The effect of single weekly paclitaxel in heavily pretreated patients with recurrent or persistent advanced ovarian cancer

OBJECTIVES: We have reported that single weekly paclitaxel has moderate activity in heavily pretreated ovarian cancer patients and is associated with a favorable toxicity profile. The purpose of this study was to reconfirm the effect of weekly paclitaxel in more number of cases. METHODS: Although 39 patients were enrolled, 37 patients with recurrent or persistent ovarian cancer previously treated with between one and three chemotherapeutic regimens containing platinum were eligible. Patients had measurable or assessable disease defined by clinical exam, radiographic studies, or serum CA 125. One cycle of treatment consisted of paclitaxel 80 mg/m2/week in 1-h infusion, 3 weeks on, 1 week off, and repeated at least twice. Two patients were withdrawn because of refusal of further treatment for neuropathy after the first cycle. Clinical responses were defined by established criteria. RESULTS: Thirty-seven patients were included in this intent-to-treat study. The overall clinical response rate was 45.9% (5 complete responses, 12 partial responses). The clinical response rate in patients with measurable tumor was 25.0% (2 complete responses, 1 partial response), while that in patients without measurable tumor and with assessable CA 125 levels was 56.0% (3 complete responses, 11 partial responses). Clinical response rate in patients with chemotherapy-free interval more than 6 months had about twice higher than that in patients with chemotherapy-free interval less than 6 months. The clinical response rate by number of prior regimens revealed that as number of prior regimens increases, the response rate decreases. CONCLUSION: Weekly paclitaxel has significant antitumor activity in heavily pretreated patients with recurrent or persistent ovarian carcinoma and warrants as second or third line chemotherapy in such setting.     

Dose-dense chemotherapy with weekly paclitaxel and 3-weekly carboplatin for recurrent ovarian cancer

ObjectiveTo analyze the response to dose-dense chemotherapy of weekly paclitaxel and 3-weekly carboplatin in recurrent ovarian cancer, and to report results of literature review.Materials and methodsPatients accepted weekly paclitaxel 80 mg/m² on day 1, 8, 15 and carboplatin on day1 at area under curve (AUC) 6 every 21 days were reviewed for the response rate, progression-free survival, overall survival, and toxicity during January 2012 to April 2016 in Chang Gung Memorial Hospital at Linkou, Taiwan.ResultsSixteen patients with recurrent ovarian cancer, including 1 platinum-resistant, 7 partially platinum-sensitive, and 8 platinum-sensitive, accepted a median of 6 cycles of chemotherapy (range 3–10). The overall response rate (ORR) and complete response (CR) rate were 93.8%, and 62.5%, respectively. The median PFS of all patients were 10.9 months (range 4.3–40.5). The median time to response (TTR) was 29.0 days (range 19.6–38.4). The median disease-free survival (DFS) after CR was 5.6 months (range 1.2–34.2). Grade 3 at least toxicity included anemia (6.3%), neutropenia (50%), and thrombocytopenia (18.8%).Twenty-nine articles on phase I, II, III, or retrospective studies of dose-dense chemotherapy with weekly paclitaxel were reviewed.ConclusionThis is the first report using Japanese Gynecologic Oncology Group 3016 protocol, weekly paclitaxel and 3-weely carboplatin, on recurrent ovarian cancer. The current study showed high ORR and CR with tolerable toxicities. Our study suggested dose-dense chemotherapy with paclitaxel, especially combining carboplatin created high efficacy probably by anti-angiogenesis. However, consolidation or maintenance therapy is needed to prolong DFS.     

A prognostic nomogram to predict overall survival in women with recurrent ovarian cancer treated with bevacizumab and chemotherapy

Objective

To develop a nomogram to predict overall survival (OS) in women with recurrent ovarian cancer treated with bevacizumab and chemotherapy.

Methods

A multicenter retrospective study was conducted. Potential prognostic variables included age; stage; grade; histology; performance status; residual disease; presence of ascites and/or pleural effusions; number of chemotherapy regimens, treatment-free interval (TFI) prior to bevacizumab administration, and platinum sensitivity. Multivariate analysis was performed using Cox proportional hazards regression. The predictive model was developed into a nomogram to predict five-year OS.

Results

312 women with recurrent ovarian cancer treated with bevacizumab and chemotherapy were identified; median age was 59 (range: 19–85); 86% women had advanced stage (III–IV) disease. The majority had serous histology (74%), high grade cancers (93.5%), and optimal cytoreductions (69.5%). Fifty-one percent of women received greater than two prior chemotherapeutic regimens. TFI (AHR = 0.98, 95% CI 0.97–1.00, p = 0.022) was the only statistically significant predictor in a multivariate progression-free survival (PFS) analysis. In a multivariate OS analysis, prior number of chemotherapy regimens, TFI, platinum sensitivity, and presence of ascites were significant. A nomogram to predict five-year OS was constructed and internally validated (bootstrap-corrected concordance index = 0.737).

Conclusion

Our multivariate model identified prior number of chemotherapy regimens, TFI, platinum sensitivity, and the presence of ascites as prognostic variables for OS in women with recurrent ovarian cancer treated with bevacizumab combined with chemotherapy. Our nomogram to predict five-year OS may be used to identify women who may benefit from bevacizumab and chemotherapy, but further validation is needed.     

Phase II study of bevacizumab and pemetrexed for recurrent or persistent epithelial ovarian,fallopian tube or primary peritoneal cancer

Objective

We aimed to evaluate the efficacy and safety of combination bevacizumab/pemetrexed for the treatment of recurrent epithelial ovarian cancer (EOC).

Methods

Platinum-sensitive or -resistant patients with recurrent or persistent EOC were eligible if they had received up to 2 prior chemotherapy regimens, including a platinum/taxane regimen without prior bevacizumab. Pemetrexed 500 mg/m² IV and bevacizumab 15 mg/kg IV were administered every 3 weeks. The primary endpoint was 6-month progression-free survival (PFS); other endpoints included toxicities, PFS and overall survival (OS).

Results

Thirty-four patients received a median of 7 treatment cycles (range, 2–26). Median follow-up was 25.7 months (range, 3.0–47.2). Six month progression-free survival (PFS) was 56% (95% CI: 38–71). The following response rates were documented (%; 95% CI): 0 complete response, 14 partial responses (41%; 25–59), 18 stable disease (53%; 35–70) and 2 progressive disease (6%; 1–20). Median PFS was 7.9 months (95% CI, 4.6–10.9), with a median OS of 25.7 months (95% CI, 15.4–29.8). Twenty-two patients (64.7%) had a platinum-free interval (PFI) of > 6 months prior to enrollment. Grade 3–4 hematologic toxicities included neutropenia (50%), leukopenia (26%), thrombocytopenia (12%) and anemia (9%). Non-hematologic grade 3–4 toxicities included metabolic (29%), constitutional (18%), pain (18%) and gastrointestinal (15%). Two patients developed hematologic malignancies within one year of treatment.

Conclusions

Combination bevacizumab/pemetrexed is an active option for both platinum-sensitive and -resistant recurrent EOC. Further investigation of cost and novel toxicities associated with this regimen may be warranted.     

Combination gemcitabine, platinum, and bevacizumab for the treatment of recurrent ovarian cancer

ObjectiveTo describe the response rate (RR), progression-free survival (PFS), and toxicity profile of combination gemcitabine, platinum, and bevacizumab (GPB) for the treatment of recurrent epithelial ovarian cancer (EOC).MethodsA chart review of all patients with recurrent EOC who were treated with D1, D15 GPB in a 28-day cycle at a single institution was performed. Standard doses were gemcitabine 1000 mg/m², cisplatin 30 mg/m² or carboplatin AUC 3, and bevacizumab 10 mg/kg. All patients were analyzed for toxicity. RR and PFS were assessed in all patients who received at least 2 cycles of GPB.ResultsThirty-five patients were identified, and 33 received at least 2 cycles of GPB. The majority of patients (80%) were platinum sensitive. Patients received a median of 6 cycles of GPB (range 1–24). Sixteen patients (48%) had a complete response (CR), and 10 patients (30%) had a partial response (PR), for a total RR of 78%. An additional 5 patients (15%) had stable disease, and only 2 (6%) patients had progressive disease. The median overall PFS was 12 months (95% CI 7–15), with a median follow-up time of 10 months (2–22). Two patients (6%) had bowel perforations, and both survived. Hematologic toxicities were most common, with 29% and 14% of patients experiencing grade 3 or 4 neutropenia and thrombocytopenia respectively.ConclusionsThe combination of GPB demonstrated excellent efficacy for the treatment of recurrent EOC. However, serious toxicities occurred, and the safety profile of this combination requires further study.     

A phase II study of gemcitabine,carboplatin and bevacizumab for the treatment of platinum-sensitive recurrent ovarian cancer

Purpose

The doublet gemcitabine and carboplatin is effective for the treatment of recurrent ovarian cancer, while multi-agent chemotherapy with bevacizumab may add additional benefit. This phase II study tested the efficacy and safety of a biweekly gemcitabine, carboplatin, and bevacizumab combination in patients with platinum-sensitive recurrent ovarian, peritoneal, or tubal cancer (ROC).

Patients and methods

Eligible patients received concurrent gemcitabine 1000 mg/m², carboplatin area under the curve 3, and bevacizumab 10 mg/kg administered intravenously on days 1 and 15 every 28 days for six cycles or up to 24 cycles if clinical benefit occurred. The primary end points were progression-free survival (PFS) by RECIST, and safety; the secondary end points were objective response rates and overall survival.

Results

Overall, 45 patients were enrolled. The median PFS was 13.3 months (95% CI, 11.3 to 15.3). The objective response rate was 69%. Grade 4 hematologic toxicities included neutropenia (27%) and thrombocytopenia (2%). Grades 3 and 4 non-hematologic toxicities included fatigue (18%), pain (9%), and nausea/vomiting (4%). There were 2 episodes of cerebrovascular accidents, 2 noted DVTs, and no episodes of bowel perforation. Median OS was 36.1 months (95% CI, 26.7 to 45.5).

Conclusion

Biweekly gemcitabine, carboplatin, and bevacizumab were an effective regimen in recurrent ovarian cancer, with comparable toxicity to recently reported day 1 gemcitabine, carboplatin, bevacizumab, and day 8 gemcitabine. Response rate and PFS are improved from reported outcomes of the gemcitabine carboplatin doublet. The degree to which biweekly dosing may present a more rationale schedule for this triplet should be evaluated further.     

影响复发上皮性卵巢癌化疗疗效的临床病理因素分析

目的:分析影响铂类敏感型及耐药型复发上皮性卵巢癌(EOC)患者预后的相关临床病理因素。方法:回顾分析1985年1月至2011年11月广西医科大学附属肿瘤医院收治的复发EOC患者83例,其中铂类敏感型56例,耐药型27例。采用Kaplan-meier生存率曲线、Log-rank test检验和Cox模型多因素回归分析法分析影响复发EOC患者预后的相关因素。结果:(1)铂类敏感型复发EOC患者的中位无进展生存期(PFS)为11个月(95%CI 9.105～12.895),中位总生存期(OS)为16个月(95%CI 13.144～18.856);铂类耐药型复发EOC患者的中位PFS为8个月(95%CI 4.219～11.781),中位OS为10个月(95%CI 3.824～16.176)。(2)复发后伴有腹水、复发后化疗方案、化疗疗程、化疗效果是影响敏感型复发EOC患者的重要预后因素(P<0.05);无复发生存时间(RFS)、复发后伴有腹水、复发部位、化疗效果是影响耐药型复发EOC患者的重要预后因素(P<0.05)。(3)复发后化疗疗程数、复发后伴有腹水、化疗疗效是影响敏感型复发EOC患者预后的独立危险因素,而复发部位是影响耐药型复发EOC患者预后的独立危险因素。结论:铂类敏感型患者复发后宜选择与一线类似的铂类联合方案化疗,并尽可能化疗至6疗程。复发病灶位于盆腹腔是影响耐药型患者预后的独立危险因素,应积极治疗。     

Chemotherapy and PARP inhibitors in heavily pretreated BRCA1/2 mutation ovarian cancer (BMOC) patients

Objectives

The hallmarks of germline(g) and/or somatic(s) BRCA1/2 mutation ovarian cancer (BMOC) patients are increased sensitivity to platinum-based chemotherapy (PCT) and PARP inhibitors (PARPi). There is little information on the effectiveness of chemotherapy in heavily pretreated (≥3 CT lines) g/sBMOC patients.

Secondary leukemia after treatment with paclitaxel and carboplatin in a patient with recurrent ovarian cancer

Abstract.   See HT, Thomas DA, Bueso-Ramos C, Kavanagh J. Secondary leukemia after treatment with paclitaxel and carboplatin in a patient with recurrent ovarian cancer. Int J Gynecol Cancer 2006; 16(Suppl. 1): 236–240.
The occurrence of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) has been reported after treatment with cytotoxic alkylating agent–based chemotherapy for solid tumors. We report a patient with metastatic ovarian carcinoma treated with carboplatin and paclitaxel, who developed secondary acute erythroid leukemia. The overall survival of patients with stage III and IV ovarian cancer has increased in the past decade. Monitoring of the long-term outcome of paclitaxel- and platinum-based regimens is warranted, particularly with regard to monitoring the development of secondary MDS and/or AML. The incidence and outcome of secondary leukemia in the setting of active ovarian carcinoma is reviewed.     

Effectiveness of weekly topotecan in patients with recurrent epithelial ovarian cancer

The objective of this study was to investigate the effectiveness and toxicity of weekly topotecan in patients with recurrent epithelial ovarian cancer. Twenty patients were treated with topotecan at a dose of 4 mg/m(2) weekly. Efficacy was determined according to the Response Criteria in Solid Tumors (RECIST) Gynecologic Cancer Inter Group criteria. Median age was 62 years (45-78). Patients had received 1-7 (median 3) prior chemotherapy lines. A total of 203 weekly treatments were administered. In 13 patients (65%) treatment delay was necessary due to bone marrow toxicity. Grade 3/4 neutropenia occurred in 11 patients (55%) and grade 3/4 thrombocytopenia in four patients (20%). Six patients (30%) needed a dose reduction, and 42 cycles (21%) were given with dose reduction. No neutropenia, fever, or sepsis was observed. There was one complete response and one partial response (response rate 10%). All patients with response had platin-sensitive disease (three out of eight). Six patients needed blood transfusion. None of the patients required granulocyte/granulocyte-macrophage colony-stimulating factor. The median duration of response was 13 months. In addition, there were four patients (20%) with a stable disease lasting at least for 4 months. Based on the results of this Phase II study, the toxicity of weekly topotecan seems to be lower than with the 3-weekly topotecan. The response rate of 10% is low but was not expected to be higher as these patients were heavily pretreated.     

A phase II study of biweekly administration of paclitaxel in patients with recurrent epithelial ovarian cancer

Abstract. Lorenz E, Hagen B, Himmelmann A, Kjørstad K, Onsrud M, Tingelstad S, Gundersen G. A phase II study of biweekly administration of paclitaxel in patients with recurrent epithelial ovarian cancer.
The purpose of this study was to assess the efficacy and toxicity of single agent paclitaxel administered biweekly to patients with relapse of epithelial ovarian cancer previously treated with platinum-based regimen. Forty patients received an initial paclitaxel dose of 134 mg/m² administered intravenously over three hours every two weeks.
283 cycles were given. All 40 patients were evaluable for toxicity, which mainly consisted of granulocytopenia, myalgia/arthralgia, and peripheral neuropathy. Two patients developed severe hypersensitivity reactions. Dose escalation was possible by one level in 11 patients and by two levels in 12 patients, dose reductions were not necessary. Thirty-five patients were evaluated for response. Five obtained complete response (14%), eight obtained partial response (23%), and nine had stable disease (26%), while 11 patients showed progression (31%). The overall response rate was 37% (95% confidence interval 22–57%). The median duration of responses (complete and partial) was six months. Overall median time to progression and overall median survival for eligible patients ( n = 35) was 4.3 months and 11 months, respectively.
We conclude that biweekly administration of paclitaxel in recurrent epithelial ovarian carcinoma was active with manageable toxicity.     

Consolidation paclitaxel is more cost-effective than bevacizumab following upfront treatment of advanced epithelial ovarian cancer

Introduction

Randomized trials have demonstrated significant improvements in progression-free survival (PFS) with consolidation paclitaxel (P) and bevacizumab (B) following cytoreduction and adjuvant carboplatin/paclitaxel (CP) for advanced epithelial ovarian cancer (EOC). We sought to evaluate the cost-effectiveness (C/E) of these consolidation strategies.

Methods

A decision model was developed based on Gynecologic Oncology Group (GOG) protocols #178 and #218. Arm 1 is 6 cycles of CP. Arm 2 is 6 cycles of CP followed by 12 cycles of P (CP + P). Arm 3 is 1 cycle of CP, 5 cycles of CPB, and 16 cycles of B (CPB + B). Parameters include PFS, overall survival (OS), cost, complications (neuropathy for P and bowel perforation for B), and quality-of-life utility values. Sensitivity analyses were performed.

Results

The incremental cost-effectiveness ratio (ICER) for CT + T is $13,402/quality adjusted life year (QALY) gained compared to CP. For CPB + B compared to CP, the ICER is $326,530/QALY. When compared simultaneously, CPB + B is dominated, i.e. is more costly and less effective than CP + P. Results were robust to parameter variation. At a willingness to pay threshold of $100,000/QALY, CP + P was the preferred option throughout most of the decision space. Sensitivity analyses suggest that CPB + B would become the preferred option if it were to improve OS by 6.1 years over CP + P.

Conclusions

In this model, B consolidation for advanced EOC was associated with a modest improvement in effectiveness that is less than that with P consolidation and more costly. A statistically significant improvement in survival may improve the value of B consolidation.     

A phase I study evaluating the safety and pharmacokinetics of weekly paclitaxel and carboplatin in relapsed ovarian cancer

This phase I study sought to determine the toxicity profile, pharmacokinetics, and antitumor activity of giving carboplatin every 3 weeks and paclitaxel weekly in patients with relapsed ovarian cancer. Eligible patients with relapsed epithelial ovarian cancer and prior treatment with platinum- and paclitaxel-based therapy were treated with an escalating regimen of carboplatin (day 1) at an area under the curve (AUC) of 4-6 and 1-h infusions of paclitaxel (days 1, 8, and 15) at 50-80 mg/m(2) cycled at 3-week intervals. Pharmacokinetic studies were performed on the first day of cycles 1 and 2. All patients had a platinum-free interval of greater than 6 months from the most recent platinum treatment. A total of 77 cycles were administered to 16 patients, with a similar median number of cycles per patient at each dose level varying from 4.6 to 5.3. Febrile neutropenia and grade 4 thrombocytopenia were the dose-limiting toxicities at dose levels 3 and 4 after the third cycle, with no mucositis, nausea, vomiting, or peripheral neuropathy observed greater than grade 2. The maximum tolerated dose of carboplatin was an AUC of 5 and 80 mg/m(2) for paclitaxel. Pharmacokinetic analysis showed a marginal statistical difference with regard to reduced systemic paclitaxel concentration after cycle 2 compared with cycle 1 (P= 0.06). Of nine patients evaluable for a radiographic response, the response rate was 66.6% with a complete response of 33.3%. All five patients with nonmeasurable disease achieved a biochemical response. The combination of carboplatin given every 3 weeks at an AUC of 5 and 1-h weekly paclitaxel at 80 mg/m(2) is a feasible and reasonably well-tolerated regimen and may have significant antitumor activity in relapsed ovarian cancer patients.     

Novel treatment options in platinum-sensitive recurrent ovarian cancer: A review

Epithelial ovarian cancer (EOC) is the leading cause of death due to gynecologic malignancy. The majority of advanced stage EOC patients, even those who respond well to frontline therapy, will ultimately recur and succumb to their disease. In platinum-sensitive EOC patients, or those who recur ≥6?months from initial diagnosis, treatment of recurrent disease has traditionally consisted of repeat platinum-based chemotherapy. Secondary cytoreduction remains controversial. Due to recent advances in molecularly targeted treatment options, outcomes for advanced stage EOC patients are significantly improving and hold great promise. This review discusses pivotal trials establishing platinum-based combination chemotherapy as the standard of care and addresses the utility of increasing a patient's platinum-free interval. It then discusses the role of anti-angiogenesis therapeutics, specifically bevacizumab, cediranib, and trebananib and their side effects. Lastly, it reviews key trials for the three poly-adenosine diphosphate [ADP]-ribose polymerases (PARP) inhibitors that have been FDA-approved for maintenance therapy in platinum-sensitive recurrent EOC: olaparib, rucaparib, and niraparib. This review concludes with a discussion regarding ongoing and future clinical trials.     

透明质酸结合蛋白1在人卵巢癌细胞系中表达及其与紫杉醇敏感性的关系

目的探讨透明质酸结合蛋白1在人卵巢癌细胞系SKOV3、HO-8910PM、HO-8910LM、OVCA429和OVCA420中的表达和定位及其与紫杉醇敏感性之间的关系。方法 2007年2月至2008年12月在哈尔滨医科大学附属三院研究所应用荧光定量RT-PCR技术和免疫荧光化学法结合激光共聚焦显微镜分别检测人卵巢癌细胞系SKOV3、HO-8910PM、HO-8910LM、OVCA429和OVCA420中HABP1 mRNA和蛋白的表达以及其在细胞中的定位,MTT法分析各卵巢癌细胞系对紫杉醇的敏感性。结果 HABP1 mRNA在人卵巢癌细胞系SKOV3、OVCA429和HO-8910PM中的表达水平分别是OVCA420的3.7、2.8和2.1倍(P值均<0.05),HO-8910LM和OVCA420中HABP1 mRNA的表达水平无统计学差异(P值>0.05),激光共聚焦显示5种人卵巢癌细胞系中HABP1蛋白的表达变化趋势与mRNA水平基本一致,其中SKOV3、OVCA429和HO-8910PM细胞系中HABP1蛋白在细胞核周的表达量明显高于OVCA420和HO-8910LM。MTT分析显示,SKOV3、OVCA429、OVCA420、HO-8910PM和HO-8910LM细胞对紫杉醇的中效浓度分别是:0.047μmol/L、0.221μmol/L、0.723μmol/L、0.092μmol/L和0.672μmol/L,相关分析显示HABP1 mRNA表达水平与卵巢癌细胞对紫杉醇的中效浓度之间的相关系数为-0.888,P<0.05。结论 HABP1的表达与卵巢癌细胞对紫杉醇的敏感性呈显著正相关,其机制可能是由于其在细胞中的分布位置不同所致,HABP1可作为筛选卵巢癌化疗药物的指标之一。