Outcome In Advanced Ovarian Cancer Research Articles

First application of the Automated QUantitative Analysis (AQUA) technique to quantify PTEN protein expression in ovarian cancer: A correlative study of NCIC CTG OV.16

BackgroundPlatinum resistance is a dominant cause of poor outcomes in advanced ovarian cancer (OC). A mechanism of platinum resistance is the inhibition of apoptosis through phosphatidylinositol 3 kinase (PI3K) pathway activation. The role of phosphatase and tensin homolog (PTEN), a negative regulator of this pathway, as a tumor biomarker is unclear. Quantitative analysis of PTEN expression as an alternative to immunohistochemistry has not been considered. Patients and methodsIn 238 patient tumors from the NCIC-CTG trial OV.16, PTEN protein expression was quantified by Automated QUantitative Analysis (AQUA). Cox model was used to study the association between PTEN expression and clinical outcomes using a minimum p-value approach in univariate analysis. Multivariate analysis was used to adjust for clinical and pathological parameters. ResultsPTEN scores (range 13.9–192.3) of the 202 samples that passed quality control were analyzed. In univariate analysis, there was a trend suggesting an association between PTEN expression by AQUA as a binary variable (low ≤61 vs high >61) and progression free survival (HR=0.77, p=0.083), and in multivariate analysis, this association approached significance (HR=0.74, p=0.059). The relationship between quantitative PTEN expression and PFS differed (p=0.01 for interaction) by the extent of surgical debulking (residual disease (RD) <1cm or ≥1cm), with a numerically superior PFS in patients with high PTEN (23.5 vs 14.9m) only when RD<1cm (p=0.19). There was no association between PTEN levels and overall survival. ConclusionsAQUA is a novel method to measure PTEN expression. Further study of PTEN as a biomarker in OC is warranted.

Combination of erlotinib and a PARP inhibitor inhibits growth of A2780 tumor xenografts due to increased autophagy.

BackgroundOvarian cancer is the leading cause of death in women with gynecological malignancy worldwide. Despite multiple new approaches to treatment, relapse remains almost inevitable in patients with advanced disease. The poor outcome of advanced ovarian cancer treated with conventional therapy stimulated the search for new strategies to improve therapeutic efficacy. Although epidermal growth factor receptor (EGFR) and poly(ADP-ribose) polymerase (PARP) inhibitors have known activity in advanced ovarian cancer, the effect of combined therapy against EGFR and PARP in this population has not been reported. In the current study, we investigated the mechanisms of erlotinib used alone or in combination with olaparib (AZD2281), a potent inhibitor of PARP, in an EGFR-overexpressing ovarian tumor xenograft model.MethodsA2780 (EGFR-overexpressing, BRCA1/2 wild-type) cells were subcutaneously injected into nude mice, which were then randomly assigned to treatment with vehicle, erlotinib, AZD2281, or erlotinib + AZD2281, for up to 3 weeks. All mice were then sacrificed and tumor tissues were subjected to Western blot analysis and monodansylcadervarine staining (for analysis of autophagy).ResultsErlotinib could slightly inhibit growth of A2780 tumor xenografts, and AZD2281 alone had similar effects on tumor growth. However, the combination treatment had a markedly enhanced antitumor effect. Western blot analysis revealed that treatment with erlotinib could significantly reduce the phosphorylation level of ERK1/2 and AKT in A2780 tumor tissue. Of interest, monodansylcadervarine staining showed that the autophagic effects were substantially enhanced when the agents were combined, which may be due to downregulation of apoptosis.ConclusionThese results suggest that combination of a selective EGFR inhibitor and a PARP inhibitor is effective in ovarian cancer A2780 xenografts, and depends on enhanced autophagy.

Impact of obesity on surgical and oncologic outcomes in advanced ovarian cancer

Impact of obesity on surgical and oncologic outcomes in advanced ovarian cancer

Evolution of surgery in advanced epithelial ovarian cancer in a dedicated gynaecologic oncology unit-seven year audit from a tertiary care centre in a developing country.

AimsTo audit our performance as a dedicated gynaecologic oncology unit and to analyse how it has evolved over the years.To retrospectively evaluate the outcome of advanced ovarian cancer treated with neoadjuvant chemotherapy (NACT) followed by interval surgery versus upfront surgery.Methods and resultsOne hundred and ninety-eight patients with advanced epithelial ovarian cancer (EOC) who were treated from 2004 to 2010 were analysed. Eighty-two patients (41.4%) underwent primary surgery and 116 (58.6%) received NACT. Overall, an optimal debulking rate of 81% was achieved with 70% for primary surgery and 88% following NACT. The optimal cytoreduction rate has improved from 55% in 2004 to 97% in 2010. In primary surgery, the optimal debulking rate increased from 42.8% in 2004 to 93% in 2010, whereas in NACT group the optimal cytoreduction rate increased from 60% to 100% by 2010.On the basis of the surgical complexity scoring system it was found that surgeries with intermediate complexity score had progressively increased over the years.There was a mean follow-up of 21 months ranging from 6 to 70 months. The progression-free survival and overall survival (OS) in patients undergoing primary surgery were 23 and 40 months, respectively, while it was 22 and 40 months in patients who received NACT. However, patients who had suboptimal debulking, irrespective of primary treatment, had significantly worse OS (26 versus 47 months) compared with those who had optimal debulking.ConclusionsAs a dedicated gynaecologic oncology unit there has been an increase in the optimal cytoreduction rates. The number of complex surgeries, as denoted by the category of intermediate complexity score, has increased.Patients with advanced EOC treated with NACT followed by interval debulking have comparable survival to the patients undergoing primary surgery. Optimal cytoreduction irrespective of primary modality of treatment gives better survival.

βIII-Tubulin Overexpression Is an Independent Predictor of Prostate Cancer Progression Tightly Linked to ERG Fusion Status and PTEN Deletion

Evidence suggests that class III β-tubulin (βIII-tubulin) may represent a prognostic and predictive molecular marker in prostate cancer. βIII-Tubulin expression was determined by IHC in 8179 prostate cancer specimens in a TMA format. Results were compared with tumor phenotype, biochemical recurrence, v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) status, and deletions on PTEN, 3p13, 5q21, and 6q15. βIII-Tubulin expression was detectable in 25.6% of 8179 interpretable cancers. High βIII-tubulin expression was strongly associated with both TMPRSS2:ERG rearrangement and ERG expression (P<0.0001 each). High βIII-tubulin expression was tightly linked to high Gleason grade, advanced pT stage, and early prostate-specific antigen (PSA) recurrence in all cancers (P<0.0001 each), but also in the subgroups of ERG-negative and ERG-positive cancers. When all tumors were analyzed, the prognostic role of βIII-tubulin expression was independent of Gleason grade, pT stage, pN stage, surgical margin status, and preoperative PSA. Independent prognostic value became even more evident if the analysis was limited to preoperatively available features, such as biopsy specimen Gleason grade, preoperative PSA, cT stage, and βIII-tubulin expression (P<0.0001 each). βIII-Tubulin expression was associated with PTEN (P<0.0001) when all tumors were analyzed, but also in the subgroups of ERG-negative and ERG-positive cancers. βIII-Tubulin expression is an independent prognostic parameter. The significant associations with key genomic alterations of prostate cancer, such as TMPRSS2:ERG fusions and PTEN deletions, suggest interactions with several pivotal pathways involved in prostate cancer.

Abstract A85: A comparison of patient outcomes in advanced ovarian cancer: Assay-informed vs. empirically treated

Abstract Objective: Two decades of research have resulted in modest gains in progression-free and overall survival for ovarian cancer patients. Peer reviewed studies randomizing these patients to various standard chemotherapies consistently demonstrate remarkably similar survival, highlighting the therapeutic equivalence and ambiguity that exists with empiric treatment. Chemoresponse assays were developed to determine an individual's in vitro tumor response to various chemotherapy agents, providing sensitivity and resistance information to guide patient treatment. Utilizing a two arm clinical trial design approach, the objective of this study was to conduct a comparative analysis of the impact that a chemoresponse assay (ChemoFx®, Precision Therapeutics, Inc.) has on overall survival (OS) as compared to patients treated by non-assay informed empiric choice from previously accrued drug trials from 4 large cooperative group studies. Methods: Patient characteristics from 4 cooperative group studies (duBios JNCI 2003; Pfisterer JNCI 2006; duBois JCO 2006; Bookman 2009 JCO) totaling &amp;gt;7,000 patients were used as the empiric control arm and compared to a 192 patient cohort from a chemoresponse assay study (Herzog 2010 AJOG). These arms were compared to confirm that the assay-informed arm was representative of large trial patient populations in advanced ovarian cancer. In addition, annual rates for OS were compared among all 5 patient cohorts. An additional analysis was conducted comparing patient outcomes from the assay-informed arm with one of the cohorts from the empirically-treated arm (Bookman 2009 JCO). Patients from the assay-informed arm were categorized by in vitro response as sensitive (S), intermediate (I), or resistant (R) to the drug administered, and Kaplan Meier survival curves were created for each response category. These survival curves were compared to the Kaplan Meier curves from the selected empirically-treated cohort. Results: Patient characteristics were very similar between the empirically-treated and the assay-informed arms, though 11-16% more patients were optimally debulked in each of the 4 empirically-treated cohorts. Additionally, with the exception of one of the cohorts (Bookman 2009 JCO), patient stage was lower for the empirically-treated arm as compared to the assay-informed arm, with approximately 10% of patients earlier staged. The assay-informed arm experienced a 10% improvement in median OS (48 vs. 44 months). At the time of completion of the assay-informed study (6 years), the difference in OS rates between the 2 arms was 10%, with 39% OS for the assay-informed vs. 29% in the empirically-treated arm. The largest cohort from the empirically treated arm (Bookman 2009 JCO) included 4,312 patients and a stage distribution similar to the assay-informed arm. It was chosen for further analysis to see survival differences when patients in the assay-informed arm were separated by response category. Median OS by response category for the assay-informed was 72.5, 48.6, and 28.2 months, for S (n=20), I (n=133), and R (n=39), respectively (P=0.03; hazard ratio, 0.70; 95% CI, 0.50-0.97), as compared to 44 months for the patient subset from the empirically-treated arm. Conclusion: Realizing study design limitations and despite a generally worse prognosis, patients from the assay-informed arm experienced increased median OS when compared to the empirically-treated arm. This difference was further augmented when the assay informed arm was compared directly to one of the cohorts from the empirically treated population. These results support the use of chemoresponse assays as predictors of clinical response and OS in epithelial ovarian cancer as well as for choosing between equivalent treatments in clinical practice. Citation Format: Thomas J. Herzog, James Fiorica, James W. Orr, Jr., Robert Holloway, Mike Gabrin, Edward C. Grendys, Jr.. A comparison of patient outcomes in advanced ovarian cancer: Assay-informed vs. empirically treated. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A85.

Ovarian Cancer in BRCA Mutation Carriers: Improved Outcome After Intraperitoneal (IP) Cisplatin

Ovarian cancer arising in women with BRCA mutations is known to have a more favorable outcome and to be more responsive to platinum-based regimens than in those without a hereditary background. We analyze our previously published intraperitoneal (IP) studies in relation to BRCA mutation status and update their outcomes. Among 62 patients with ovarian cancer enrolled in IP platinum doublet studies in clinical trials (with etoposide (n = 18), with floxuridine (n = 30), and with topotecan (n = 14)), a deleterious BRCA mutation was eventually identified in 10 patients. The outcomes in these BRCA mutation carriers are described and compared with survival of others in respective trials. Ten patients that were confirmed to have BRCA mutations-all with high-grade and stages IIC to IV disease-survived a median of 10 years (range: 4-18+) after receiving IP cisplatin-based regimens. Two continue with no evidence of disease since their IP treatment, while four others remain alive with recurrences after 8, 9, 10, and 11 years, respectively. This experience suggests that IP cisplatin leads to favorable long term outcomes in advanced ovarian cancer in women with defective homologous recombination (i.e., with deleterious BRCA mutations). Whether such cisplatin dose-intensification from IP relative to (intravenous) IV drug administration leads to superior results in these mutation carriers requires further study.

Anti-Epidermal Growth Factor Receptor (EGFR) Antibodies Overcome Resistance of Ovarian Cancer Cells to Targeted Therapy and Natural Cytotoxicity

The poor outcome of advanced ovarian cancer under conventional therapy stimulated the exploration of new strategies to improve therapeutic efficacy. In our preclinical in vitro study we investigated a combination of targeted therapy and immunotherapy. Combination treatment with the anti-EGFR-antibody Cetuximab, related tyrosine kinase inhibitors (TKI) and cytolytic NK cells was tested against different ovarian cancer cell lines and primary tumour cells cultured from patient ascites. We found that selected ovarian cancer cells were susceptible to cetuximab and anti-EGFR-TKI-treatment, while the majority of cell lines were resistant to single or combination treatment with both substances. In addition, most ovarian cancer cells displayed low susceptibility to natural cytotoxicity of unstimulated NK cells. Notably, NK cytotoxicity against resistant ovarian cancer cells could be effectively enhanced by addition of Cetuximab mediating antibody-dependent cellular cytotoxicity (ADCC). Neither natural cytotoxicity nor ADCC of NK cells were negatively affected by the presence of TKIs. ADCC could be further increased when NK cells were pre-stimulated with monocytes and the immunostimulatory mycobacterial protein PstS-1. Our data suggest that targeted antibody therapy could be beneficial even against resistant tumour cells by augmenting supplementary cytolytic NK functions. Future studies should evaluate the combination of targeted therapy and immunotherapeutic approaches in patients with advanced ovarian cancer being resistant to standard treatment.

A study of denileukin diftitox to treat refractory ovarian cancer.

e13121 Background: The number of circulating CD4+ regulatory T-cells (Tregs) has been correlated with outcome in advanced ovarian cancer. A prior report (Barnett, et al; AACR Abstracts 2006: 1148) suggested that denileukin diftitox, a fusion toxin containing interleukin-2 fused to diphtheria toxin, may be of therapeutic value in this disease acting via Treg depletion. As part of a larger study of denileukin diftitox with dendritic cell-based vaccination, we treated patients with the agent alone to determine if it depletes circulating CD4+CD25HiFoxP3+CD127Low Tregs and induces clinical responses. Methods: Patients with relapsed/refractory ovarian or primary peritoneal carcinoma were eligible. No chemotherapy or immunotherapy was allowed for the preceding 4 weeks. Denileukin diftitox 18 μg/kg IV was given every 28 days for up to 4 cycles. Weekly monitoring of CD4 Tregs and CD8+CD28- Tregs was done by monoclonal antibody labeling of PBMC and flow cytometry studies. Clinical responses were measured by standard methods of disease assessment including CA125 testing. Results: Seven women were treated, of whom 3 had minimal residual disease (MRD). No Grade III-IV toxicities were seen. Unlike the prior report, no clinical responses were seen in 4 patients with bulky measurable disease. Median progression free survival was 5.5 months (range 0.5-20.5) and median overall survival will exceed 21.6 months (range 1.4-26.5+) with MRD a marker for prolonged remissions and survival. We saw no Treg depletion after the 1st cycle; i.e., no patient had ≥25% reduction in Tregs at the expected nadir at day 14. Mean CD4+CD25HiFoxP3+CD127Low Tregs/CD4 cells for controls was 1.16% (range .35-2.13) at baseline, with no significant temporal variation. Mean Tregs/CD4 cells for treated subjects was 2.89% (range 1.06-5.40) at baseline and 3.11% (range .81-5.13) at day 14. For 6 patients who received ≥2 cycles, mean Tregs/CD4 cells dropped to 1.95% (range .71-3.74) at day 42 and 1.65% (range .78-2.36) at day 70. CD8+CD28- Tregs were only increased (&gt;50% of CD8 T-cells) in 2 patients and not correlated with remission duration. Conclusions: These data suggest that denileukin diftitox depletes Tregs in relapsed ovarian cancer only with repeated dosing and may be of clinical value in MRD.

Abstract 1382: Increased expression of placental growth factor is linked with shortened survival of patients with advanced ovarian cancer

Abstract Background: Ovarian cancer (OC) is the leading cause of gynecologic cancer death in the United States. Survival in advanced OC is highly variable; some patients are cured of their disease with a combination of surgery and systemic chemotherapy, while the majority of patients develop recurrence and ultimately die of metastatic OC. While markers of poor prognosis within advanced OC exist, they have not translated to changes in therapy or outcomes. Vascular growth factors are important soluble mediators of tumor growth, vasculogenesis and angiogenesis that may be targeted therapeutically. We therefore explored the association between plasma levels of vascular growth factors and clinical outcomes in advanced OC. Methods: We enrolled 200 patients with OC or benign surgical conditions from the Mayo Ovarian SPORE Biospecimens Core. Presurgical plasma samples from patients with advanced OC (AJCC Stage III and IV, n = 100), early stage OC (Stage I and II, n = 50), and benign surgical conditions (n = 50) were assayed for vascular growth factors via multiplex electrochemiluminescence and by ELISA. Differences in plasma levels between benign, early, and advanced OC patient groups were assessed using plate-adjusted linear models. Associations between plasma levels of vascular growth factors and overall survival in advanced OC patients were assessed by Cox proportional hazards models. Results: Both vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) levels were increased in patients with advanced OC (mean ng/mL = 130.8, p = 0.004; mean ng/mL = 20.1, p = 0.025, respectively) compared to patients with early stage (mean ng/mL = 75.1 and 19.0 respectively) and benign conditions (mean ng/mL = 86.8 and 15.0, respectively). An increase in PlGF levels was associated with poor overall survival in patients with advanced OC (HR = 2.52, p = 0.005), while increase in VEGF levels were of borderline significance (HR = 1.21, p = 0.061) Conclusions: Soluble PlGF and VEGF are increased in the setting of advanced OC. Increased plasma PlGF is strongly linked to poor prognosis, while VEGF levels have a borderline association with prognosis. These data provide a rationale for therapeutic targeting of both VEGF and PlGF. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1382. doi:1538-7445.AM2012-1382

Ten Years’ Experience With Centralized Surgery of Ovarian Cancer in One Health Region in Norway

Better outcome of advanced ovarian cancer after centralized surgery has led to the recommendation for centralized surgery in a Norwegian health region. Whether the practice pattern has changed according to this recommendation has not been examined. The objective of this study was to evaluate the referral practice and treatment of ovarian cancer in a Norwegian health region after the introduction of centralized surgery. This was a retrospective, population-based study, including all women undergoing surgery for primary ovarian, tubal, and peritoneal cancer between 2000 and 2005, in Health Region IV of Norway. Clinical data and data regarding treatment and 5-year follow-up were analyzed. In total, 279 cases of ovarian, peritoneal, and tubal cancer were included. Eighty-four percent underwent primary surgery at the teaching hospital and 16% at the nonteaching hospitals. After an immediate rise in the number of cases undergoing primary surgery at the teaching hospital after the introduction of centralization in 1995, the percentage distribution between the teaching and nonteaching hospitals was stable during the study period. The women who underwent surgery at the nonteaching hospitals had a higher percentage of early-stage disease and were at higher risk of reoperation for comprehensive staging. Centralization of ovarian cancer surgery has been successfully accomplished in a health region in Norway. The referral practice of assumed advanced ovarian cancer cases shows satisfactory compliance with centralization at 10 years after the implementation of centralized surgery.

Impact of a structured quality management program on surgical outcome in primary advanced ovarian cancer

Objective Surgical outcome in advanced ovarian cancer (AOC) is an important prognostic factor and the only factor amendable to improvement by optimization. Therefore, introduction of quality management programs (QM) regarding the surgical therapy in ovarian cancer may help to improve outcome. Methods We introduced a specific ovarian cancer quality management program in 2001 in our gynecologic oncology center. Analysis of 396 consecutive patients with primary surgery for advanced ovarian cancer FIGO stages IIB–IV operated before the introduction of the quality management program 1997–2000, or during the introduction years 2001–2003, or after establishing 2004–2008. Results Thirty-three percent had complete debulking to no macroscopic residual disease from 1997 to 2000. This rate increased to 47% in 2001–2003 ( n = 86) and 62% in 2004–2008 ( n = 259). The utilization of extended surgical procedures increased over time. Patients with complete resection had 5-YSR of 55% compared to 16% in patients with residuals 1-10 mm, and 13% in patients with residuals > 1 cm ( p < 0.001). The median OS increased from 26 months 1997–2000 to 37 months 2001–2003 and 45 months in 2004–2008 ( p < 0.003). Conclusions Optimizing surgical skills, infrastructure, and introduction of quality management programs may improve both surgical and overall outcome in advanced ovarian cancer.

Chemotherapy Resistance as a Predictor of Progression-Free Survival in Ovarian Cancer Patients Treated with Neoadjuvant Chemotherapy and Surgical Cytoreduction Followed by Intraperitoneal Chemotherapy: A Southwest Oncology Group Study

Purpose: In vitro testing of the activity of chemotherapeutic agents has been suggested as 1 method to optimally select drugs for patients with ovarian cancer. There are limited prospectively obtained data examining the clinical utility of this approach. We sought to obtain a preliminary assessment of this strategy in a trial that examined the administration of neoadjuvant chemotherapy followed by surgical cytoreduction and intraperitoneal chemotherapy in women with advanced ovarian cancer. Methods: Women with stage III/IV epithelial ovarian carcinoma that presented with large-volume disease were treated with neoadjuvant intravenous paclitaxel and carboplatin for three 21-day cycles followed by cytoreductive surgery. If optimally debulked, patients received intravenous paclitaxel, intraperitoneal carboplatin and intraperitoneal paclitaxel for six 28-day cycles. Tumor cloning assay results (Oncotech) were correlated with progression-free survival. Results: Sixty-two patients (58 eligible) were registered from March 2001 to February 2006. Thirty-six eligible patients had interval debulking and 26 received postcytoreduction chemotherapy. Twenty-two patients had tumor cloning assay results available. The clinical features of this population were similar to those of the larger group of women who entered this study. There was no difference in progression-free survival between patients whose cancers were defined as ‘resistant’ or ‘nonresistant’ to either platinum or paclitaxel. Conclusions: While the small patient numbers in this trial do not permit definitive conclusions, these data fail to provide support for the argument that prospectively obtained in vitro data regarding platinum or paclitaxel resistance will be highly predictive of clinical outcome in advanced ovarian cancer.

Intraperitoneal Alpha-Radioimmunotherapy of Advanced Ovarian Cancer in Nude Mice Using Different High Specific Activities.

BackgroundThe aim of this study was to investigate the therapeutic efficacy of advanced ovarian cancer in mice, using α-radioimmunotherapy with different high specific activities. The study was performed using the monoclonal antibody (mAb) MX35 F(ab′)2 labeled with the α-particle emitter 211At.MethodsAnimals were intraperitoneally inoculated with ≥1 × 107 cells of the ovarian cancer cell line NIH:OVCAR-3. Four weeks later 9 groups of animals were given 25, 50, or 400 kBq 211At-MX35 F(ab′)2 with specific activities equal to 1/80, 1/500, or 1/1200 (211At atom/number of mAbs) for every activity level respectively (n = 10 in each group). As controls, animals were given PBS or unlabeled MX35 F(ab′)2 in PBS (n = 10 in each group). Eight weeks after treatment the animals were sacrificed and the presence of macroscopic tumors was determined by meticulous ocular examination of the abdominal cavity. Cumulated activity and absorbed dose calculations on tumor cells and tumors were performed using in house developed program. Specimens for scanning electron-microscopy analysis were collected from the peritoneum at the time of dissection.ResultsSumming over the different activity levels (25, 50, and 400 kBq 211At-MX35 F(ab′)2) the number of animals with macroscopic tumors was 13, 17, and 22 (n = 30 for each group) for the specific activities equal to 1/80, 1/500, or 1/1200, respectively. Logistic-regression analysis showed a significant trend that higher specific activity means less probability for macroscopic tumors (P = 0.02).ConclusionsIncreasing the specific activity indicates a way to enhance the therapeutic outcome of advanced ovarian cancer, regarding macroscopic tumors. Further studies of the role of the specific activity are therefore justified.

Outcome in Advanced Ovarian Cancer following an Appropriate and Comprehensive Effort at Upfront Cytoreduction: A Twenty-Year Experience in a Single Cancer Institute

Objectives. The purpose of this retrospective evaluation of advanced-stage ovarian cancer patients was to compare outcome with published findings from other centers and to discuss future options for the management of advanced ovarian carcinoma patients. Methods. A retrospective series of 340 patients with a mean age of 58 years (range: 17–88) treated for FIGO stage III and IV ovarian cancer between January 1985 and January 2005 was reviewed. All patients had primary cytoreductive surgery, without extensive bowel, peritoneal, or systematic lymph node resection, thereby allowing initiation of chemotherapy without delay. Chemotherapy consisted of cisplatin-based chemotherapy in combination with alkylating agents before 2000, whereas carboplatin and paclitaxel regimes were generally used after 1999-2000. Overall survival and disease-free survival were analyzed by the Kaplan-Meier method and the log-rank test. Results. With a mean followup of 101 months (range: 5 to 203), 280 events (recurrence or death) were observed and 245 patients (72%) had died. The mortality and morbidity related to surgery were low. The main prognostic factor for overall survival was postoperative residual disease (P < .0002), while the main prognostic factor for disease-free survival was histological tumor type (P < .0007). Multivariate analysis identified three significant risk factors: optimal surgery (RR = 2.2 for suboptimal surgery), menopausal status (RR = 1.47 for postmenopausal women), and presence of a taxane in the chemotherapy combination (RR = 0.72). Conclusion. These results confirm that optimal surgery defined by an appropriate and comprehensive effort at upfront cytoreduction limits morbidity related to the surgical procedure and allows initiation of chemotherapy without any negative impact on survival. The impact of neoadjuvant chemotherapy to improve resectability while lowering the morbidity of the surgical procedure is discussed.

A Gene Signature Predictive for Outcome in Advanced Ovarian Cancer Identifies a Survival Factor: Microfibril-Associated Glycoprotein 2

Advanced stage papillary serous tumors of the ovary are responsible for the majority of ovarian cancer deaths, yet the molecular determinants modulating patient survival are poorly characterized. Here, we identify and validate a prognostic gene expression signature correlating with survival in a series of microdissected serous ovarian tumors. Independent evaluation confirmed the association of a prognostic gene microfibril-associated glycoprotein 2 (MAGP2) with poor prognosis, whereas in vitro mechanistic analyses demonstrated its ability to prolong tumor cell survival and stimulate endothelial cell motility and survival via the alpha(V)beta(3) integrin receptor. Increased MAGP2 expression correlated with microvessel density suggesting a proangiogenic role in vivo. Thus, MAGP2 may serve as a survival-associated target.

PP11 Expression differences of proteolytic factors uPA, PAI-1, and seven kallikrein-related peptidases (KLK5, 6, 7, 8, 10, 11, 13) between primary tumor and omentum metastasis impact outcome in advanced ovarian cancer

PP11 Expression differences of proteolytic factors uPA, PAI-1, and seven kallikrein-related peptidases (KLK5, 6, 7, 8, 10, 11, 13) between primary tumor and omentum metastasis impact outcome in advanced ovarian cancer

Oregovomab Maintenance Monoimmunotherapy Does Not Improve Outcomes in Advanced Ovarian Cancer

Oregovomab Maintenance Monoimmunotherapy Does Not Improve Outcomes in Advanced Ovarian Cancer

Oregovomab Maintenance Monoimmunotherapy Does Not Improve Outcomes in Advanced Ovarian Cancer

Oregovomab Maintenance Monoimmunotherapy Does Not Improve Outcomes in Advanced Ovarian Cancer

Oregovomab Maintenance Monoimmunotherapy Does Not Improve Outcomes in Advanced Ovarian Cancer

This phase III study tested the hypothesis that the CA-125-specific murine monoclonal antibody, oregovomab, administered as a monoimmunotherapy after front-line therapy in a selected ovarian cancer population would prolong time to relapse (TTR) and, ultimately, survival. Patients with stage III to IV ovarian cancer with preoperatively elevated CA-125 and objectively defined characteristics were randomly assigned 4 to 12 weeks after front-line carboplatin and paclitaxel chemotherapy to maintenance monoimmunotherapy in a fully blinded protocol. Two mg of oregovomab or placebo was infused over 20 minutes at weeks 0, 4, and 8 and then 12 weeks until recurrence or up to year 5. Patients were evaluated with serial imaging and clinical evaluation for evidence of recurrence at quarterly visits. TTR was the primary end point. Three hundred seventy-three patients were accrued at more than 60 centers; 251 patients were assigned to oregovomab and 120 patients were assigned to placebo. The treatment arms were well balanced. There were no differences in the clinical outcomes between treatment groups. Median TTR measured from randomization after completion of chemotherapy for the integrated study was 10.3 months (95% CI, 9.7 to 13.0 months) for oregovomab and 12.9 months (95% CI, 10.1 to 17.4 months) for placebo (P = .29, log-rank test). The treatment was well tolerated. Grade 3 to 4 toxicity was reported in 24.6% of patients in the placebo group and 20.1% of patients in the oregovomab group, respectively. Although oregovomab has demonstrated bioactivity, the strategy of monoimmunotherapy is not effective as maintenance therapy after front-line treatment of a favorable subset of patients with advanced ovarian cancer. Future studies of this or other tumor-antigen specific immunization strategies should seek ways to further augment induced immunity.