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.     

卵巢癌初次治疗后随访及巩固治疗

卵巢癌患者在经过初次肿瘤细胞减灭术和一线药物化疗后大部分能得到临床完全缓解,但是仍有很多患者特别是晚期患者将复发。文章主要对初次治疗后达到临床完全缓解患者的监测与随访,以及是否需要进一步巩固治疗以延长无进展生存期和提高总生存率的最新进展进行阐述。     

Weekly and monthly regimens of paclitaxel and carboplatin in the management of advanced ovarian cancer. A preliminary report on side effects

Abstract. Wu CH, Yang CH, Lee JN, Hsu SC, Tsai EM. Weekly and monthly regimens of paclitaxel and carboplatin in the management of advanced ovarian cancer. A preliminary report on side effects.
This preliminary study was carried out over 18 months to evaluate whether the side effects in patients with advanced ovarian cancer receiving chemotherapy using paclitaxel-carboplatin differed between weekly (98 cycles in 14 patients) and monthly (102 cycles in 15 patients) administrations. We used paclitaxel (60 mg/m²) and carboplatin (AUC of 2) in the weekly regimen and 175 mg/m² of paclitaxel and carboplatin (AUC of 6) in the monthly regimen. All eligible patients received at least four cycles of treatment in both regimens. The results revealed significantly decreased hematological toxicity in weekly regimens relative to monthly ones, ie, 7.1% vs. 18.6% of anemia (≥ grade 2), 7.1% vs. 32.3% of grade 3/4 granulocytopenia, and 0% vs. 15.7% of >grade 2 thrombocytopenia. There was no significant difference in nonhematological toxicities between the two regimens. The incidence of unscheduled events was much less in the weekly regimen than in the monthly one; ie, delayed treatment (3 vs. 18 events), unanticipated hospitalizations (3 vs. 15 times), and supplemental support with G-CSF (7 vs. 33 times). Complete responses were observed in 6 of 14 patients in the weekly regimen and in five of 15 patients in the monthly regimen, while partial responses were seen in four and five patients in the weekly and monthly regimens, respectively. The present results demonstrate that the weekly regimen can achieve the benefits of tolerable toxicity with significantly reduced myelosuppression and improved cost-effectiveness in terms of unscheduled events.     

Weekly carboplatin and paclitaxel is safe, active, and well tolerated in recurrent ovarian cancer cases of Japanese women previously treated with cisplatin-containing multidrug chemotherapy

The safety and efficacy of weekly carboplatin and paclitaxel administration in recurrent ovarian cancers after platinum-containing multidrug chemotherapy were tested. Japanese patients who achieved complete response with surgery and adjuvant platinum-based chemotherapy and who had a recurrence after at least 6 months were included in the case - control study. Twenty-seven cases received the weekly TJ (WTJ) regime (cohort 1: T = 80 mg/m(2), J = AUC 2, median course = 13, range = 3-26) and 41 received other regimens [cohort 2: CAP = 37, monthly TJ (MTJ) = 4]. Toxicity profile, response rate, therapeutic index (TI), and survival were analyzed. Neutropenia, thrombocytopenia, and peripheral neuropathy (grades 3 and 4) in cohorts 1 and 2 were 1.7% and 90%, 5.1% and 14.3%, and 0% and 4.8%, respectively. Response rates were 77.8% and . Thus, TI of the two cohorts was 3.9 and 1.9, respectively. The median survival of cohort 1 was 48.3 months (95% CI 11.5-85.0) whereas that of cohort 2 was 17.8 months (95% CI 5.3-30.3, P < 0.005). WTJ has better toxicity profile and TI than monthly platinum-based multidrug regimens for recurrent ovarian cancers in Japanese women. As second-line treatment of ovarian cancer should primarily provide high TI, WTJ regimen appears a better candidate, but its long-term survival benefit should be tested against MTJ.     

A case of rapidly growing ovarian squamous cell carcinoma successfully controlled by weekly paclitaxel-carboplatin administration

BACKGROUND: Primary squamous cell carcinoma of the ovary is uncommon and has a poor prognosis. Because of its rarity, the effective postoperative treatment is unknown. We describe a remarkable response of this tumor to weekly paclitaxel-carboplatin administration. CASE: A 53-year-old woman had rapidly growing primary squamous cell carcinoma of the ovary that metastasized to the abdominal wall and transverse colon after maximum cytoreductive surgery. The tumor was resistant to primary chemotherapy with cisplatin, vincristine, mitomycin C, and bleomycin. A combination of paclitaxel and carboplatin was used for second-line chemotherapy and was repeated every week. The patient tolerated the chemotherapy well and demonstrated a pathological complete response in the abdominal metastases following the five courses of chemotherapy. CONCLUSION: Weekly paclitaxel-carboplatin administration may be a safe and effective treatment for advanced and rapidly growing ovarian squamous cell carcinoma with primary resistance to chemotherapy.     

Adenocarcinoma of mammary-like glands in the vulva successfully treated by weekly paclitaxel

An 87-year-old was referred for gynecologic evaluation of a lesion involving the left labia majus noted 3 years earlier. Fine-needle aspiration cytology revealed clusters with an acinous structure or glandular formation. The tumor appeared as cell clusters with linear arrangements. Histologic examination showed the same morphologic findings as scirrhus type of primary breast carcinoma. Examinations of the breasts and axillary lymph nodes were normal. This disease was diagnosed as an adenocarcinoma arising in mammary-like glands of the vulva. Bone scan showed multiple foci in the sternum, costa, and vertebrae, consistent with metastatic disease. We administered five courses of weekly paclitaxel chemotherapy, which achieved a partial response. There were no severe adverse effects. In our case, the fine-needle aspiration cytology was a rapid and minimally invasive method of diagnosis, and the findings were extremely similar to those of the scirrhus type of primary breast carcinoma. Rapid and accurate diagnosis made with this technique might contribute to a good prognosis in the early-staged cases. Weekly paclitaxel chemotherapy may be one of the safe and effective treatments for this disease with distant metastases, even in extremely aged patients (over 80 years).     

A pilot study of three-cycle consolidation chemotherapy with paclitaxel and platinum in epithelial ovarian cancer patients with clinical complete response after paclitaxel and platinum chemotherapy

The aim of this study is to evaluate the efficacy of three additional cycles of paclitaxel and platinum chemotherapy in epithelial ovarian cancer patients with clinical complete response (CR). Patients with histologically confirmed epithelial ovarian cancer stages II-IV with clinical CR after primary surgery and six cycles of chemotherapy with paclitaxel/platinum entered into the study. Three cycles of paclitaxel/platinum (cisplatin, carboplatin) were administered as a consolidation chemotherapy only in patients who agreed to the informed consent. Patients without further treatment served as controls. A total of 81 patients entered into the study. According to the informed consent, 42 patients were treated by the consolidation chemotherapy, and 39 patients were followed up without further treatment. The median actuarial disease-free survival for the patients with and without consolidation chemotherapy was 25.0 months and 26.0 months, respectively (P= 0.80). The median overall survival is not reached. World Health Organization grade 3-4 toxicities in the consolidation arm were increased but showed no significant differences statistically. Although the sample size is small and not randomized, these results suggest that three cycles of consolidation chemotherapy with paclitaxel/platinum might not provide a favorable outcome in patients with a clinical CR.     

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.     

Addition of bevacizumab to weekly paclitaxel significantly improves progression-free survival in heavily pretreated recurrent epithelial ovarian cancer

Objective

Weekly paclitaxel has been shown to be an effective cytotoxic regimen for recurrent epithelial ovarian cancer (EOC), and may act through inhibition of angiogenesis. Bevacizumab, a potent angiogenesis inhibitor, has also been shown to have activity in patients with EOC. Therefore, we sought to determine if the addition of bevacizumab to weekly paclitaxel led to an increased survival compared to weekly paclitaxel alone.

Methods

A single institutional review was conducted for patients with recurrent EOC treated with weekly paclitaxel (60-70 mg/m²) on days 1, 8, 15, and 22 of a 28 day cycle and those treated with weekly paclitaxel and bevacizumab (10-15 mg/kg on day 1 and 15). Response rates (RR) were calculated, and progression-free survival (PFS), and overall survival (OS) were compared using Kaplan-Meier survival analysis.

Results

Twenty-nine patients treated with weekly paclitaxel and 41 patients treated with paclitaxel/bevacizumab were identified. The groups were similar in demographics, initial optimal cytoreduction, stage, histology, grade, platinum sensitivity, and median number of previous regimens (4 vs. 4, p = 0.69).The overall response rate (ORR) was 63% (complete response (CR) 34% and partial response (PR) 29%) for paclitaxel/bevacizumab and 48% (CR 17% and PR 31%) for weekly paclitaxel (p = 0.23). Improvement in PFS was seen in those treated with paclitaxel/bevacizumab in comparison to weekly paclitaxel alone (median PFS 13.2 vs. 6.2 months, p < .01). There was a trend towards improved OS for paclitaxel/bevacizumab (median OS 20.6 vs. 9.1 months; p = 0.12). Toxicities were similar between the two regimens although more bowel perforations (2 vs. 0) were seen in the paclitaxel/bevacizumab group.

Conclusion

A significant increase in PFS with a trend towards improved OS was demonstrated in this heavily pretreated population treated with paclitaxel/bevacizumab as compared to weekly paclitaxel alone. This data should be helpful in guiding future trials to determine the optimal care for women with recurrent EOC.     

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.     

Consolidation therapy with weekly paclitaxel infusion in advanced epithelial ovarian cancer and primary peritoneal cancer: an extended follow-up

OBJECTIVE: To determine the impact of weekly paclitaxel consolidation on progression-free survival (PFS) of women undergoing treatment for ovarian cancer. METHODS: All women with advanced epithelial ovarian or primary peritoneal carcinoma, treated with paclitaxel consolidation therapy from August 1997 to March 2002, were identified. Patients received weekly paclitaxel infused at a median dose of 80 mg/m(2) (range: 60-80 mg/m(2)) for a maximum of 12 weeks. A chart review was performed to assess disease status and chemotherapy-related toxicities. PFS was calculated from the date of initiation of induction chemotherapy until the date of documented disease recurrence. RESULTS: 31 women received paclitaxel consolidation therapy over the study period (29 stage III and 2 stage IV). 24 women had epithelial ovarian carcinoma and 7 were diagnosed with primary peritoneal carcinoma. The median PFS was 27 months (range: 12-62 months). The overall 2-year survival was 94%, where 17 women (55%) were without evidence of disease and 12 (39%) were alive with disease. The median follow-up was 41 months (range: 15-77 months). Over 337 weeks of consolidation therapy, 1 patient experienced Grade 3 neuropathy and 1 patient developed Grade 3 neutropenia. CONCLUSION: Consolidation therapy with weekly paclitaxel infusion is a well-tolerated regimen that resulted in a median PFS of 27 months in women who obtained a complete clinical response following induction therapy. Given the lack of side effects and the potential for extending the PFS of those treated, a prospective randomized study of weekly paclitaxel should be considered.     

Effective desensitization protocol to paclitaxel following hypersensitivity reaction

The objective of this paper is to describe our experience with a desensitization protocol to paclitaxel using the original paclitaxel solution in patients following severe hypersensitivity reactions. A retrospective review of 75 consecutive patients with ovarian cancer who received intravenous paclitaxel-based chemotherapy between January 1996 and May 1998 at the Gynecologic Oncology Unit at Meir Hospital-Sapir Medical Center, Kfar-Saba, Israel. All patients who developed a hypersensitivity reaction to paclitaxel were treated with a desensitization protocol. The protocol included serial 10-fold dilutions (up to 1:100,000) of the actual paclitaxel infusate, delivered in successive volumes of 1, 2, 4, and 8 ml. These escalating doses of paclitaxel were given intravenously at 15-min intervals for each dilution. Following administration of the last diluted dose, the patient received a 1-ml dose of the undiluted solution. If no side effects were recorded, the rest of the actual dose was delivered at a 3-h infusion rate. Vital signs were monitored and recorded throughout the course of treatment. Six patients with a previous paclitaxel-associated hypersensitivity reaction were successfully treated with the desensitization protocol.
In conclusion, we demonstrate that the desensitization protocol is feasible and safe without compromising cytotoxic activity. Our results show that this strategy is a reasonable choice in this clinical setting and potentially avoids paclitaxel-based regimen interruption.     

Taxol given weekly in advanced previously treated ovarian carcinomas – a pilot study

In this pilot study, 42 patients with advanced ovarian carcinoma were treated with Taxol weekly instead of every 3 weeks. The initial dose was 67 mg m⁻². The clinical response rate was 29%. The response rate was 22% for patients with platinum-resistant tumors compared to 42% for patients with platinum-sensitive tumors. This difference was not statistically significant. The median progression free survival was 110 days and the median overall survival 341 days. The toxicity was acceptable and probably less pronounced than with the standard tri-weekly schedule. A randomized multicenter study comparing these two treatment schedules is presently under way in Scandinavia.