A multi-institutional phase II trial of paclitaxel and carboplatin in the treatment of advanced or recurrent cervical cancer

Objective

The aim of this prospective trial was to evaluate the efficacy and safety of the combination of paclitaxel and carboplatin (TC) in patients with metastatic or recurrent cervical cancer.

Methods

This was a multicenter phase II trial of 3 weekly paclitaxel 175 mg/m² 3-hour iv day 1 followed by carboplatin AUC5 1-hour iv day 1 for maximum of 6 cycles until disease progression or prohibitive toxicity. Eligible patients had squamous or adenocarcinoma of the cervix with measurable stage IVB or recurrent, aged 20-75 years, Eastern Cooperative Oncology Group performance status 0-2, prior platinum-containing regimen 0-1, and no prior taxane. The primary endpoint was overall response rate (ORR) by RECIST.

Results

41 patients were enrolled, of which 39 were evaluable for analysis. 33 patients (84.6%) received prior radiotherapy. The confirmed ORR was 59% (95% CI, 43% to 75%); 5 patients (13%) achieved a complete response and median response duration was 5.2 months. The response rates for patients who had adenocarcinoma (n = 10) and prior platinum-based chemotherapy < 6 months (n = 7) were 40.0% and 0%, respectively. The median progression-free survival and overall survival times were 5.3 and 9.6 months, respectively. The most frequent grade 3 or 4 adverse events were neutropenia (79%), anemia (46%), thrombocytopenia (15%), and fatigue (8%). No treatment-related death was seen.

Conclusions

TC seemed to be feasible and effective similar to other cisplatin-based doublets for the treatment of metastatic or recurrent cervical cancer. Phase III trial is warranted to establish the clinical benefits of this combination.     

A phase II trial of oral capecitabine in patients with platinum--and taxane--refractory ovarian, fallopian tube, or peritoneal cancer

PURPOSE: To determine the efficacy, toxicity, and quality of life of capecitabine (Xeloda), an oral 5-fluorouracil derivative, in patients with chemorefractory recurrent mullerian cancers. PATIENTS AND METHODS: Patients with chemorefractory persistent or recurrent ovarian, fallopian tube, or peritoneal cancer with measurable disease were enrolled. Capecitabine was administered beginning at 2000 mg/m2/day orally in two divided doses with meals on a 21-day cycle: 14 days of capecitabine followed by a 7-day rest period. One dose escalation or reduction was allowed. Response was assessed after cycle 2 and cycle 4 and every third cycle thereafter. Standard evaluation included two-dimensional measurement of evaluable disease. Standard criteria for response were used. Therapy was discontinued if progression occurred after at least two cycles of therapy. Quality of life and symptoms were assessed. RESULTS: Forty-one patients were enrolled. Ninety-two percent of patients had >2 previous chemotherapy regimens. All patients had platinum- and taxane-resistant disease. Thirty-six patients were evaluable for response. Three patients had a partial response, with a median response duration of five cycles. Twenty-two patients had stable disease for 3 to 11 cycles (median, 6 cycles). Eleven had progressive disease. The only grade 4 toxicity was abdominal pain (n = 2). The most common grade 3 toxicities were fatigue (n = 19), hand-foot syndrome (n = 11), abdominal pain (n = 7), and diarrhea (n = 4). One patient had a grade 3 hematologic toxicity (anemia). CONCLUSION: Capecitabine at the dosages used in this study is well tolerated and has minimal hematologic toxicity.     

Predictive value of serum CA-125 levels in patients with persistent or recurrent epithelial ovarian cancer or peritoneal cancer treated with bevacizumab on a Gynecologic Oncology Group phase II trial

Objective

To compare two methods of determining therapeutic response and disease progression — modified Gynecologic Cancer Intergroup (GCIG) criteria based on CA-125 and Radiographic Evaluation Criteria in Solid Tumors (RECIST), in a phase II trial of bevacizumab for patients with recurrent or persistent epithelial ovarian and peritoneal carcinoma.

Methods

Patients were treated with bevacizumab 15 mg/kg every 21 days. Modified GCIG definitions of progression and response were retrospectively applied and compared to RECIST-defined progression and response. The prognostic significance of CA-125- and RECIST-defined responses and progressions were explored.

Results

Sixty-two patients were evaluable by RECIST, 59 for progression by CA-125, and 45 for response by CA-125. Median progression-free survival (PFS) by RECIST and progression-free interval (PFI) by CA-125 were 4.7 and 5.2 months respectively. However, 12.9% of those with CA-125 defined progression remained progression-free according to RECIST for at least 8 months. Thirteen of 62 patients (21%) had response by RECIST and 14/45 (31%) by CA-125. Time dependent analyses indicated that progression by CA-125 was associated with a 5.2 fold increased risk of progression by RECIST, and response by CA-125 had a 5 fold decrease in risk of progression by RECIST. Landmark and time dependent analyses showed prognostic value of responses by CA-125 and RECIST.

Conclusions

In this study, disease assessment by RECIST and CA-125 appears to correlate in general. However, approximately 10% of patients might demonstrate progression earlier by CA-125.     

A phase II clinical trial of topotecan and carboplatin in patients with newly diagnosed advanced epithelial ovarian cancer

A phase II clinical trial conducted to evaluate the efficacy and tolerability of topotecan and carboplatin as first-line therapy for women with advanced epithelial ovarian cancer was the objective of this study. Patients had histologically confirmed ovarian epithelial cancer with at least one measurable lesion. Patients received topotecan 1.5 mg/m(2) on days 1-3 and carboplatin at an area under the curve (AUC) of 5 on day 3 every 21 days for six cycles. All 42 patients enrolled were evaluable for response and toxicity. Median number of cycles delivered was six. Overall response rate was 71%, with 19 clinical complete responses (45%) and 11 clinical partial responses (26%). Median survival time was 47 months and 5-year survival was 42%. Myelosuppression was the predominant toxicity, with grade 3 or 4 neutropenia occurring in 100% of patients. However, this toxicity was transient and easily manageable; no patients experienced febrile neutropenia. The combination of topotecan and carboplatin is active in advanced epithelial ovarian cancer. Delay of therapy by 1 week or topotecan dose reduction to 1.25 mg/m(2) is the first-choice option to reduce topotecan toxicity without affecting the efficacy. Moreover, a chemotherapy regimen using weekly topotecan, which is currently being tested, should be considered.     

First-line chemotherapy with epidoxorubicin,paclitaxel, and carboplatin for the treatment of advanced epithelial ovarian cancer patients

OBJECTIVE: A combination of carboplatin (CBDCA) and paclitaxel (TAX) is the standard treatment in advanced ovarian cancer (AOC) patients. Epidoxorubicin (EDX) is an active treatment in AOC and exhibits nonoverlapping toxicities with CBDCA and TAX; moreover, when added to platinum-based chemotherapy, it improves long-term survival. We have therefore conducted a phase II study to evaluate the tolerability and antitumor activity of an EDX/TAX/CBDCA (ETC) triplet in AOC patients. METHODS: Patients with histologically confirmed suboptimal stage III-IV ovarian cancer who had not previously received cytotoxic drugs were treated with TAX (175 mg/m(2) in a 3-h iv infusion), CBDCA (AUC 6, Calvert formula), and EDX (75 mg/m(2) iv bolus) all given on day 1 every 28 days for a maximum of six courses on an outpatient basis. EDX dosage was chosen after a pilot phase I study. RESULTS: Fifty-five patients were registered, of whom 5 were determined ineligible bacause of age. Forty-two of the 50 are evaluable for response; 27 (64%) achieved a clinical complete response (CR) and 9 (21%) a partial response (PR) for a response rate of 86% (95% CI 71-94%). Thirty-three patients underwent a secondary debulking procedure after a median of 6 courses (range 2-6). Pathological CR and PR were observed in 9 (27.3%) and 21 (63.6%), respectively; among patients with persistent disease a successful cytoreduction (<1 cm) was obtained in 53.8% of patients. At a median follow up of 35.6 months (range 0-55.5) median progression-free survival is 19.5 months and median overall survival is 36 months. The most common adverse effects were G3-4 leukopenia and thrombocytopenia which occurred in 59 and 37% of patients, respectively. CONCLUSIONS: The ETC combination given according to the outlined doses and schedule is highly active in AOC patients with poor prognostic factors and deserves further study.     

Ifosfamide, paclitaxel, and carboplatin, a novel triplet regimen for advanced, recurrent, or persistent carcinoma of the cervix: a phase II trial

Objectives

(1) To determine the response rate of advanced, recurrent, or persistent carcinoma of the cervix to ifosfamide, paclitaxel, and carboplatin chemotherapy; (2) to determine the progression free interval and survival rate in patients treated with this regimen; (3) to describe the toxicities associated with this regimen; and (4) to evaluate the quality of life of patients while on treatment.

Methods

Eligible patients had histologically proven stage IVB, recurrent, or persistent carcinoma of the cervix not amenable to curative treatment with surgery and/or radiation therapy. Chemotherapy was given on day 1 of a 28-day cycle: mesna (600 mg/m²) prior to ifosfamide (2 g/m²), paclitaxel (175 mg/m²), carboplatin (AUC 5). Response rates were determined according to RECIST criteria. Toxicity was graded according the National Cancer Institute's common toxicity criteria. Quality of life measurements were obtained using the FACT-Cx.

Results

Twenty-eight patients participated in this study, with 21 evaluable for response rate. Overall, 7 patients (33%) had a demonstrated objective response (4 complete responses, 3 partial responses). Stable disease was documented in 3 patients. The overall median survival for all patients was 10 months. Median progression free survival for evaluable patients was 5.0 months. Bone marrow suppression was the most common toxicity. There were no negative effects of this treatment regimen on quality of life assessments.

Conclusion

Ifosfamide, paclitaxel, and carboplatin is an effective regimen in treating advanced or recurrent carcinoma of the cervix and has an acceptable toxicity profile.     

Phase II trial of vinorelbine for relapsed ovarian cancer: a Southwest Oncology Group study

OBJECTIVES: To assess the activity of vinorelbine in women with recurrent or resistant epithelial ovarian cancer following treatment with platinum and paclitaxel in terms of survival rate at 6 months, objective response rate (in the subset of patients with bidimensionally measurable disease), and health-related quality of life. METHODS: Seventy-nine evaluable patients with progressive ovarian cancer following platinum and taxane therapy received vinorelbine 30 mg/m(2) days 1 and 8 of a 21-day treatment cycle. RESULTS: Six-month survival rate for the entire group was 65% (95% CI: 54-75%) and median survival was 10.1 months (95% CI: 7.7-13.6 months). In the 71 women with measurable disease, 0 complete and 2 partial responses were observed (RR = 3%) (95% CI: 0.3-10%). Patients reported substantial symptom-related distress at baseline, which persisted, but did not worsen, during treatment. Patients also had impaired physical functioning at baseline and this continued to decline during treatment. CONCLUSIONS: The 6-month survival rate achieved with salvage vinorelbine is comparable to the results obtained with other salvage therapies in patients with relapsed ovarian cancer. During the initial 10 weeks of treatment, vinorelbine did not appear to be effective in alleviating the symptom-related distress or progressive impairment of physical functioning associated with this disease.     

Phase II trial of adjuvant pelvic radiation "sandwiched" between combination paclitaxel and carboplatin in women with uterine papillary serous carcinoma

Objective

To evaluate the safety and survival in women treated with adjuvant pelvic radiation “sandwiched” between six cycles of paclitaxel and carboplatin chemotherapy with completely resected UPSC.

Methods

Surgically staged women with UPSC (FIGO stage 1-4) and no visible residual disease were enrolled. Treatment involved paclitaxel (175 mg/m²) and carboplatin (AUC = 6.0-7.5) every 21 days for 3 doses, followed by radiation therapy (RT), followed by an additional 3 cycles of paclitaxel and carboplatin (AUC = 5-6). Survival analysis, using Kaplan-Meier methods, was performed on patients who completed at least 3 cycles of chemotherapy and RT.

Results

A total of 81 patients were enrolled, of which 72 patients completed the first 3 cycles of chemotherapy followed by prescribed RT. Median age was 67 years (range: 43-82 years). 59/72 (82%) had disease confined to the uterus and 13/72 (18%) had completely resected extra-uterine disease (stage 3 and 4). 65 (83%) completed the protocol. Overall PFS and OS for combined stage 1 and 2 patients was 65.5 ± 3.6 months and 76.5 ± 4.3 months, respectively. PFS and OS for combined stage 3 and 4 patients was 25.8 ± 3.0 and 35.9 ± 5.3 months, respectively. Three-year % survival probability for stage 1 and 2 patients was 84% and for stage 3 and 4 patients was 50%. Of the 435 chemotherapy cycles administered, there were 11(2.5%) G3/G4 non-hematologic toxicities. 26(6.0%) cycles had dose reductions and 37(8.5%) had dose delays.

Conclusions

Compared to prior studies of single modality adjuvant therapy, RT “sandwiched” between paclitaxel and carboplatin chemotherapy is well-tolerated and highly efficacious in women with completely resected UPSC.     

Phase II study of irinotecan in combination with bevacizumab in recurrent ovarian cancer

Objectives

To evaluate the efficacy and safety of irinotecan and bevacizumab in recurrent ovarian cancer. The primary objective was to estimate the progression free survival (PFS) rate at 6 months. Secondary objectives included estimation of overall survival (OS), objective response rate (ORR), duration of response, and an evaluation of toxicity.

Exploratory outcome analyses according to stage and/or residual disease in the ICON7 trial of carboplatin and paclitaxel with or without bevacizumab for newly diagnosed ovarian cancer

Objective

In the randomized phase 3 ICON7 trial (ISRCTN91273375), adding bevacizumab to chemotherapy for newly diagnosed ovarian cancer significantly improved progression-free survival (PFS; primary endpoint) but not overall survival (OS; secondary endpoint) in the intent-to-treat (ITT) population. We explored treatment effect according to stage and extent of residual disease.

Phase III trial of induction gemcitabine or paclitaxel plus carboplatin followed by paclitaxel consolidation in ovarian cancer

Objective

The safety and efficacy of gemcitabine plus carboplatin (GC) or paclitaxel plus carboplatin (TC) induction regimens with or without paclitaxel consolidation therapy were assessed in ovarian cancer (OC).

Methods

Patients with stage IC-IV OC were randomized to either GC (gemcitabine 1000 mg/m², days 1 and 8, plus carboplatin area under the curve [AUC] 5, day 1) or TC (paclitaxel 175 mg/m² plus carboplatin AUC 6, day 1) every 21 days for up to six cycles. Patients with complete response (CR) were allowed optional consolidation with paclitaxel 135 mg/m² every 28 days for ≤ 12 months. Patients without CR received single-agent crossover therapy at induction doses/schedules until CR, disease progression (PD), or unacceptable toxicity. PD or death in 636 patients was required to compare induction arms with 80% statistical power for progression-free survival (PFS), the primary endpoint.

Results

Randomized induction therapy was received by 820 of 919 patients enrolled; 352 patients with CR received paclitaxel consolidation whereas 155 patients without CR received single-agent crossover therapy. PFS was similar for GC and TC (median, 20.0 and 22.2 months, respectively; P = .199). Despite high censoring rates (> 52%), overall survival was longer for TC (median, 57.3 versus 43.8 months for GC; P = .013). Controlling for patient characteristics including performance status, residual tumor size, and tumor stage, there was no statistical difference in a multivariate analysis (HR = 1.22; 95% CI = 0.99-1.52; P = .067).

Conclusions

GC does not improve PFS over TC as first-line induction chemotherapy in OC. Although favoring TC, overall survival analyses were limited by the study design and high censoring rates.     

A phase I study with an expanded cohort to assess the feasibility of intravenous paclitaxel, intraperitoneal carboplatin and intraperitoneal paclitaxel in patients with untreated ovarian, fallopian tube or primary peritoneal carcinoma: a Gynecologic Oncology Group study

Objective

To define the maximum tolerated dose (MTD) and assess the feasibility of intravenous (IV) paclitaxel, intraperitoneal (IP) carboplatin, and IP paclitaxel in women with newly diagnosed Stages II-IV ovarian, fallopian tube, or primary peritoneal carcinoma.

Methods

Patients received escalating doses of paclitaxel IV and carboplatin IP on day 1 and paclitaxel IP 60 mg/m² on day 8. A standard 3 + 3 design was used in the escalation phase. A two-stage group sequential design with 20 patients at the MTD was used in the feasibility phase. Patient-reported neurotoxicity was assessed pre and post treatment.

Results

Patients were treated with paclitaxel 175 mg/m² IV and carboplatin IP from AUC 5-7 on day 1 and paclitaxel 60 mg/m² IP on day 8. The MTD was estimated at carboplatin AUC 6 IP and 25 patients enrolled at this dose level. Within the first 4 cycles, seven (35%) of twenty evaluable patients had dose-limiting toxicities (DLTs) including grade 4 thrombocytopenia (1), grade 3 neutropenic fever (3), > 2 week delay due to ANC recovery (1), grade 3 LFT (1), and grade 3 infection (1). De-escalation to paclitaxel 135 mg/m² IV was given to improve the safety. After six evaluable patients completed 4 cycles without a DLT, bevacizumab was added and six evaluable patients completed 4 cycles with one DLT (grade 3 hyponatremia).

Conclusions

Paclitaxel at 175 mg/m² IV, carboplatin AUC 6 IP day 1 and paclitaxel 60 mg/m² IP day 8 yield 18-56% patients with DLTs. The tolerability of the regimen in combination with bevacizumab was indicated in a small cohort.     

奥先达联合紫杉醇或卡铂联合紫杉醇治疗卵巢上皮癌的多中心随机对照初步研究

目的:比较奥先达联合紫杉醇或卡铂联合紫杉醇治疗卵巢上皮癌的疗效和安全性。方法:2010年8月到2012年4月入组了Ⅱ期以上行满意的肿瘤细胞减灭术的卵巢上皮癌患者182例。术后将患者随机分为奥先达组(92例)和卡铂组(90例),分别采用奥先达或卡铂联合紫杉醇方案治疗。奥先达剂量80mg/m2,或卡铂AUC=5,第2天给药;紫杉醇135mg/m2,第1天给药,21天1个疗程。研究两组患者治疗的近期疗效和药物安全性。结果:奥先达组、卡铂组患者完成的治疗周期数分别为5.02±1.63和5.39±1.30。奥先达组化疗第3、6个周期结束时,CA125下降到正常水平的比率分别为80.00%和86.36%,卡铂组为72.88%和86.00%,两组比较均无统计学差异;治疗后两组患者的KPS、QOL评分均明显改善,但两组间比较无统计学差异。奥先达组恶心呕吐发生率为3.26%,卡铂组为5.56%;奥先达组和卡铂的Ⅲ～Ⅳ度白细胞减少的发生率分别为10.87%和23.33%,两组差异有统计学意义(P<0.05);两组的其他毒性反应发生率无统计学差异(P>0.05)。结论:奥先达联合紫杉醇治疗卵巢上皮癌近期疗效与卡铂方案相似,但其毒副反应较轻,患者耐受性好。     

A phase II study of gemcitabine in combination with tanespimycin in advanced epithelial ovarian and primary peritoneal carcinoma

Objective

To evaluate the efficacy and biological effects of the gemcitabine/tanespimycin combination in patients with advanced ovarian and peritoneal cancer. To assess the effect of tanespimycin on tumor cells, levels of the chaperone proteins HSP90 and HSP70 were examined in peripheral blood mononuclear cells (PBMC) and paired tumor biopsy lysates.

Methods

Two-cohort phase II clinical trial. Patients were grouped according to prior gemcitabine therapy. All participants received tanespimycin 154 mg/m² on days 1 and 9 of cycle 1 and days 2 and 9 of subsequent cycles. Patients also received gemcitabine 750 mg/m² on day 8 of the first treatment cycle and days 1 and 8 of subsequent cycles.

Results

The tanespimycin/gemcitabine combination induced a partial response in 1 gemcitabine naïve patient and no partial responses in gemcitabine resistant patients. Stable disease was seen in 6 patients (2 gemcitabine naïve and 4 gemcitabine resistant). The most common toxicities were hematologic (anemia and neutropenia) as well as nausea and vomiting. Immunoblotting demonstrated limited upregulation of HSP70 but little or no change in levels of most client proteins in PBMC and paired tumor samples.

Conclusions

Although well tolerated, the tanespimycin/gemcitabine combination exhibited limited anticancer activity in patients with advanced epithelial ovarian and primary peritoneal carcinoma, perhaps because of failure to significantly downregulate the client proteins at clinically achievable exposures.     

Phase II study of carboplatin followed by sequential gemcitabine and paclitaxel as first-line treatment for advanced ovarian cancer

The aim of this exploratory phase II study was to evaluate sequential chemotherapy with carboplatin followed by gemcitabine-paclitaxel combination in chemonaive patients with advanced ovarian cancer. The primary objective was to evaluate time to progressive disease (TTPD); secondary objectives included the evaluation of 1- and 3-year survival, response rates, and toxicity. Following initial debulking surgery or biopsy, patients with FIGO stage IIC-IV disease received four cycles of carboplatin area under the curve (AUC) 6 (day 1) every 21 days, followed by four cycles of gemcitabine 1000 mg/m(2) (days 1 and 8) and paclitaxel 175 mg/m(2) (day 8) every 21 days. A total of 47 patients enrolled, 44 (93.6%) completed the initial four cycles, and 39 patients (82.9%) completed the planned eight cycles. The median and maximum lengths of follow-up were 31.2 and 43.7 months, respectively. Median TTPD was 13.8 months (95% CI, 11.6-21.0 months), and median survival time was 31.2 months (95% CI, 25.2-39.6 months). Survival at 1 and 3 years was 95.7% and 44.2%, respectively. Of the 43 evaluable patients, most (95.3%) of them achieved a CA-125 marker response based on Gynecologic Cancer Intergroup (GCIG) definition. The partial response rate in the seven patients with measurable disease was 46.4%. Myelosuppression was the major toxicity, with grade 3 and 4 neutropenia observed in 76.6% patients and thrombocytopenia in 12.8% patients. The sequential approach of carboplatin followed by gemcitabine-paclitaxel as first-line treatment for patients with ovarian cancer is feasible and well tolerated, and depending upon the findings from other major trials, it may merit further evaluation.     

Pilot study of outpatient paclitaxel, carboplatin and gemcitabine for advanced stage epithelial ovarian, peritoneal, and fallopian tube cancer

OBJECTIVE: The purpose of this study was to determine the feasibility, response rate, and toxicity of paclitaxel, carboplatin, and gemcitabine as an outpatient regimen in the treatment of ovarian/non-ovarian and tubal adenocarcinoma. This is the largest completed study using this regimen as first-line treatment of these patients. METHODS: Following cytoreductive surgery, eligible patients were initially treated with paclitaxel (175 mg/m(2) via 1 h infusion), carboplatin (AUC = 5), and gemcitabine (800 mg/m(2)) as an outpatient every 21 days. Gemcitabine (800 mg/m(2)) was repeated on day 8. After six cycles of treatment, responders were eligible for an additional three cycles of paclitaxel and gemcitabine. Colony-stimulating factors were used at the discretion of the treating physician. RESULTS: Fifty-seven patients (median age = 58; range 41-81) with stage III/IV epithelial carcinoma of the ovary, fallopian tube, and peritoneum received a total of 476 cycles of chemotherapy. Grades 3 and 4 neutropenia developed in 19.7% and 9% of cycles while grades 3 and 4 thrombocytopenia developed in 4.2% and 1.3% of the cycles. One hundred thirty-seven (28.8%) cycles of a possible 476 cycles of gemcitabine were delayed primarily due to grades 3 and 4 neutropenia. Forty-five (84.9%) patients exhibited a complete response and three (5.7%) patients demonstrated a partial response, for a total response rate of 90.4%. Twenty-two patients developed some degree of neuropathy, although there was no reported interference with activities of daily living. The patients' median progression-free interval and median overall survival was 15.5 and 40.8 months, respectively. Forty-one of the original 57 patients were alive at the conclusion of data collection. CONCLUSIONS: This report represents the largest completed study in the world employing this triplet regimen in the first-line treatment of advanced stage epithelial ovarian, fallopian tube, or peritoneal cancer patients. Although the study exhibited a high response rate, the neuropathy encountered in the study, and the need to eliminate gemcitabine in 54% of the patients due to bone marrow suppression merits further investigation of the dosing schedule. More recent gemcitabine data suggest that lower doses and a 2-week regimen may be as effective with less toxicity. A comparison of our results with the GOG-0182 study, that utilizes the same regimen, should be informative.     

A phase II study of outpatient first-line paclitaxel, carboplatin, and bevacizumab for advanced-stage epithelial ovarian, peritoneal, and fallopian tube cancer

The purpose of this study was to assess the response rate and toxicity of paclitaxel, carboplatin, and bevacizumab (PCB) primary induction therapy for the treatment of advanced-stage ovarian carcinoma. Twenty patients were treated with paclitaxel (175 mg/m(2)), carboplatin (AUC of 5 IV), and bevacizumab (15 mg/kg) of body weight; q21 days for six cycles. Bevacizumab was administered at cycles two through six. Patients received 116 cycles of PCB chemotherapy (median = 6, range 2-6) and were evaluable for toxicity assessment. Grade 3 and 4 neutropenia developed in 23.3% and 25% of cycles, with no incidence of grades 3/4 thrombocytopenia or anemia. Prior to cycle six, one patient was removed from the study due to grade 3 neuropathy and another patient was excluded due to clinical deterioration. There was no incidence of gastrointestinal perforations, and only two patients demonstrated grade 3 hypertension (HTN). No grade 4 HTN was observed. Eighteen patients were evaluated for response following induction therapy. Six demonstrated a complete response (30%) and ten exhibited a partial response (50%), resulting in a total response rate of 80%. One patient exhibited stable disease (5%), and one demonstrated disease progression (5%). The lack of bowel perforations and wound complications should mitigate some concerns regarding these side effects. This study suggests that first-line treatment with PCB can be safely administered to previously untreated advanced-stage ovarian carcinoma patients. The favorable toxicity results and reasonable response rate warrant additional study in a larger patient population.     

A phase I study with an expanded cohort to assess the feasibility of intraperitoneal carboplatin and intravenous paclitaxel in untreated ovarian, fallopian tube, and primary peritoneal carcinoma: A Gynecologic Oncology Group study

Objective

This study aimed to determine the first-cycle maximum tolerated dose (MTD) of intraperitoneal carboplatin in combination with intravenous paclitaxel and then assess the feasibility of this dose over multiple cycles.

Methods

Beginning at an intraperitoneal (IP) carboplatin dose area under the curve (AUC) of 5 and a fixed intravenous dose of 175 mg/m² paclitaxel, patients were entered on a dose-escalating phase evaluating first-cycle dose-limiting toxicity (DLT). After estimating the MTD, cohorts of 20 patients were then entered in an expanded phase to evaluate DLT over four cycles.

Results

Twenty-one patients were entered on the dose-escalating phase. A first-cycle MTD of carboplatin at AUC 8 was tolerated although thrombocytopenia was dose-limiting over multiple cycles. An additional 69 patients were treated in expanded cohorts. Only 5/90 (5.6%) patients discontinued treatment because of a port problem. Four-cycle DLT required de-escalation to a carboplatin AUC of 6, and even at that dose, there were 14 dose-limiting toxic effects in 40 patients (35%). Seven dose-limiting toxicities were due to neutropenia, and 6 were due to grade 3/4 thrombocytopenia. Six cycles of therapy were completed in 75% of eligible patients, but dose adjustments were required.

Conclusions

The first-cycle MTD did not predict the tolerability of this regimen over multiple cycles. Using an IP carboplatin dose of AUC 6 in combination with paclitaxel, the regimen can be administered with a high completion rate over multiple cycles. Because neutropenia is a frequent DLT, the addition of hematopoietic growth factors may permit a high completion rate while maintaining this dose.