Efficacy of subsequent chemotherapy for patients with BRCA1/2-mutated recurrent epithelial ovarian cancer progressing on olaparib versus placebo maintenance: post-hoc analyses of the SOLO2/ENGOT Ov-21 trial.

BACKGROUND: In the SOLO2 trial (ENGOT Ov-21; NCT01874353), maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer (PSROC) and BRCA mutation significantly improved progression-free survival (PFS) and prolonged overall survival (OS). Following disease progression on olaparib, efficacy of subsequent chemotherapy remains unknown. PATIENTS AND METHODS: We conducted a post-hoc hypothesis-generating analysis of SOLO2 data to determine the efficacy of different chemotherapy regimens following RECIST disease progression in patients who received olaparib or placebo. We evaluated time to second progression (TTSP) calculated from the date of RECIST progression to the next progression/death. RESULTS: The study population comprised 147 patients who received chemotherapy as their first subsequent treatment after RECIST progression. Of these, 69 (47%) and 78 (53%) were originally randomized to placebo and olaparib arms, respectively. In the placebo-treated cohort, 27/69 and 42/69 received non-platinum and platinum-based chemotherapy, respectively, compared with 24/78 and 54/78, respectively, in the olaparib-treated cohort. Among patients treated with chemotherapy (N = 147), TTSP was significantly longer in the placebo than in the olaparib arm: 12.1 versus 6.9 months [hazard ratio (HR) 2.17, 95% confidence interval (CI) 1.47-3.19]. Similar result was obtained on multivariable analysis adjusting for prognostic factors at RECIST progression (HR 2.13, 95% CI 1.41-3.22). Among patients treated with platinum-based chemotherapy (n = 96), TTSP was significantly longer in the placebo arm: 14.3 versus 7.0 months (HR 2.89, 95% CI 1.73-4.82). Conversely, among patients treated with non-platinum-based chemotherapy (n = 51), the TTSP was comparable in the placebo and olaparib arms: 8.3 versus 6.0 months (HR 1.58, 95% CI 0.86-2.90). CONCLUSIONS: Following progression from maintenance olaparib in the recurrent setting, the efficacy of platinum-based subsequent chemotherapy seems to be reduced in BRCA1/2-mutated patients with PSROC compared to patients not previously receiving poly (ADP-ribose) polymerase inhibitors (PARPi). The optimal strategy for patients who relapse after PARPi is an area of ongoing research.

The impact of olaparib dose reduction and treatment interruption on treatment outcome in the SOLO2/ENGOT-ov21 platinum-sensitive recurrent ovarian cancer.

BACKGROUND: Maintenance treatment with poly (ADP-ribose) polymerase (PARP) inhibitor is now the standard of care in patients with BRCA-mutated platinum-sensitive recurrent ovarian cancer following response to chemotherapy. In the SOLO2 trial, adverse event (AE)-associated olaparib interruption, dose reduction, and discontinuation occurred in 50%, 28%, and 17% of patients, respectively. We used data from the SOLO2 trial to evaluate the impact of dose alterations on survival outcomes and identified baseline characteristics associated with dose alteration. PATIENTS AND METHODS: We computed relative dose intensity (RDI) defined as the received dose as a percentage of the standard dose (300 mg twice a day) during the first 12 weeks on treatment. Patients were categorized into RDI >98%, RDI 90%-98%, and RDI <90%. The association between RDI categories with progression-free survival (PFS) and overall survival (OS) were examined using a 12-week landmark Cox regression analysis. Logistic regression analysis was used to correlate baseline factors with RDI at 12 weeks. RESULTS: In patients on olaparib included in the landmark analysis (n = 185), the mean 12-week RDI was 91.4%. There was no significant difference across 12-week RDI >98% (n = 110), 90%-98% (n = 29), and <90% (n = 45) categories for PFS (median, 14.2 versus 19.3 versus 34.4 months; P = 0.37) and OS (median, 49.7 versus 49.5 versus 54.1 months; P = 0.84). Risk of RDI ≤90% increased with baseline performance status 1 [odds ratio (OR): 2.54; 95% confidence interval (CI): 1.11-5.82] any nausea (OR: 3.17; 95% CI: 0.9-11.23), and with body weight ≤70 kg (OR: 1.86; 95% CI: 0.92-3.76). CONCLUSIONS: Dose reduction and interruption for the management of olaparib-associated AEs during the first 12 weeks did not impact on PFS and OS. When counselling patients requiring dose reductions or interruptions due to AEs, the results of this study will help assure patients that their outcomes will not be adversely affected.

Final report on serial phase II trials of all-intraperitoneal chemotherapy with or without bevacizumab for women with newly diagnosed, optimally cytoreduced carcinoma of Müllerian origin.

BACKGROUND: Intraperitoneal (IP) chemotherapy can improve outcomes for women with optimally cytoreduced epithelial ovarian cancer but toxicities are a concern. We conducted 2 phase 2 trials of an IV/IP regimen using carboplatin and paclitaxel without (Trial A) and with bevacizumab (Trial B). METHODS: Both trials consisted of carboplatin AUC 6 day 1, and paclitaxel 60 mg/m2 on days 1,8, 15 of a 21-day cycle; in Trial B, patients received IV bevacizumab 15 mg/kg every cycle starting cycle 2. Chemotherapy was administered IV for cycle 1 and then IP for all subsequent cycles. Primary objectives included safety and tolerability, pathologic CR rate (Trial A), and the rate of completion of IP cycles of therapy (Trial B). Progression-free (PFS), overall survival (OS), and pharmacokinetic analysis were secondary endpoints. RESULTS: 81 patients were treated on both trials (n = 40 and 41 in trials A and B, respectively). Median age for trials A and B was 59 (range, 36-76) and 55 (range, 19-69) years, respectively. 68% and 85% of patients, respectively for A and B, completed at least 4 cycles of treatment in both trials. Treatment with bevacizumab resulted in higher rates of grade 3 fatigue (37 versus 33%) and grade 3-4 diarrhea (22 versus 8%). Median PFS was 23.5 (95%CI 16.2-35.3) and 25 (95%CI 16.4-42.7) months, respectively; median OS was 68 (95%CI 49.5-NR) and 79.7 (95%CI 59.0-79.7) months, respectively for Trial A and B. CONCLUSIONS: Weekly administered IP carboplatin and IP paclitaxel is tolerable and safe with similar activity with and without concommittant bevacizumab in these 2 trials.

Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety.

BACKGROUND: The PARP inhibitor olaparib (Lynparza™) demonstrates antitumor activity in women with relapsed ovarian cancer and a germline BRCA1/2 mutation (gBRCAm). Data from olaparib monotherapy trials were used to explore the treatment effect of olaparib in patients with gBRCAm ovarian cancer who had received multiple lines of prior chemotherapy. PATIENTS AND METHODS: This analysis evaluated pooled data from two phase I trials [NCT00516373 (study 2); NCT00777582 (study 24)] and four phase II trials [NCT00494442 (study 9); NCT00628251 (study 12); NCT00679783 (study 20); NCT01078662 (study 42)] that recruited women with relapsed ovarian, fallopian tube or peritoneal cancer. All patients had a documented gBRCAm and were receiving olaparib 400 mg monotherapy twice daily (capsule formulation) at the time of relapse. Objective response rate (ORR) and duration of response (DoR) were evaluated using original patient outcomes data for patients with measurable disease at baseline. RESULTS: Of the 300 patients in the pooled population, 273 had measurable disease at baseline, of whom 205 (75%) had received ≥3 lines of prior chemotherapy. In the pooled population, the ORR was 36% [95% confidence interval (CI) 30-42] and the median DoR was 7.4 months (95% CI 5.7-9.1). The ORR among patients who had received ≥3 lines of prior chemotherapy was 31% (95% CI 25-38), with a DoR of 7.8 months (95% CI 5.6-9.5). The safety profile of olaparib was similar in patients who had received ≥3 lines of prior chemotherapy compared with the pooled population; grade ≥3 adverse events were reported in 54% and 50% of patients, respectively. CONCLUSION: Durable responses to olaparib were observed in patients with relapsed gBRCAm ovarian cancer who had received ≥3 lines of prior chemotherapy. CLINICALTRIALSGOV: NCT00516373; NCT00494442; NCT00628251; NCT00679783; NCT00777582; NCT01078662.

A SNaPshot of potentially personalized care: Molecular diagnostics in gynecologic cancer.

BACKGROUND: Genetic abnormalities underlie the development and progression of cancer, and represent potential opportunities for personalized cancer therapy in Gyn malignancies. METHODS: We identified Gyn oncology patients at the MGH Cancer Center with tumors genotyped for a panel of mutations by SNaPshot, a CLIA approved assay, validated in lung cancer, that uses SNP genotyping in degraded DNA from FFPE tissue to identify 160 described mutations across 15 cancer genes (AKT1, APC, BRAF, CTNNB1, EGFR, ERBB2, IDH1, KIT, KRAS, MAP2KI, NOTCH1, NRAS, PIK3CA, PTEN, TP53). RESULTS: Between 5/17/10 and 8/8/13, 249 pts consented to SNaPshot analysis. Median age 60 (29-84) yrs. Tumors were ovarian 123 (49%), uterine 74(30%), cervical 14(6%), fallopian 9(4%), primary peritoneal 13(5%), or rare 16(6%) with the incidence of testing high grade serous ovarian cancer (HGSOC) halving over time. SNaPshot was positive in 75 (30%), with 18 of these (24%) having 2 or 3 (n=5) mutations identified. TP53 mutations are most common in high-grade serous cancers yet a low detection rate (17%) was likely related to the assay. However, 4 of the 7 purely endometrioid ovarian tumors (57%) harbored a p53 mutation. Of the 38 endometrioid uterine tumors, 18 mutations (47%) in the PI3Kinase pathway were identified. Only 9 of 122 purely serous (7%) tumors across all tumor types harbored a 'drugable' mutation, compared with 20 of 45 (44%) of endometrioid tumors (p<0.0001). 17 pts subsequently enrolled on a clinical trial; all but 4 of whom had PIK3CA pathway mutations. Eight of 14 (47%) cervical tumors harbored a 'drugable' mutation. CONCLUSION: Although SNaPshot can identify potentially important therapeutic targets, the incidence of 'drugable' targets in ovarian cancer is low. In this cohort, only 7% of subjects eventually were treated on a relevant clinical trial. Geneotyping should be used judiciously and reflect histologic subtype and available platform.

A phase I study of the safety and pharmacokinetics of the histone deacetylase inhibitor belinostat administered in combination with carboplatin and/or paclitaxel in patients with solid tumours.

BACKGROUND: This phase I study assessed the maximum tolerated dose, dose-limiting toxicity (DLT) and pharmacokinetics of belinostat with carboplatin and paclitaxel and the anti-tumour activity of the combination in solid tumours. METHODS: Cohorts of three to six patients were treated with escalating doses of belinostat administered intravenously once daily, days 1-5 q21 days; on day 3, carboplatin (area under the curve (AUC) 5) and/or paclitaxel (175 mg m(-2)) were administered 2-3 h after the end of the belinostat infusion. RESULTS: In all 23 patients received 600-1000 mg m(-2) per day of belinostat with carboplatin and/or paclitaxel. No DLT was observed. The maximal administered dose of belinostat was 1000 mg m(-2) per day for days 1-5, with paclitaxel (175 mg m(-2)) and carboplatin AUC 5 administered on day 3. Grade III/IV adverse events were (n; %): leucopenia (5; 22%), neutropenia (7; 30%), thrombocytopenia (3; 13%) anaemia (1; 4%), peripheral sensory neuropathy (2; 9%), fatigue (1; 4%), vomiting (1; 4%) and myalgia (1; 4%). The pharmacokinetics of belinostat, paclitaxel and carboplatin were unaltered by the concurrent administration. There were two partial responses (one rectal cancer and one pancreatic cancer). A third patient (mixed mullerian tumour of ovarian origin) showed a complete CA-125 response. In addition, six patients showed a stable disease lasting > or =6 months. CONCLUSION: The combination was well tolerated, with no evidence of pharmacokinetic interaction. Further evaluation of anti-tumour activity is warranted.

Potential benefit of Sunitinib in recurrent and refractory ovarian clear cell adenocarcinoma.

Ovarian clear cell adenocarcinoma (OCCA) is a unique biological subtype of epithelial ovarian cancer, with a similar gene profile to renal cell carcinoma (RCC). Sunitinib is a vascular endothelial growth factor receptor tyrosine kinase inhibitor with proven antitumor activity in RCC and a rational biological option for treatment of OCCA. A 60-year-old woman presented with recurrent and refractory stage IA OCCA, after 9 years of remission. Sunitinib was initiated as fifth-line chemotherapy, associated with cystic degeneration of liver metastasis and a short downward trend in her CA125 level. Recurrent and refractory OCCA may respond to Sunitinib. Clinical trials are needed to objectively confirm these findings, as benefit may be limited in patients with extensively pretreated tumors.

Discovery of differentially expressed genes associated with paclitaxel resistance using cDNA array technology: analysis of interleukin (IL) 6, IL-8, and monocyte chemotactic protein 1 in the paclitaxel-resistant phenotype.

In an attempt to define the molecular changes associated with the paclitaxel-resistant phenotype in human cancer, a paclitaxel-resistant ovarian cancer cell line, SKOV-3TR, was established through stepwise selection in increasing paclitaxel concentrations. SKOV-3TR was cross- resistant to doxorubicin and vincristine and overexpressed multidrug resistance gene 1 but not multidrug resistance associated protein. SKOV-3TR and the paclitaxel-sensitive SKOV-3 parent line were characterized using human cDNA array technology that examined expression of a wide variety of genes involved in cell growth, signal transduction, cell death, and immune function. cDNA probes from reverse transcribed mRNAs of both paclitaxel-resistant and parent cells were compared to identify genes differentially expressed in the paclitaxel-resistant cells. Of 588 different human cDNA transcripts compared, 6 genes were found to be markedly decreased, and 12 genes increased in the resistant subline. Northern analysis and/or reverse transcription-PCR confirmed that 12 of these 18 genes were over- or underexpressed in SKOV-3TR. In addition, at least eight of the genes were found differentially expressed in several other paclitaxel- and/or doxorubicin-resistant cell lines, both those with increased multidrug resistance expression and those without. Included in the set of overexpressed genes were the cytokines/chemokines interleukin 6, interleukin 8, and monocyte chemotactic protein 1. ELISA assays confirm that mRNA overexpression of these cytokine/chemokines was associated with the increased secretion of these molecules in the tissue culture supernatant. Evaluation of supernatants from an expanded collection of paclitaxel- and Adriamycin-resistant cell lines demonstrated that all of the resistant lines had significant overexpression of at least one cytokine/chemokine as compared with their drug-sensitive parent line. The overexpression of these cytokines seemed to be stable and associated with a drug-resistant phenotype with only a modest induction of cytokine expression in the parent line with short-term paclitaxel exposure. These findings suggest that the development of paclitaxel resistance is accompanied by multiple changes in gene expression including stable alterations in selective chemokine and cytokine expression. The role these associated genetic changes have in the drug-resistant phenotype is discussed.

Paclitaxel resistance: molecular mechanisms and pharmacologic manipulation.

It has been approximately ten years since the Food and Drug Administration (FDA) approved paclitaxel for the treatment of platinum resistant epithelial ovarian carcinoma. Since the approval, the drug has found therapeutic applications in a variety of schedules and in a wide variety of epithelial malignancies. Its novel mechanism of action provided the hope that it would demonstrate anti-neoplastic activity in multidrug resistant tumor cells. Unfortunately, as with other chemotherapeutic drugs, resistance is commonly seen. Laboratory investigation has defined a wide variety of resistance mechanisms including overexpression of multidrug resistance (MDR-1) gene, molecular changes in the target molecule (betatubulin), changes in apoptotic regulatory and mitosis checkpoint proteins, and more recently changes in lipid composition and potentially the overexpression of interleukin 6 (IL-6). This review describes the in vitro molecular data that define and support the various mechanisms of resistance and critically evaluates the evidence for the participation of these mechanisms in clinically relevant paclitaxel resistance. This review also explores pharmacologic attempts to modulate paclitaxel resistance, principally through inhibition of the MDR-1 drug efflux pump. Future avenues for drug resistance research and its pharmacologic manipulation in the clinic are discussed.

Randomized placebo-controlled trial of the activity of the morphine glucuronides.

BACKGROUND: Morphine-6-glucuronide (M6G) is an active metabolite of morphine with potent analgesic activity. Morphine-3-glucuronide (M3G), the most prevalent metabolite, has minimal affinity for opioid receptors. It has been suggested from animal model data and by examination of metabolite ratios in humans that M3G may functionally antagonize the respiratory depressant and analgesic actions of morphine and M6G. METHODS: We performed a double-blind placebo-controlled trial with 10 healthy volunteers. The trial had 6 arms: (1) placebo, (2) 10 mg/70 kg of morphine, (3) 3.3 mg/70 kg of M6G, (4) 30.6 mg/70 kg of M3G, (5) 30.6 mg/70 kg of M3G with 10 mg/70 kg of morphine, and (6) 30.6 mg/70 kg of M3G with 3.3 mg/70 kg of M6G; all were give by slow intravenous bolus. Analgesia was assessed with the use of the submaximal ischemic pain model. The effects were quantified on numerical and visual analogue scales. Respiratory parameters and response to steady state 5% carbon dioxide challenge were assessed with spirometry, mass spectroscopy, and earlobe blood gas analysis. RESULTS: Morphine and M6G produced significant pain relief compared with placebo (morphine, P < .0001; M6G, P = .033). Pain relief after M6G was less than after morphine (P = .009) and M3G was no better than placebo (P = .26). Pain relief with morphine and M6G were not significantly altered by M3G (P = .59 and P = .28, respectively). Significant and similar dysphoria and sedation occurred with both morphine (P < .002) and M6G (P < .016) but were absent with both M3G and placebo. Respiratory parameters suggested that M6G produced less respiratory depression than morphine. Both morphine and M6G caused a significant reduction in respiratory drive compared with placebo (morphine, P = .002; M6G, P = .013); this effect was not reversed by M3G (P = .35 and P = .83, respectively). CONCLUSIONS: M3G appears to be devoid of significant activity; in these circumstances and at these doses, it does not antagonize either the analgesic or respiratory depressant effects of M6G or morphine.

A phase II study of combined intravenous and subcutaneous interleukin-2 in malignant pleural mesothelioma.

A total of 29 previously untreated patients with histologically proven malignant pleural mesothelioma, with an ECOG score of < or = 2 and UICC stage I-II disease, were enrolled between May 1994 and October 1996. On days 1 and 2, 18 x 10(6) IU/day of rIL-2 was administered by continuous intravenous infusion, and 6 x 10(6) IU/day of rIL-2 by subcutaneous injection on days 5--20 inclusive of a 42-day cycle. Further treatment was administered if no radiological disease progression was demonstrated. A total of 29 patients were assessable for toxicity and 25 for response, and 49 cycles of IL-2 were administered with a median of one per patient (range, < 1-4). Toxicity included mild fever, nausea and vomiting, and skin rashes, < grade II. Three patients failed to complete one cycle of treatment because of toxicity and one died of disease before response evaluation. Two patients achieved a partial response (8%, 95% CI 1-26%) surviving 18.1 and 18.7 months from diagnosis. A total of 11 patients (44%, 95% CI 24-65%) with stable disease had a median survival of 13.6 months (range 6.5-33.8). The median survival was 8.6 months (range 3.7-34.5) for the 12 patients with progressive disease (48%, 95% CI 28-69%). This regimen of rIL-2 is well tolerated and shows limited activity in mesothelioma.

Overexpression of human phosphoglycerate kinase 1 (PGK1) induces a multidrug resistance phenotype.

BACKGROUND: Multidrug resistance is a significant barrier to the development of successful cancer treatment. To identify genetic alterations that are directly involved in paclitaxel resistance, a functional cloning strategy was developed. MATERIALS AND METHODS: Using mRNA from paclitaxel resistant human ovarian cancer cell line SW626TR, a cDNA library was established in a pCMV-Script vector that permits expression of cDNA inserts in mammalian cells. Transfection of the pCMV-Script/SW626TR cDNA library into the paclitaxel-sensitive human osteogenic sarcoma cell line, U-20S, resulted in several paclitaxel-resistant clones. RESULTS: DNA sequencing of clone C16 demonstrates complete homology to human phosphoglycerate kinase 1 (PGK1). Retransfection of the PGK1 insert into U-20S confers a multidrug resistant phenotype, characterized by a 30-fold increase in paclitaxel resistance, and cross-resistance to vincristine; adriamycin and mitoxantrone, but not methotrexate or cisplatin. Enzymatic analysis of the PGK1 transfectants demonstrates an increase in PGK1 activity as compared to the parental cell line, U-20S. Northern and Western analysis of PGK1 transfectants reveals no change in MDR-1 expression compared with the parental cell line. In addition, co-culture of PGK1 transfectants with verapamil only partially reverses the multidrug resistant phenotype. Rhodamine 123 studies are also consistent with an MDR-1 independent mechanism of increased drug efflux. CONCLUSION: Together this data suggests that PGK1 can induce a multidrug resistant phenotype through an MDR-1 independent mechanism.

Limited phase I study of morphine-3-glucuronide.

The toxicity of morphine-3-glucuronide (M3G) has been investigated in an open, uncontrolled, single-blinded, single dose study over a limited range of doses. Three cohorts each of three healthy volunteers received 7.5, 15, and 30 mg/70 kg intravenous (IV) M3G. Blood sampling was undertaken for the following 24 h. Subjective toxicity was recorded on visual analogue scales and plasma M3G concentrations measured by a specific HPLC assay. Virtually no effects and no change in cardiovascular or respiratory parameters were seen. The pharmacokinetics fitted a two-compartment model. The mean elimination half-life (+/- S.D.) of M3G was 1.66 (+/- 0.47) h. Mean AUC standardized to a dose of 1 mg/70 kg was 228 (+/- 62) etamolL(-1) x h. Mean M3G clearance was 169 (+/- 48) mLmin(-1) and the mean volume of distribution was 23.1 (+/- 4.8) liters. At the doses investigated there were no clear neuroexcitatory effects, no opioid effects, and the pharmacokinetics were very similar to those of morphine-6-glucuronide (M6G).

Cytokines IL-1beta, IL-2, IL-6, IL-8, MCP-1, GM-CSF and TNFalpha in patients with epithelial ovarian cancer and their relationship to treatment with paclitaxel.

In vitro work suggests that cytokines may be important modulators of the cytotoxic effects of paclitaxel and subsequent drug resistance. This has been investigated in vivo in patients with ovarian cancer by ELISA. There was consistently elevated expression of IL-6 and IL-8 but not MCP-1, IL-1beta, IL-2, GM-CSF or TNFalpha. Peritoneal fluid concentrations of IL-6, IL-8 and MCP-1 were two to three logs greater than serum concentrations. Elevated concentrations of IL-6 correlated with a poor final outcome (P = 0.039), and increased IL-6 and IL-8 correlated with a poor initial response to chemotherapy (P = 0.041 and P = 0.041, respectively). There was a relatively clear pattern of change in all three cytokines. In serum, IL-6, IL-8 and MCP-1 decreased with the administration of steroids prior to paclitaxel, and increased in the 24 h after paclitaxel. Postoperative drainage fluid was relatively acellular, preventing flow-cytometric analysis of epithelial cells for apoptosis, but suggested activation of T cells by paclitaxel. IL-6 and IL-8 appear to be of prognostic importance in epithelial ovarian cancer. Treatment with paclitaxel is associated with an increase in expression of a limited number of cytokines in patients with ovarian cancer, notably IL-6, IL-8 and MCP-1.

Ovarian cancer: an update on genetics and therapy.

This article reviews the important aspects of the management of both early and advanced ovarian cancer with a particular emphasis on genetic predisposition and recent and anticipated advances in treatment.

Bevacizumab and ovarian cancer.

Epithelial ovarian cancer is the most lethal of gynecologic malignancies in the United States, with a significant proportion of patients with advanced disease achieving clinical remission with conventional treatment approaches, but dying of recurrence. Bevacizumab is a first-in-class antiangiogenic. This recombinant humanized monoclonal antibody neutralizes vascular endothelial growth factor (VEGF) and inhibits endothelial and tumor cell activation and proliferation. It has a low clearance and long elimination half-life, supporting a convenient 2- or 3-weekly dosing schedule. It is generally well tolerated, although trials have highlighted some toxicity-related concerns, notably gastrointestinal perforation. Phase III trials that evaluate overall survival are not yet mature, and cost-effectiveness of bevacizumab is hotly debated. As more evidence for the role of anti-VEGF agents in augmenting therapy and inducing durable tumor dormancy continues to emerge, it is anticipated that antiangiogenic therapy will play an important role in the management ovarian malignancy.