Combined weekly topotecan and biweekly bevacizumab in women with platinum-resistant ovarian, peritoneal, or fallopian tube cancer: results of a phase 2 study

BACKGROUND:

A phase 2 trial was conducted to determine the toxicity and efficacy of combined weekly topotecan and biweekly bevacizumab in patients with primary or secondary platinum‐resistant ovarian, peritoneal, or fallopian tube cancer (OC).

METHODS:

Patients were treated with bevacizumab 10 mg/kg on days 1 and 15 and topotecan 4 mg/m² on days 1, 8, and 15 of a 28‐day cycle until progressive disease (PD) or excessive toxicity. The primary endpoint was progression‐free survival (PFS); secondary objectives included overall survival (OS), objective response, and toxicity.

RESULTS:

Patients (N = 40) received a median of 8 treatment cycles. Toxicity was generally mild or moderate, with neutropenia (18%), hypertension (20%), gastrointestinal toxicity (18%), pain (13%), metabolic toxicity (15%), bowel obstruction (10%), and cardiotoxicity (8%) being the most common grade 3 and 4 adverse events. No bowel perforations, febrile neutropenia, or treatment‐related deaths occurred. Median PFS and OS were 7.8 (95% confidence interval [CI], 3.0‐9.4) and 16.6 months (95% CI, 12.8‐22.9), with 22 (55%) patients progression‐free for ≥6 months. Ten (25%) patients had partial response (PR), 14 (35%) had stable disease (SD), and 16 (40%) had PD. Patients treated with 2 prior regimens received greater benefit than patients treated with 1: PR/SD, 78.9% versus 42.9% (P = .03); median PFS, 10.9 versus 2.8 months (P = .08); median OS, 22.9 versus 12.8 months (P = .02).

CONCLUSIONS:

A weekly topotecan and biweekly bevacizumab combination demonstrates acceptable toxicity and encouraging efficacy in patients with platinum‐resistant OC; further study is warranted. Cancer 2011;. © 2011 American Cancer Society.     

Serous ovarian, fallopian tube and primary peritoneal cancers: a comparative epidemiological analysis

Invasive serous cancers are diagnosed in the ovary, fallopian tube and peritoneum. It is widely believed that these are variants of the same malignancy but little is known about fallopian tube and primary peritoneal cancers. A comparison of risk factors for these tumor types may shed light on common or distinct aetiological pathways involved in these types of cancer. We investigated risk factors for the three cancers using data from a large Australian population-based case-control study. We included women with incident invasive serous ovarian (n = 627), primary peritoneal (n = 129) and fallopian tube (n = 45) cancer and 1,508 control women. Participants completed a comprehensive reproductive and lifestyle questionnaire. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Hormonal contraceptive use was inversely related to risk of all three cancers. Parity and breast-feeding were also inversely related to risk of serous ovarian and fallopian tube cancer. In contrast, parous women had an increased risk of peritoneal cancer (OR = 1.8, 95%CI 0.8-3.9), and increasing parity did not lower risk. There was also no association between breast-feeding and peritoneal cancer. However, obesity was associated with a doubling of risk for peritoneal cancer alone (OR = 2.1, 95%CI = 1.3-3.4). The strikingly similar patterns of risk for serous ovarian and fallopian tube cancers and the somewhat different results for primary peritoneal cancer suggest that peritoneal cancers may develop along a different pathway. These results also call into question the role of the physical effects of ovulation in the development of serous ovarian cancer.     

Combination of docetaxel-carboplatin for adjuvant chemotherapy of epithelial ovarian, primary peritoneal and fallopian tube cancers： a meta-analysis

Objective: The aim of this study was to compare the efficacies and safeties of the combination of docetaxel-carboplatin with the combination of non docetaxel-carboplatin as first-line chemotherapy for advanced epithelial ovarian,primary peritoneal or fallopian tube cancers.Methods: Relevant articles were identified from MEDLINE(1993-2010),EMBASE(1980-2010),MEDION,the Cochrane library,Science Citation Index Expanded databases,hand searching of reference lists from primary articles and reviews,conference abstracts and contact with experts in the field.The review included 5 relevant primary studies(1430 women).Data was extracted for study characteristics and quality.Bivariate random-effect model metaanalysis was used to estimate diagnostic accuracy of the various index tests.A quantitative meta-analysis was carried out by two reviewers based on the inclusion criteria from all available studies.Results: The frequency of the subgroup analysis of toxicity showed that toxicity action of combination of docetaxel-carboplatin was more severe than that of non docetaxel-carboplatin group(OR=1.33,95% CI=1.13-1.56,P=0.0005),whereas that of clinical responses was equivalent in comparison combination of docetaxel-carboplatin with combination of paclitaxel-carboplatin or docetaxel-cisplatin(OR=1.0,95%CI=0.87-1.16,P=0.95).There were heterogeneity(χ2=79.36,P<0.00001)and inconsistency(83.6%)in toxicity analysis among the trials,while neither heterogeneity(χ2=3.21,P=0.99)nor inconsistency(I2=0%)in clinical responses among the trials.Conclusion: The safety of combination of docetaxel-carboplatin is less than that of combination of paclitaxel-carboplatin or docetaxel-cisplatin.However,the clinical responses of combination of docetaxel-carboplatin are comparable with combination of paclitaxel-carboplatin or docetaxel-cisplatin.     

A phase 1 and pharmacodynamic study of decitabine in combination with carboplatin in patients with recurrent,platinum‐resistant,epithelial ovarian cancer

BACKGROUND:

Aberrant DNA methylation is a hallmark of cancer, and DNA methyltransferase inhibitors have demonstrated clinical efficacy in hematologic malignancies. On the basis of preclinical studies indicating that hypomethylating agents can reverse platinum resistance in ovarian cancer cells, the authors conducted a phase 1 trial of low‐dose decitabine combined with carboplatin in patients with recurrent, platinum‐resistant ovarian cancer.

METHODS:

Decitabine was administered intravenously daily for 5 days, before carboplatin (area under the curve, 5) on Day 8 of a 28‐day cycle. By using a standard 3 + 3 dose escalation, decitabine was tested at 2 dose levels: 10 mg/m² (7 patients) or 20 mg/m² (3 patients). Peripheral blood mononuclear cells (PBMCs) and plasma collected on Days 1 (pretreatment), 5, 8, and 15 were used to assess global (LINE‐1 repetitive element) and gene‐specific DNA methylation.

RESULTS:

Dose‐limiting toxicity (DLT) at the 20‐mg/m² dose was grade 4 neutropenia (2 patients), and no DLTs were observed at 10 mg/m². The most common toxicities were nausea, allergic reactions, neutropenia, fatigue, anorexia, vomiting, and abdominal pain, the majority being grades 1‐2. One complete response was observed, and 3 additional patients had stable disease for ≥6 months. LINE‐1 hypomethylation on Days 8 and 15 was detected in DNA from PBMCs. Of 5 ovarian cancer‐associated methylated genes, HOXA11 and BRCA1 were demethylated in plasma on Days 8 and 15.

CONCLUSIONS:

Repetitive low‐dose decitabine is tolerated when combined with carboplatin in ovarian cancer patients, and demonstrates biological (ie, DNA‐hypomethylating) activity, justifying further testing for clinical efficacy. Cancer 2010. © 2010 American Cancer Society.     

BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study

Background:

Breast cancer 1, early onset (BRCA1) is a tumour-suppressor gene associated with familial epithelial ovarian cancer (EOC). Reduced BRCA1 expression is associated with enhanced sensitivity to platinum-based chemotherapy. We sought to examine the prognostic relevance of BRCA1 expression in EOC patients treated with intraperitoneal platinum/taxane.

Methods:

The GOG-172 was a phase III, multi-institutional randomised trial of intravenous paclitaxel and cisplatin (IV therapy) vs intravenous paclitaxel, intraperitoneal cisplatin plus paclitaxel (IP therapy) in patients with optimally resected stage III EOC. The BRCA1 expression was assessed with immunohistochemistry (IHC) staining blinded to clinical outcome in archival tumour specimens. Slides with ⩽10% staining were defined as aberrant and >10% as normal. Correlations between BRCA1 expression and progression-free survival (PFS) and overall survival (OS) were analysed using Kaplan–Meier method and Cox regression analysis.

Results:

Of the 393 patients, 189 tumours had aberrant expression, and 204 had normal BRCA1 expression. There was an interaction between BRCA1 expression and route of administration on OS (P=0.014) but not PFS (P=0.054). In tumours with normal BRCA1 expression, the median OS was 58 months for IP group vs 50 months for IV group (P=0.818). In tumours with aberrant BRCA1 expression, the median OS was 84 vs 47 months in the IP vs IV group, respectively (P=0.0002). Aberrant BRCA1 expression was an independent prognostic factor for better survival in women randomised to IP therapy (hazard ratio (HR)=0.67, 95% confidence interval (CI)=0.47–0.97, P=0.032). Similar survival was observed in the IV and IP patients with normal BRCA1 expression. Multivariate but not univariate modelling demonstrated that IV patients with aberrant vs normal BRCA1 expression had worse survival.

Conclusion:

Decreased BRCA1 expression is associated with a 36-month survival improvement in patients with EOC treated with IP chemotherapy. Although these results merit validation in future studies, the results suggest that decreased BRCA1 expression predicts for improved response to cisplatin-based IP chemotherapy with cisplatin and paclitaxel.     

Low drug resistance to both platinum and taxane chemotherapy on an in vitro drug resistance assay predicts improved survival in patients with advanced epithelial ovarian,fallopian and peritoneal cancer

The objective of this study was to evaluate the role of an in vitro drug resistance assay to platinum and taxane in the management of advanced epithelial ovarian, fallopian and primary peritoneal cancer. All patients with FIGO Stage IIIc and IV who received postoperative chemotherapy with platinum and taxane for more than 4 courses after the initial cytoreductive surgery between 1995 and 2008 were evaluated. Patients who received neoadjuvant chemotherapy were not included. An in vitro drug resistance assay (EDR Assay, Oncotech, Tustin, CA) was used to determine drug resistance for each patient's tumor tissue. Level of drug resistance was described as extreme (EDR), intermediate (IDR), or low (LDR). Response to chemotherapy and survival were correlated to the EDR Assay. Of the 335 patients who underwent primary cytoreductive surgery, 173 cases met the criteria for statistical evaluation. The 58 patients (33.5%) whose tumors had LDR to both platinum and taxane had statistically improved progression‐free survival and overall survival (OS) compared with the 115 patients (66.5%) who demonstrated IDR or EDR to platinum and/or taxane (5‐year OS rates, 41.1% vs. 30.9%, p = 0.014). The 5‐year OS rates for the 28 (16.2%) cases that had optimal cytoreduction with LDR to both platinum and taxane was significantly improved over the 62 (35.8%) cases that were suboptimally cytoreduced with IDR or EDR to platinum and/or taxane (54.1% vs. 20.4%, respectively, p < 0.001). In conclusion, LDR to both platinum and taxane chemotherapy, as determined by an in vitro drug resistance assay, independently predicts improved survival in patients with advanced epithelial ovarian, fallopian and peritoneal cancer, especially in those patients who undergo optimal primary cytoreduction. © 2009 UICC     

Randomised phase II study of docetaxel plus vandetanib versus docetaxel followed by vandetanib in patients with persistent or recurrent epithelial ovarian,fallopian tube or primary peritoneal carcinoma: SWOG S0904

BackgroundVandetanib is an oral tyrosine kinase inhibitor of VEGFR-2/3, EGFR and RET, which has demonstrated clinical activity as a single agent and in combination with taxanes. We explored the efficacy, safety and toxicity of docetaxel and vandetanib in women with recurrent ovarian cancer (OC).MethodsWomen with refractory or progressive OC were randomised 1:1 to docetaxel (75 mg/m², IV) + vandetanib (100 mg daily, PO, D + V) or docetaxel (75 mg/m², D). Up to three additional cytotoxic regimens for recurrence and prior anti-angiogenic agents (as primary therapy) were allowed. The primary end-point was progression free survival (PFS). The study had 84% power to detect a PFS hazard ratio of 0.65, using a one-sided P of 0.1. This corresponds to an increase in median PFS from 3.6 months to 5.6 months. Patients progressing on D were allowed to receive single agent vandetanib (D → V).Results131 Patients were enrolled; two were excluded. 16% had received prior anti-angiogenic therapy. The median PFS estimates were 3.0 mos (D + V) versus 3.5 (D); HR: 0.99 (80% CI: 0.79–1.26). 61 Patients on D + V were assessable for toxicity; 20(33%) had treatment-related Grade (G) 4 events, primarily haematologic. Similarly, 17 (27%) of 64 patients receiving D had G4 events, primarily haematologic. 27 Evaluable patients crossed-over to V. 1/27(4%) experienced a G4 event. G3 diarrhoea was observed in 4% D → V patients. Median OS was 14 mos (D + V) versus 18 mos (D → V); HR(OS): 1.25 (80% CI: 0.93–1.68). Crossover vandetanib response was 4% (1/27 evaluable patients). High plasma IL-8 levels were associated with response to D + V.ConclusionsCombination docetaxel + vandetanib did not prolong PFS relative to docetaxel alone in OC patients. No unexpected safety issues were identified.     

A single-arm,phase II study of niraparib and bevacizumab maintenance therapy in platinum-sensitive,recurrent ovarian cancer patients previously treated with a PARP inhibitor: Korean Gynecologic Oncology Group (KGOG 3056)/NIRVANA-R trial

BackgroundGiven the expanding clinical use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPis), there is a significant need for optimal strategies with which to treat patients whose cancer progresses while using a PARPi. However, the treatment consensus after PARPi has not been established. The aim of the Korean Gynecologic Oncology Group (KGOG) 3056/NIRVANA-R trial is to investigate the efficacy of niraparib in combination with bevacizumab as a maintenance therapy in platinum-sensitive ovarian cancer patients who were previously treated with a PARPi.MethodsThe KGOG 3056/NIRVANA-R is a multi-centre, investigator-initiated, single-arm, phase II trial of patients with platinum-sensitive recurrent ovarian cancer recruited from seven KGOG sites. This study included patients with platinum-sensitive recurrent epithelial ovarian cancer who received at least 2 previous courses of platinum-containing therapy and had been treated with a PARPi. Mucinous histology type was excluded. Patients who had responded to the last platinum regimen (either complete or partial response) were eligible to participate in this study. Forty-four patients will be recruited. All enrolled patients are treated with niraparib and bevacizumab for maintenance therapy until disease progression, unacceptable toxicity, or withdrawal of patient consent. The primary endpoint of the study is 6-month progression-free survival rate. Accrual is expected to be completed in 2022, followed by presentation of results in 2023.Trial RegistrationClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT04734665","term_id":"NCT04734665"}}NCT04734665