Dose finding study of paclitaxel and carboplatin for ovarian cancer (JKTB)

We conducted a dose-finding study for combination therapy of paclitaxel (Taxol; TXL) and carboplatin (Paraplatin; CBDCA). TXL is a novel plant-derived anticancer agent that is a diterpene derivative possessing the taxane ring. The subjects were patients with ovarian carcinoma, who were evaluated by a modified Fibonacci method. The dosage of TXL was 150 to 180 mg/m2. CBDCA was administered by dose escalation from AUC = 4 to 7. The administration schedule was as follows. Pre-medication was administered before TXL was given. TXL was then administered by intravenous infusion over 3 hours, followed by CBDCA. The dose of CBDCA was determined using the Calvert formula: [AUCX (GFR + 25)]. GFR was calculated with the Jelliffe equation. The non-hematological toxicities observed in 15 eligible cases were mainly grade 1, with no grade 3 or above, and no increase in severity was observed with stepping up. The hematological toxicities were grade 3 leukopenia in 5 of 15 cases, neutropenia in 5 cases and thrombocytopenia in 0 cases. No grade 4 toxicity was observed. The lowest counts of leukocytes and neutrophils were reached after 10.8 and 11.7 days, respectively. The toxicities were reversible in most cases with subsequent recovery. The above findings indicate that the recommended dosages for TJ therapy for Japanese ovarian cancer patients should be TXL 180 mg/m2 and CBDCA at a target of AUC = 6.     

Combined chemotherapy with weekly paclitaxel and carboplatin for recurrent and refractory epithelial ovarian cancer--phase I study

The current initial standard chemotherapy for advanced ovarian cancer is a regimen with a combination of platinum and taxane. However, the 5-year survival rate remains at 40% or lower, and the recurrence rate is as high as 70-80%. Second-line chemotherapy for recurrent cases has not yet been established. We conducted a phase I study of combined chemotherapy with paclitaxel (TXL) and carboplatin (CBDCA) administered weekly for recurrent and refractory ovarian cancer. The subjects were patients with a histopathologically confirmed diagnosis of malignant epithelial ovarian cancer, with recurrent or refractory disease after the initial chemotherapy. TXL was administered at escalating concentrations up to 60-100 mg/m(2), while the dose of CBDCA was fixed at an AUC of 2. In regard to the dosing schedule, premedication was performed as defined before TXL administration, and TXL and CBDCA were administered, in that order, by intravenous infusion for over at least 1 hour. The 4-week period, including the administration of both drugs on Day 1, 8, and 15, was regarded as one course of treatment. No cases developed grade 4 hematoxicity, but leukopenia and neutropenia occurred. All cases of leukopenia of step 4 and step 5 developed grade 3 leukopenia. Grade 2 thrombocytopenia was one example at a low rate. Non-hematological toxicity included neuropathy, arthralgia and muscle pain, but none of the patients developed grade 3 or 4. The response rate was 41.7% (5/12). The response rate of cases administered over TXL 80 mg was 66.7% (4/6). Based on these results,the following dose schedule was recommended for planning and designing a phase II study in the future: CBDCA AUC 2+TXL 80 mg/m(2) (Days 1, 8, and 15 q 4 weeks).     

A pilot study of whole body hyperthermia and carboplatin in platinum-resistant ovarian cancer

The aim of this study was to determine whether the addition of whole body hyperthermia (WBH) to carboplatin (CBDCA) can induce responses in patients with platinum-resistant ovarian cancer. 16 pretreated patients with platinum-resistant ovarian cancer were entered on a Systemic Hyperthermia Oncological Working Group (SHOWG) study; (14 patients were eligible with 14 evaluable for toxicity and 12 for response). The patients were treated with WBH (Aquatherm) 41.8 degrees C x 60 min in combination with carboplatin (CBDCA) (area under the curve (AUC) of 8) every 4 weeks. Disease status was evaluated every two cycles. Patients were treated for a maximum of six cycles. One patient had a complete response (CR) and 4 had a partial response (PR). 4 patients had stable disease (SD). 3 patients had progressive disease (PD). 2 patients were unevaluable: 1 had a bowel obstruction shortly after her first treatment; the second patient achieved a CR, but only had one treatment secondary to an idiosyncratic reaction to sedative drugs. 2 patients entered on study were ineligible, as they did not meet criteria for platinum resistance; 1 entered a CR and 1 had SD. Dose-limiting toxicity, which required CBDCA dose reductions, was grade 4 thrombocytopenia. Other toxicities included neutropenia (grade 3/4), and nausea and/or vomiting. Consistent with preclinical modelling, these results suggests that 41.8 degrees C WBH can overcome platinum resistance in ovarian cancer. These observations suggest further investigation of the therapeutic potential of WBH in a group of patients who historically fail to respond to salvage therapies is warranted.     

Weekly paclitaxel infusion in patients with recurrent ovarian cancer--a pilot study

This preliminary study was performed to evaluate the safety and efficacy of weekly paclitaxel administration by 1-hour infusion. A total of 7 patients with recurrent ovarian cancer were treated with weekly paclitaxel (TXL). TXL was given at a dose of 70 mg/m2 in 1-hour infusions every week for at least 20 consecutive weeks unless lesions became progressive. Premedication was administered 30 min before TXL infusion. The 7 patients received a total 110 cycles of therapy. Hypersensitivity reactions were not observed. Grade 3 or 4 neutropenia occurred in only 0.9% of the cycles. Neurotoxicity was commonly observed, but that of grade 3 or greater severity was not recorded. No other severe non-hematologic toxicities were observed. Partial responses were seen in three of 7 patients. Weekly 1-hour TXL is considered to be safe and effective as a salvage therapy in patients with recurrent ovarian cancer.     

A clinical and pharmacokinetic study of the combination of carboplatin and paclitaxel for epithelial ovarian cancer.

The aim of this phase I study was to determine the maximum tolerated dose of a 3-h infusion of paclitaxel, combined with carboplatin at a fixed AUC of 7 mg ml-1 min every 4 weeks for up to six cycles and to evaluate any possible pharmacokinetic interaction. Twelve chemonaive patients with ovarian cancer were treated with paclitaxel followed by a 30-min infusion of carboplatin. Paclitaxel dose was escalated from 150 mg m-2 to 225 mg m-2 in cohorts of three patients. Carboplatin dose was based on renal function. Pharmacokinetic studies were performed in nine patients (at least two at each dose level). A total of 66 courses were evaluable for assessment. Grade 3 or 4 neutropenia was seen in 70% of the courses, however hospitalization was not required. Grade 3 or 4 thrombocytopenia occurred in 24% of the courses. Alopecia, myalgia and peripheral neuropathy were common but rarely severe. The pharmacokinetics of paclitaxel was non-linear and did not appear to be influenced by co-administration of carboplatin. The AUC of carboplatin was 7.0 +/- 1.4 mg ml-1 min, indicating that there was no pharmacokinetic interaction. The combination of carboplatin and paclitaxel may be administered as first-line treatment for advanced ovarian cancer. Although myelosuppression is the dose-limiting toxicity of the component drugs, the severity of thrombocytopenia was less than anticipated. The results of this study, with only a small number of patients, need to be confirmed in future investigations.     

A feasibility study of paclitaxel and carboplatin therapy in Japanese patients with epithelial ovarian cancer

The aim of this study was clarification of the feasibility, effects, and adverse events of combination chemotherapy with paclitaxel and carboplatin in Japanese women with epithelial ovarian cancer. In patients with stage Ic to IV epithelial ovarian cancer, primary cytoreductive surgery was performed. Paclitaxel (175 mg/m(2)) was intravenously infused for 3 h. Subsequently, carboplatin was infused, with an area under the plasma concentration-time curve of 5. Ninety-one patients were enrolled in this study. The mean dose of paclitaxel at the sixth course was 161 mg/m(2). Of 51 patients, a complete response was observed in 19 patients (37%), and a partial response in 23 patients (45%). The response rate for clear cell adenocarcinoma was 25%. With regard to adverse events, grade 4 granulopenia was observed in 80% of patients, suggesting dose-limiting toxicity. However, none of the patients developed serious infection. With regard to non-hematological toxicity, grade 2 or 3 alopecia, arythralgia/myalgia, and peripheral neurotoxicity were noted in 97, 29, and 20% of the patients, respectively. Although hematological toxicity was relatively marked, this regimen can be applied in Japanese women.     

Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer.

PURPOSE: To determine the side effects and feasibility of cisplatin and carboplatin each in combination with paclitaxel as front-line therapy in advanced epithelial ovarian cancer. PATIENTS AND METHODS: Patients were randomly allocated to receive paclitaxel 175 mg/m(2) intravenously as a 3-hour infusion followed by either cisplatin 75 mg/m(2) or carboplatin (area under the plasma concentration-time curve of 5), both on day 1. The schedule was repeated every 3 weeks for at least six cycles. Women allocated to paclitaxel-cisplatin were admitted to the hospital, whereas the carboplatin regimen was administered to outpatients. RESULTS: A total of 208 eligible patients were randomized. Both regimens could be delivered in an optimal dose and without significant delay. Paclitaxel-carboplatin produced significantly less nausea and vomiting (P: <.01) and less peripheral neurotoxicity (P: =.04) but more granulocytopenia and thrombocytopenia (P: <.01). The overall response rate in 132 patients with measurable disease was 64% (84 of 132 patients), and in patients with elevated CA 125 levels at start, it was 74% (132 of 178 patients). With a median follow-up time of 37 months, the median progression-free survival time of all patients was 16 months and the median overall survival time was 31 months. The small number of patients entered onto the study caused wide confidence intervals (CIs) around the hazards ratio for progression-free survival of paclitaxel-carboplatin compared with paclitaxel-cisplatin (hazards ratio, 1.07; 95% CI, 0.78 to 1.48) and did not allow conclusions about efficacy. CONCLUSION: Paclitaxel-carboplatin is a feasible regimen for outpatients with ovarian cancer and has a better toxicity profile than paclitaxel-cisplatin.     

紫杉醇脂质体联合卡铂与紫杉醇联合卡铂治疗卵巢癌的疗效比较

目的探讨和比较紫杉醇脂质体联合卡铂与紫杉醇联合卡铂治疗卵巢癌的疗效。方法选取2012年5月至2015年5月间收治的60例卵巢癌患者,按照随机数字表法分为研究组和对照组,每组30例。研究组患者采用紫杉醇脂质体联合卡铂治疗,对照组患者采用紫杉醇联合卡铂治疗,比较两组的疗效及不良反应。结果研究组患者的总有效率为73.3%(22/30),对照组为70.0%(21/30),差异无统计学意义(P>0.05)。研究组患者的过敏反应、白细胞减少、血红蛋白减少、血小板减少、皮疹、肌痛、胃肠道反应发生率均显著低于对照组,差异有统计学意义(P<0.05),但两组患者的脱发发生率差异无统计学意义(P>0.05)。结论紫杉醇脂质体联合卡铂治疗卵巢癌与紫杉醇联合卡铂治疗卵巢癌疗效相当,但不良反应少。     

Weekly dose-dense paclitaxel and carboplatin in recurrent ovarian carcinoma: A phase II trial

PurposeThe aim of this study was to investigate efficacy and toxicity of the dose-dense weekly paclitaxel (T) and carboplatin (C) in the management of platinum-resistant/sensitive recurrent epithelial ovarian cancer (EOC) previously treated with 3 weekly paclitaxel/carboplatin.MethodsThirty two patients with recurrent EOC who had received 3 weekly TC before were enrolled. Nine patients relapsed within 6 months (platinum-resistant), 13 patients relapsed after 12 months (platinum-sensitive) and in 10 patients recurrence occurred between 6 and 12 months (intermediate platinum-sensitive). Weekly (T) at a dose of 80 mg/m², followed by weekly (C) AUC 2 on day 1, 8, and 15 of a 28-day cycle for 6 planned cycles were administrated. End-points were overall response rate (ORR), progression free survival (PFS), overall survival (OS) and toxicity.ResultsThe ORR was 62.5%. For the platinum-resistant, intermediate platinum-sensitive and platinum-sensitive patients the ORR was 44.4% (4/9), 60% (6/10) and 76.9% (10/13), respectively, and 1 (11.1%), 2 (20%) and 5 (38.46%) patients, respectively had CR. PFS was 9.1 months (6.13, 9.1 and 12.17 months, for the 3 groups, respectively) (P < 0.001). OS was 14 months (9.17, 15.2, and 19.23 months, for the 3 groups, respectively) (P < 0.001). Treatment-related adverse events were manageable with only 1 patient (3.1%) suffering from grade 4 neutropenia. Grade 3 hematological and non-hematological toxicities were neutropenia in 8 (25%), and peripheral neuropathy in 4 (12.5%) patients, respectively.ConclusionWeekly TC is active and well-tolerated in platinum-resistant and platinum-sensitive patients with recurrent EOC previously treated with TC given every 3 weeks.     

A phase I/II study of carboplatin and paclitaxel in patients with epithelial ovarian cancer

BACKGROUND: This study was conducted to investigate the recommended dose of paclitaxel for use in combination with a fixed dose of carboplatin and to evaluate the toxicity and efficacy of carboplatin-paclitaxel combination chemotherapy in patients with epithelial ovarian cancer. METHODS: One hundred and ten patients were enrolled in the Phase I/II study and 97 patients were evaluated for further analysis, excluding 13 ineligible patients or patients with infringement of protocol: 15 patients for the Phase I and 82 for the Phase II study. In the Phase I trial, we studied dose escalation using a carboplatin dose of AUC 5 and paclitaxel levels of 150, 175 and 200 mg/m(2). The grades of toxicity of the regimen of all patients enrolled in the Phase II study (n = 82), the progression-free survival time (PFS) of optimal-debulked patients and complete responders (n = 62) and the response rate of suboptimal-debulked patients (n = 39) were investigated. RESULTS: After observing grade 4 neutropenia in four of six patients in the paclitaxel 200 mg/m(2) administration group, we chose 175 mg/m(2) as the recommended dose of paclitaxel in this regimen. At this dose, the median of PFS and response rate were 432 days (range, 19-907 days) and 66.7%, respectively. CONCLUSION: Combination chemotherapy using paclitaxel 175 mg/m(2) and carboplatin AUC 5 is very well tolerated and highly effective for the treatment of ovarian cancer.     

Phase II study of the combination carboplatin and paclitaxel in patients with ovarian cancer

Background: Recently the feasibility of combining carboplatin withpaclitaxel has been demonstrated in dose-finding studies. Maximum tolerateddoses were 550 mg/m² and 200 mg/m² (threehours), respectively. We report now a phase II study in ovarian cancerpatients.Patients and methods: Twenty-one chemo-naïve patients with optimally(n = 6) or suboptimally (n = 15) debulked stage III or IV ovarian cancer weretreated every three weeks for six courses with paclitaxel (200mg/m²) as a three-hour infusion, immediately followed bycarboplatin (550 mg/m²) as a 30-minute infusion.Results: Uncomplicated neutropenia was the principal toxicity, with mildanemia occurring regularly. As observed in the preceding phase I study, arelative lack of thrombocytopenia, generally grade III was found. Othertoxicities consisted of mild neurotoxicity, nausea and vomiting, alopecia,myalgia, and bone pain. All suboptimally debulked patients responded totherapy. Overall, 12 patients underwent second-look laparoscopy, whichrevealed a pathologically confirmed complete remission in six. The medianfollow-up interval at the time of analysis was 14 months. Twelve patients arecurrently free of progression, at 8+ to 19± months after the start oftherapy.Conclusion: The carboplatin/paclitaxel combination appears to be awell-tolerated regimen, yielding high response rates. This combination has nowgone forward to be evaluated in prospective randomized trials versus thecisplatin/paclitaxel combination.     

Weekly paclitaxel and cisplatin in recurrent ovarian cancer

This study was performed to assess the feasibility of weekly paclitaxel (TXL) and cisplatin (CDDP) in patients with recurrent ovarian cancer. Ten of eleven patients experienced recurrence after more than 6 months after first line CDDP-based chemotherapy. TXL and CDDP were given at initial doses of 60 mg/m2 and 30 mg/m2 on days 1, 8, and 15 in 2 patients and an increase in the respective dose level was planned to 60/35 in 5 patients, 70/35 in 2 patients, and 70/40 in 2 patients. Toxicities were well tolerated. None of the patients suffered from neurotoxicity or myalgia of more than grade 2. Gastrointestinal disorder was recognized as grade 1-2, and grade 3-4 hematological toxicity included leucocytopenia (64%), anemia (36%), and thrombocytopenia (9%). We set the recommended dose of TXL at 70 mg/m2 and that of CDDP at 35 mg/m2, considering toxicity and performed planned schedule. Of eleven patients, nine were assessable by computed tomographic scan. The overall response rate was 67% (CR: 1, PR: 5, NC: 1, PD: 2). One of two patients with standard TXL/CDDP therapy showed PR by switching to a weekly schedule. The median follow-up duration was 490 days and the median response duration was 371 days. From the results presented here, it is suggested that this regimen with increased DI might be quite effective and well tolerated in patients who experience relapse after CDDP-based chemotherapy.     

A phase-I trial of pemetrexed plus carboplatin in recurrent ovarian cancer

Background

Carboplatin-based combinations are established in platinum-sensitive recurrent ovarian cancer. To improve the therapeutic index, new platinum-based combinations are required. Pemetrexed is a multi-targeted antifolate inhibiting thymidylate synthase. The aim of this study was to determine the maximally tolerated dose (MTD) and dose-limiting toxicity (DLT) and to characterize toxicities of the combination of pemetrexed (Pem) and carboplatin (Cb).

Design

A standard three-patient cohort dose escalation was performed starting at Cb AUC-5 and Pem 500 mg/m². Patients with platinum-sensitive recurrent ovarian cancer were eligible. Two levels of Cb (AUC-5, 6) and five levels of Pem (500, 600, 700, 800, and 900 mg/m²) were evaluated. DLTs were based on cycle 1.

Results

Twenty patients were enrolled. The median age was 57.4 years (37.3–75.3) and the median platinum-free interval was 26.2 months (7.2–124.4). There was one DLT at dose level 3 in cycle one. No serious adverse events related to the study therapy were observed. The 20 patients completed 112 cycles of Cb (104 were planned) and 115 cycles of Pem (112 were planned). The maximum dose level of Cb AUC-6 and Pem 900 mg/m² was well tolerated. Response rates in 19 patients were: CR: 63.2%; PR: 21.1%; SD; 5.3%, PD: 10.5%.

Conclusions

The combination carboplatin and pemetrexed is safe and well tolerated. A multicenter phase-II trial is currently underway.     

3-Hour infusion of single-agent paclitaxel for recurrent ovarian cancer

Background. The clinical response, survival, and toxicity of a 3-h infusion of single-agent paclitaxel (175 mg/m²) for Japanese patients with recurrent ovarian cancer were investigated. We also examined whether or not cancer antigen (CA) 125 would be suitable as an indicator of the effects of the paclitaxel on ovarian cancer. Methods. Twenty-one patients clinically diagnosed as having recurrent ovarian cancer met the entry criteria, agreed to participate in this study, and received the treatment. Results. One hundred and twenty-six courses were administered to the 21 patients. One patient achieved a complete response, and 5 a partial response; the overall response rate was 35.3%. Using CA125 criteria, 42.1% of patients achieved a response. The median progression-free interval was 4.4 months, and the median overall survival time was 14.5 months. While hematological toxicity was not severe, 3 patients experienced severe peripheral neuropathy, and 2 patients experienced grade 4 myalgia/arthralgia. Conclusion. The 3-h infusion of single-agent paclitaxel (175 mg/m²) was an effective treatment for patients with recurrent ovarian cancer. CA125 was a useful indicator of the response to the treatment. While peripheral neuropathy and the myalgia/arthralgia were severe, 3-h infusion of single-agent paclitaxel offers a promising treatment for recurrent ovarian cancer. Received: December 11, 2000 / Accepted: March 30, 2001     

A case of ovarian cancer stage IV and advanced rectal cancer responding to paclitaxel/carboplatin

A 43-year-old woman who had ovarian cancer with massive ascites and pleural effusion as well as rectal cancer underwent probe laparotomy. However, only bilateral adnexectomy was performed since radical surgery was impossible due to severe carcinomatosa peritonitis. Three courses of chemotherapy with paclitaxel and carboplatin (T-J therapy) were carried out. Following chemotherapy, the ascites and pleural effusion had completely disappeared and the size of rectal cancer had shrunk as well. The chemotherapeutic effect was evaluated as a partial response in the rectal cancer. Therefore, as interval debulking surgery, abdominal total hysterectomy, omentectomy, low anterior resection pelvic lymphadenectomy were performed. Three further courses of chemotherapy were performed. There is no evidence of recurrence of ovarian cancer and rectal cancer 3 years after the first surgery.     

A phase II feasibility study of carboplatin followed by sequential weekly paclitaxel and gemcitabine as first-line treatment for ovarian cancer

A total of 53 women with chemotherapy-na?ve stage Ic-IV ovarian cancer were treated with four cycles of carboplatin area under the curve 7 every 3 weeks, followed by four cycles of paclitaxel 70 mg m(-2) (days 1, 8, and 15) and gemcitabine 1000 mg m(-2) (days 1 and 8) every 3 weeks. In all, 37 (70%) had stage III/IV disease, with 22 (42%) having tumour >2 cm; 38 patients (72%) completed all planned treatment; 27 of the 32 (84%) patients with radiologically evaluable disease had partial or complete responses; and 30 of the 39 patients (77%) with elevated cancer antigen (CA) 125 had a greater than 75% fall in this value. At a median follow-up of 28 months, 31 patients had relapsed with a median progression-free survival of 19.5 months. In total, 79% of patients were alive at 2 years. Common Toxicity Criteria grade 3/4 haematological toxicity, predominantly neutropenia, was seen in 57% of the patients. A certain degree of pulmonary toxicity was observed; eight patients had symptomatic breathlessness, +/- decreased diffusing capacity of the lung for carbon monoxide, and interstitial chest X-ray changes during the weekly phase. In all cases, this toxicity was reversible. No significant neurotoxicity was seen. This regimen is generally well tolerated with encouraging efficacy. However, the observation of pulmonary toxicity, potentially a feature of the weekly taxane-gemcitabine regimen, was of some concern. Alternative schedules, including 3-weekly taxanes, are currently being evaluated.     

A phase I study of intraperitoneal topotecan in combination with intravenous carboplatin and paclitaxel in advanced ovarian cancer

The aim of this study was to determine the maximum tolerated dose (MTD) of intraperitoneal (i.p.) topotecan combined with standard doses of intravenous (i.v.) carboplatin and paclitaxel and to investigate its pharmacokinetics. Women with primary ovarian cancer stage IIb - IV received six cycles of i.v. carboplatin and paclitaxel with escalating topotecan doses i.p. of 10, 15, 20 and 25 mg/m(2). Twenty-one patients entered this trial. Febrile neutropenia, thrombocytopenia requiring platelet transfusion and fatigue grade 3 were dose-limiting toxicities (DLT) at 25 mg/m(2) i.p. and 20 mg/m(2) i.p. of topotecan was considered to be the MTD. The mean plasma t(1/2) was 3.8 +/- 2.3 h for total topotecan and 4.4 +/- 3.9 h for active lactone. The area under the curve (AUC) was proportional with dose, R = 0.54, p < 0.05 for total topotecan and the peritoneal / plasma AUC ratio was 46 +/- 30. Fifteen patients who completed treatment had a median progression-free survival (PFS) of 27 months. In this setting the MTD of topotecan is 20 mg/m(2) i.p. The efficacy of this regimen should be explored further in a formal phase III study.