-free survival rate of 65%, 67%, 49%, and 17% was achieved for patients with Stage IB, II, III, and IV disease, respectively. Eighteen (10%) of the 185 patients developed Radiation Therapy Oncology Group Grade 3 or 4 late complications. CONCLUSION: Patients with locally advanced cervical cancer, or with distorted anatomy, may be treated adequately with interstitial brachytherapy to achieve excellent locoregional control and a reasonable chance of cure with acceptable morbidity.

Stages III and IV invasive epithelial ovarian carcinoma in younger versus older women: what prognostic factors are important?

UNLABELLED: OBJECTIVE; To compare the survival rates in younger (45 years or younger) and older women (over 45) diagnosed with advanced-stage invasive epithelial ovarian cancer. Clinical and pathologic factors responsible for survival differences between the two groups were also determined. METHODS: All younger women with advanced-stage epithelial ovarian carcinoma diagnosed between 1984 and 2001 were identified from tumor registry databases at two hospitals. Patients with borderline tumors were excluded. An older group of comparable controls was selected for comparison. Kaplan-Meier and Cox proportional hazards analyses were used to determine the predictors for survival. RESULTS: Of 104 women with advanced-stage epithelial ovarian carcinoma, 52 were 45 or younger and the rest were over 45. The 5-year survival rate and median survival in younger patients were 48% and 54 months, compared with 22% and 34 months in the older women (P =.003). Younger women had significantly better performance status than older patients, and survival remained significantly better in younger women based on Kaplan-Meier analysis stratified by performance status (0 versus 1 to 2, P =.02). Furthermore, overall survival was significantly better in younger women after stratification by stage (III versus IV, P =.002) and by cytoreductive surgery (optimal versus suboptimal, P =.003). Multivariable analysis demonstrated that all these factors remained as significant independent prognostic factors for survival. CONCLUSION: Younger women with advanced-stage invasive epithelial ovarian cancer have significantly improved survival rates relative to older patients. Age, performance status, stage of disease, and extent of cytoreductive surgery are important independent prognostic factors for survival.

Primary prevention of uterine cervix cancer: focus on vaccine history and current strategy.

Primary prevention of uterine cervix cancer spans the gamut of human papillomavirus vaccine development, dietary adjustment, chemoprevention, and risk reduction. Lifestyle and social behaviors impact on risk for cervical cancer. Before examining the growing body of molecular evidence, animal studies, and phase I clinical trials that suggest that a virus-based vaccine for cervical cancer may soon become a reality, one must reflect on what has gone before in the vaccine-based battle with viral disease.

Borderline ovarian tumors in reproductive-age women. Fertility-sparing surgery and outcome.

OBJECTIVE: To evaluate the fertility and survival outcomes in young women with borderline ovarian tumors treated with fertility-sparing surgery. STUDY DESIGN: From 1985 to 2002, 25 women with borderline ovarian cancers surgically managed with preservation of the uterus and at least a portion of 1 ovary were identified from tumor registry databases at 2 southern California hospitals. Data for analysis were collected from hospital charts, office records and tumor registry files. RESULTS: Twenty-five patients (median age, 29 years) with borderline ovarian tumors, including 10 with stage IA, 3 with stage IC, 1 with stage IIIA and 11 with unstaged disease, underwent fertility-sparing surgery, consisting of unilateral adnexectomy in 19, unilateral adnexectomy with contralateral cystectomy in 5 and unilateral cystectomy in 1. No disease recurred, providing an overall survival of 100%. Fertility status was available on 15 patients 4-157 months after surgery; 6 of them attempted to become pregnant. Five women had successful pregnancies, with a total of 5 live births. One woman underwent assisted reproductive techniques, became pregnant but aborted. The median follow-up was 80 months (range, 4-157). CONCLUSION: Conservative surgery for borderline ovarian tumors should be considered for women in the reproductive age group who desire preservation of fertility.

Outcomes of high-dose-rate interstitial brachytherapy in the treatment of locally advanced cervical cancer: long-term results.

PURPOSE: The purpose of this study was to determine locoregional control (LRC), disease-free survival (DFS), and toxicity of high-dose-rate interstitial brachytherapy (HDR-ISBT) in the treatment of locally advanced cervical cancer. METHODS AND MATERIALS: Between March 1996 and May 2009, 116 patients with cervical cancer were treated. Of these, 106 (91%) patients had advanced disease (International Federation of Gynecology and Obstetrics stage IIB-IVA). Ten patients had stage IB, 48 had stage II, 51 had stage III, and 7 had stage IVA disease. All patients were treated with a combination of external beam radiation therapy (EBRT) to the pelvis (5040 cGy) and 2 applications of HDR-ISBT to a dose of 3600 cGy to the implanted volume. Sixty-one percent of patients also received interstitial hyperthermia, and 94 (81%) patients received chemotherapy. RESULTS: Clinical LRC was achieved in 99 (85.3%) patients. Three-year DFS rates were 59%, 67%, 71%, and 57% for patients with stage IB, II, III, and IVA disease, respectively. The 5-year DFS and overall survival rates for the entire group were 60% and 44%, respectively. Acute and late toxicities were within acceptable limits. CONCLUSIONS: Locally advanced cervical cancer patients for whom intracavitary BT is unsuitable can achieve excellent LRC and OS with a combination of EBRT and HDR-ISBT.

Margin distance and other clinico-pathologic prognostic factors in vulvar carcinoma: a multivariate analysis.

OBJECTIVES: To determine the importance of margin status and other prognostic factors associated with the recurrence and survival of patients with squamous cell vulvar carcinoma. METHODS: Data were analyzed using Kaplan-Meier methods and Cox proportional hazards regression. All slides were re-reviewed by two gynecologic pathologists. RESULTS: Ninety patients (median age: 69) were treated for vulvar carcinoma from 1984 to 2002, including 28 FIGO stage I, 20 stage II, 26 stage III and 16 with stage IV disease. Sixty-three (70%) patients underwent complete radical vulvectomies and 27 (30%) had modified radical vulvectomies. Nineteen (20%) patients received adjuvant radiotherapy. Five-year disease-specific survival rates were 100%, 100%, 86% and 29% for stages I-IV, respectively. None of the 30 patients with a pathologic margin distance >8 mm had local recurrence. Of the 53 women with tumor-free pathologic margin of <8 mm, 12 (23%) had a local recurrence. Moreover, women with >2 positive groin nodes had significantly higher recurrence risk compared to those with <2 metastatic groin nodes (p<0.001). On multivariate analysis, positive groin nodes and margin distance were important prognostic factors for recurrence. Moreover, stage, tumor size, margin distance, and depth of invasion were significant independent predictors for disease-specific survival. The median follow-up was 58 months (range: 2-188). CONCLUSIONS: Pathologic margin distance is an important predictor of local vulvar recurrence. Our data suggest that a > or =8-mm pathologic margin clearance leads to a high rate of loco-regional control.

Mast cell density, angiogenesis, blood clotting, and prognosis in women with advanced ovarian cancer.

OBJECTIVE: To determine clinical or biological associations between mast cell density, blood clotting, angiogenesis, and survival of patients with advanced ovarian cancer. METHODS: Tumor tissue sections were assessed for mast cell density by staining for mast cell tryptase, blood clotting by staining of thrombosed blood vessels, and angiogenesis by CD34 expression. Chi-square, Kaplan-Meier, and Cox proportional hazard statistical analyses were used. RESULTS: 44 women with stage III-IV ovarian cancers had tumor blocks available for immunohistochemical analysis. Higher mean vessel density (MVD) (>11 vessels/400x field) predicted for better survival than lower MVD (< or =11 vessels/400x field) (P = 0.004). Women whose tumors had low levels of peri-tumoral mast cell infiltration had a mean survival of 40.6 months compared to 50.6 months in those whose tumors had high levels (P = 0.47). Tumors with higher MVD and high peri-tumoral mast cell infiltration had a mean survival of 80.3 months compared to 37.8 months in those with low mast cell density or low MVD (P = 0.015). Patients with tumors showing a low degree of blood clotting had a mean survival of 45.5 compared to 45.1 months in those with tumors showing a high degree of blood clotting (P = 0.91). There was no significant association between angiogenesis and mast cell density (P = 0.123). In multivariate analysis, higher MVD remained as a significant prognostic factor for improved survival after adjusting for clotting and mast cell density. CONCLUSIONS: Our data suggest that peri-tumoral mast cell infiltration in tumors with high MVD predicts for improved survival in women with advanced epithelial ovarian cancer.