Phase I study of alternating doublets of topotecan/carboplatin and paclitaxel/carboplatin in patients with newly diagnosed, advanced ovarian cancer

OBJECTIVE: The aim of this study was to evaluate topotecan with carboplatin in an alternating doublet with carboplatin and paclitaxel in first-line ovarian cancer. METHODS: Patients with newly diagnosed stage III/IV ovarian cancer were studied. The maximum tolerated dose (MTD) of topotecan (cycles 1, 3, 5, 7) in an alternating doublet regimen was determined through standard dose escalation in cohorts of three; doses of carboplatin (area under the curve [AUC] 4 to 5) and paclitaxel (175 mg/m(2), cycles 2, 4, 6, 8) were fixed. Dose-limiting toxicity (DLT) was defined only for cycle 1 as febrile neutropenia, prolonged grade 4 granulocytopenia, grade 4 thrombocytopenia, > or =grade 3 nonhematologic toxicity, or failure to recover in < or =7 days. The use of granulocyte colony-stimulating factor (G-CSF) to permit further dose escalation was also studied. RESULTS: Thirty-seven patients received 142 cycles of topotecan/carboplatin. Hematologic DLTs included grade 4 neutropenia (59 events, 42% of cycles) and thrombocytopenia (32 events, 23% of cycles). Granulocytopenia was generally short-lived, and only 2 cases of febrile neutropenia occurred. The MTD was 1.0 mg/m(2)/day topotecan and carboplatin AUC 4, alternating with 175 mg/m(2) paclitaxel and carboplatin AUC 4. Although G-CSF effectively managed myelosuppression, thrombocytopenia developed in later cycles, limiting further topotecan dose escalation. The median progression-free survival was 20.5 months, and elevated pretreatment CA-125 levels normalized in 29 of 34 (85%) patients. CONCLUSION: The establishment of a reasonably well-tolerated alternating doublet regimen, coupled with evidence of antitumor activity, provides the basis for further investigation of topotecan in first-line therapy of ovarian cancer. Topotecan (1.0 mg/m(2) daily for 3 days) was chosen for further evaluation in a phase II study.     

Phase II study of sequential doublets: topotecan and carboplatin, followed by paclitaxel and carboplatin, in patients with newly diagnosed advanced ovarian cancer

OBJECTIVE: Incorporating topotecan into standard platinum/taxane chemotherapy for advanced ovarian cancer has been complicated by myelosuppression. This study evaluated sequential doublets of topotecan and carboplatin, followed by paclitaxel and carboplatin, in newly diagnosed advanced ovarian cancer patients. METHODS: Forty-five patients (median age, 56 years; range, 38-77 years) with stage III/IV disease and GOG performance status <2 were enrolled and received four cycles of topotecan (1.0 mg/m(2)/day on days 1 to 3) and carboplatin (AUC 4 on day 1), followed by four cycles of paclitaxel (175 mg/m(2) via 3-h IV infusion on day 1) and carboplatin (AUC 5 on day 1). All cycles were 21 days. Antitumor response was assessed after four and eight cycles; patients with clinical complete response (CR) underwent second-look laparotomy for determination of pathologic CR (PCR). Dose reductions were instituted for grade 4 neutropenia and thrombocytopenia, and for grade 3/4 nonhematologic toxicity. RESULTS: Among 41 CA-125 evaluable patients, complete and partial responses were observed in 29 (70.7%) and 11 (26.8%) patients, respectively. Of the 12 clinical CRs (43%) in 28 evaluable patients, 10 patients underwent second-look laparotomy, with 3 PCRs (30%). Median time to progression was 14 months and actuarial survival was 23 months. Neutropenia was the primary toxicity and cause of dose adjustments and delays, including two deaths. CONCLUSION: The antitumor activity observed is comparable with other series, although neutropenic complications were increased. Progression-free and actuarial survivals were slightly inferior. A Phase III trial (GOG 182) of sequential doublets in the reverse sequence is ongoing.     

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.     

Phase I feasibility trial of carboplatin, paclitaxel, and gemcitabine in patients with previously untreated epithelial ovarian or primary peritoneal cancer: a Gynecologic Oncology Group study

PURPOSE: To determine the feasibility of administering a minimum of four cycles of carboplatin, paclitaxel, and gemcitabine (CPG) every 21 days without excessive dose modification or cycle delay in patients with previously untreated epithelial ovarian cancer or primary peritoneal cancer. METHODS: Paclitaxel 175 mg/m(2) was given over 3 h followed by carboplatin concentration time curve (AUC) 5 (day 1) and gemcitabine 1 g/m(2) (days 1 and 8) in the first cohort. A second cohort received paclitaxel 135 mg/m(2) over 3 h followed by carboplatin AUC 5 (day 1) and gemcitabine 800 mg/m(2) (days 1 and 8). A maximum of eight cycles was administered. RESULTS: Fourteen patients received 89 cycles during the first cohort. Seven patients experienced 19 hematologic dose-limiting events (DLEs) within the first four cycles, including grade 4 thrombocytopenia (n = 9), febrile neutropenia (n = 3), and omission of gemcitabine on day 8 (n = 7). This exceeded the threshold for nonfeasibility. In the second, less intense regimen, 36 patients were entered. Thirty-one evaluable patients received a total of 200 and median of 6 (range: 2-8) cycles. Thirteen of the thirty-one had 27 DLEs within the first four cycles including grade 4 thrombocytopenia (n = 5), prolonged grade 4 neutropenia (n = 2), febrile neutropenia (n = 2), and omission of day 8 gemcitabine (n = 18). There was one patient death secondary to a wound abscess and febrile neutropenia. Myelosuppression as expected was the dose-limiting toxicity. CONCLUSION: The schedule of paclitaxel 135 mg/m(2) (day 1, 3 h), carboplatin AUC 5 (day 1), and gemcitabine 800 mg/m(2) (days 1 and 8) is feasible, with an acceptable toxicity profile.     

Experience with single-agent paclitaxel consolidation following primary chemotherapy with carboplatin, paclitaxel, and gemcitabine in advanced ovarian cancer

OBJECTIVE: Twelve cycles of single-agent paclitaxel have been demonstrated to prolong progression-free survival in women with advanced ovarian cancer whom achieved a clinical complete response to a primary platinum/paclitaxel chemotherapy regimen. This trial was conducted to compare the toxicity and disease-free interval of 3 cycles vs. 12 cycles of paclitaxel consolidation in patients treated with an intensive three-drug front-line regimen of carboplatin, paclitaxel, and gemcitabine. METHODS: Following cytoreductive surgery, 26 ovarian cancer patients received primary chemotherapy with carboplatin (AUC = 5, day 1), paclitaxel (175 mg/m(2) over 1 h, day 1), and gemcitabine (800 mg/m(2), day 1 day 8), with treatment repeated every 21 days x 6 cycles. The first 13 patients (group A) received three additional cycles of paclitaxel (175 mg/m(2) over 1 h every 21 days). The second set of 13 patients (group B) also received three cycles of paclitaxel (175 mg/m(2) over 1 h every 21 days) and then received nine additional cycles of paclitaxel (135 mg/m(2) over 1 h every 21 days) consolidation therapy. The change from 3 cycles to 12 cycles of consolidation therapy for group B was made following the published results of GOG 178. RESULTS: In group A, all 13 patients completed three courses of consolidation therapy. One patient experienced grade 3 neutropenia and two patients exhibited both grade 4 neutropenia and thrombocytopenia. Grade > or = 2 neuropathy developed in 3 patients (23%). In group B, 9 of the 13 patients whom were intended to receive 12 total cycles of paclitaxel consolidation were able to complete the program. There was no grade 3-4 neutropenia or anemia in this population, although 1 patient developed grade 3 thrombocytopenia. Grade > or = 2 neuropathy developed in 7 patients (54%). Although not a randomized experience, median progression-free interval was 76 weeks for group B, and 47 weeks for group A. CONCLUSION: Single-agent paclitaxel consolidation therapy can be administered for 12 cycles following first-line carboplatin, paclitaxel, and gemcitabine induction therapy, but there is considerable risk for development of a moderately severe peripheral neuropathy.     

Phase I/II study of tandem cycles of high-dose chemotherapy followed by autologous hematopoietic stem cell support in women with advanced ovarian cancer

The objectives of this study were to investigate the tolerability of a novel high-dose chemotherapy (HDC) regimen with peripheral blood progenitor cell (PBPC) support in patients with pretreated advanced ovarian cancer and to determine the maximum-tolerated dose (MTD) of topotecan in this setting. Advanced ovarian cancer patients previously treated with platinum-based first-line therapy were enrolled. After PBPC mobilization and harvesting, patients received three consecutive cycles of HDC with PBPC support. Cycle 1 was carboplatin area under the concentration curve 20 and paclitaxel 250 mg/m(2). Cycle 2 was topotecan starting at 5 mg/m(2), dose escalated in 2 mg/m(2) increments, and etoposide 600 mg/m(2). Cycle 3 was thiotepa 500 mg/m(2). After each cycle, PBPCs were infused. Granulocyte colony stimulating factor (5 microg/kg/day) was administered until neutrophil recovery occurred. Seventeen patients were enrolled; all were safety evaluable. The most common nonhematologic toxicity was grade 3 mucositis (44%). Engraftment of PBPCs was successful in all patients after each cycle, and no treatment-related deaths occurred. Of 14 patients with measurable disease, 5 (36%) had complete responses, 2 (14%) had partial responses, and 4 (29%) had stable disease. The median progression-free and overall survivals were 7 and 18 months, respectively. The MTD of topotecan was not reached. The tolerability and activity of this regimen in patients with advanced ovarian cancer warrant further investigation.     

The addition of topotecan to carboplatin and paclitaxel as first-line therapy for advanced ovarian cancer; is it possible only with peripheral blood stem cell support?

A phase I study was performed in order to evaluate the tolerability of the combination of fixed doses of carboplatin and paclitaxel and escalated doses of topotecan as first line chemotherapy for advanced epithelial ovarian cancer. Three stage III and one stage IV patients entered the study. The dose limiting toxicity (neutropenia and thrombocytopenia) was reached at the first dose level: paclitaxel 175 mg/m2 on day 1, carboplatin AUC 5 on day I and topotecan 0.5 mg/m2 daily from day 1 to day 3. We conclude that it is not possible to add topotecan to standard regimens of carboplatin and paclitaxel without bone marrow support.     

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.     

A phase I/II trial of weekly topotecan and carboplatin in potentially platinum-sensitive relapsed ovarian and peritoneal carcinoma

OBJECTIVE: Topotecan and carboplatin are active in relapsed ovarian cancer, but attempts to combine these agents are limited by myelotoxicity. This phase I/II trial combined weekly topotecan, which is less myelosuppressive than the standard 5-day regimen, with carboplatin in patients with potentially platinum-sensitive relapsed ovarian or peritoneal carcinoma (PS-OVCa/PCa). METHODS: Eligible patients had PS-OVCa/PCa, performance status 0-2, and normal bone marrow, renal, and hepatic functions. On day 1 of a 21-day cycle, patients received carboplatin (area under the curve [AUC] 5) followed by topotecan 2.0 mg/m2, both via 30-min intravenous infusion. Topotecan 2.0 mg/m2 also was administered on days 8 and 15. Treatment was withheld for neutropenia or thrombocytopenia on day 8 or 15. Dose escalation was planned. RESULTS: Seventeen patients received a total of 115 (median, 6) cycles of chemotherapy. With carboplatin AUC 4, neutropenia prevented dose escalation of topotecan; hematologic toxicity caused 34/105 (32%) weekly treatments to be withheld. However, carboplatin could be dose escalated to AUC 5 when the day 15 dose of topotecan was withheld. In the intent-to-treat population, there were 4 (24%) complete and 9 (53%) partial responses, 2 (12%) patients (at the carboplatin AUC 4 dose) with stable disease, and 2 (12%) nonevaluable patients. CONCLUSION: Carboplatin (AUC 5) on day 1 in combination with topotecan 2.0 mg/m2 on days 1 and 8 of a 21-day cycle is well tolerated and active in patients with PS-OVCa/PCa. A phase II trial comparing this with other carboplatin therapeutic doublets in patients with recurrent ovarian cancer is warranted.     

Paclitaxel, carboplatin and pegylated liposomal doxorubicin in ovarian and peritoneal carcinoma: a phase I study of the Gynecologic Oncology Group

PURPOSE: Based on the activity and tolerability of liposomal doxorubicin in platinum- and paclitaxel-resistant ovarian carcinoma, we conducted a phase I trial of pegylated liposomal doxorubicin with paclitaxel and carboplatin to determine the maximum tolerated dose (MTD) in chemotherapy naive ovarian, peritoneal and tubal carcinoma patients. METHODS: Three schedules were studied: paclitaxel, carboplatin and pegylated liposomal doxorubicin every 28 days; paclitaxel and carboplatin every 21 days with liposomal doxorubicin every 42 days; and weekly paclitaxel, carboplatin (AUC=5) every 21 days and liposomal doxorubicin every 42 days. The paclitaxel dose was 175 mg/m(2) over 3 h on an every 3-4 week schedule and 60 mg/m(2) when administered weekly. Based on the frequency of neutropenic sepsis, grade 4 thrombocytopenia and > or =grade 3 non-hematologic toxicity, the starting dose of liposomal doxorubicin of 20 mg/m(2) was escalated to determine the MTD. RESULTS: A total of 210 (21-day) cycles were administered to 37 patients. Dose-limiting toxicity (DLT) occurred when liposomal doxorubicin was administered at 40 mg/m(2). Because of treatment-related delays resulting in decreased paclitaxel/carboplatin dose intensity, administration was modified to be given every 21 days, with liposomal doxorubicin given every 42 days. Since neutropenia was the DLT of this schedule, the schema was further modified to administer paclitaxel weekly; however, weekly administration was inconsistent because of toxicity. CONCLUSION: Paclitaxel 175 mg/m(2), carboplatin (AUC=5) and pegylated liposomal doxorubicin 30 mg/m(2) are tolerable without supportive therapy. The usual dose intensity of paclitaxel/carboplatin was maintained by administering liposomal doxorubicin every other cycle.     

Gemcitabine and oxaliplatin followed by paclitaxel and carboplatin as first line therapy for patients with suboptimally debulked, advanced epithelial ovarian cancer. A phase II trial of sequential doublets. The GO-First Study

OBJECTIVES: Gemcitabine and oxaliplatin are active in epithelial ovarian cancer with minimal overlapping toxicity. We studied the efficacy and toxicity of this combination in patients with advanced ovarian cancer when given prior to carboplatin and paclitaxel. METHODS: Chemonaive patients with epithelial ovarian cancer and measurable disease were eligible for the study. Treatment consisted of gemcitabine 1250 mg/m2 on days 1 and 8 and oxaliplatin 130 mg/m2 on day 8 every 21 days (GO) for 4 cycles. This was followed by carboplatin AUC = 6 and paclitaxel 175 mg/m2 on day 1 every 21 days (CP) for 4 cycles. RESULTS: Twenty patients, median age 62 years (range 39-78), FIGO stages III (16) and IV (4) received treatment. The response rate (RR) after 4 cycles of GO was 80% (95%CI 61-99%) (4 complete responses (CR), 12 partial responses (PR)). Interval debulking surgery was performed in 7 patients (35%). After CP chemotherapy, RR increased to 85% (95%CI 68-100%) (CR = 13, PR = 4). Median time to progression was 14.5 months. Estimated median overall survival was 31.5 months. Toxicities of GO were mild; grade 3/4 nausea in 3 patients (15%) and vomiting in 2 patients (10%), grade 3/4 neutropenia in 5 patients (25%). Grade 2/3 peripheral neuropathy occurred in 5 patients (25%). After sequential administration of CP, grade 2/3 neuropathy occurred in 13 patients (72%). CONCLUSION: The sequential doublet regimen of GO followed by CP resulted in unacceptable neurotoxicity and is not recommended for further study; however, the doublet gemcitabine and oxaliplatin has significant activity in the first line treatment of patients with ovarian cancer.     

Preliminary toxicity analysis of intraperitoneal carboplatin in combination with intravenous paclitaxel chemotherapy for patients with carcinoma of the ovary, peritoneum, or fallopian tube

The objective of this study was to provide preliminary toxicity data of multiple-cycle combination chemotherapy with intraperitoneal (IP) carboplatin and intravenous (IV) paclitaxel for further clinical trials. The toxicity data of 42 patients with mullerian carcinoma who underwent IP carboplatin therapy in combination with IV paclitaxel were retrospectively analyzed. Chemotherapy was repeated through the Bard IP port placed at initial surgery using IV paclitaxel at 175 mg/m2 followed by IP carboplatin. The doses of carboplatin were either at area under the curve (AUC) = 5, 6, 6.5, 7, or 7.5. The toxicity data in a total of 237 cycles were analyzed. The median number of cycles for IP chemotherapy was 6 (range: 3-12). The incidences of maximal grade toxicities in all cycles were: grade (G)2/3 nausea/vomiting, 23.8%; G2/3 constipation, 42.9%; G2 abdominal pain, 28.6%; G2/3 sensory neuropathy, 14.3%; motor neuropathy, 4.8%; myalgia/arthralgia 33.4%; G3/4 neutrocytopenia, 85.4%; and G3/4 anemia, 35.4%. These were not related to the dose of carboplatin. The incidences of G3 thrombocytopenia in relation to the dose of carboplatin were AUC = 5, 0%; 6, 31.6%; 6.5, 44.4%; 7, 25.0%; and 7.5, 80%. G4 thrombocytopenia did not occur. A dose of carboplatin between AUC = 6 and 7 with IV paclitaxel at 175 mg/m2 is warranted for further evaluation.     

Bevacizumab, paclitaxel and carboplatin for advanced ovarian cancer: low risk of gastrointestinal and cardiovascular toxicity

The purpose of this preliminary study was to retrospectively assess the incidence of bowel perforation and hypertension in two separate advanced ovarian cancer patient populations following first-line therapy, comprising paclitaxel, carboplatin and bevacizumab. The first 20 patients were treated with six cycles of paclitaxel (175 mg/m2), carboplatin (AUC of 5 i.v.), and bevacizumab (15 mg/kg of body weight); q21 days per an independent protocol. The subsequent patients (n = 12) were administered weekly paclitaxel (80 mg/m2), carboplatin (AUC of 5 i.v.) every four weeks, and bevacizumab (10 mg/kg of body weight) every two weeks for six cycles according to a separate, independent protocol. Bevacizumab was not added to either chemotherapy regimen until cycle 2. In both groups patients who achieved a complete response, partial response or stable disease at the conclusion of induction therapy received bevacizumab (10 mg/kg) and paclitaxel (135 mg/m2) q21 days as maintenance therapy. A total of 170 cycles (median = 6; range 3-6) of primary induction chemotherapy, 140 of which contained bevacizumab, were administered. Moreover, 206 cycles (median = 9; range 1-12) of maintenance chemotherapy have been delivered to 28 patients thus far. There was no incidence of GI perforation and only two patients demonstrated clinically significant hypertension. Previous studies involving bevacizumab have raised concerns regarding bowel perforations and hypertension. However, we did not encounter difficulties with either of these complications. While we recognize that the risk for bowel perforation remains in the 5-11% range, the study's preliminary results suggest that first-line treatment of advanced stage ovarian carcinoma with bevacizumab can be safely administered.     

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.     

Triplet combination of gemcitabine, carboplatin, and paclitaxel in previously treated, relapsed ovarian and peritoneal carcinoma: an experience in Taiwan

OBJECTIVE: The aim of this phase II study was to evaluate the efficacy and toxicity of gemcitabine, carboplatin, and paclitaxel (GCP) combination as salvage therapy in patients with relapsed ovarian or peritoneal cancer who had previously received platinum-based chemotherapy. PATIENTS AND METHODS: Patients with progressive ovarian or peritoneal carcinoma who had previously received platinum-based chemotherapy were enrolled. Gemcitabine was administered at 800 mg/m(2) as a 30-min intravenous infusion on days 1 and 8; carboplatin (AUC of 5) and paclitaxel (175 mg/m(2)) were administered as 60-min and 3-h intravenous infusions, respectively, on day 1. Treatment cycles were repeated every 3 weeks for a maximum of nine cycles. RESULTS: Twenty patients (ovarian carcinoma, 19; peritoneal carcinoma, 1) received this triplet regimen as salvage therapy. All the patients had previously received at least one platinum-based regimen for chemotherapy and 17 of them had received platinum plus paclitaxel. The median number of previous regimens was 2 (range, 1-4), and the median platinum-free interval was 9 months (range, 1-18). A total of 130 cycles were administered with a median of six cycles per patient (range, 3-9). The overall response rate was 75%, including 12 complete responses (60%; 95% confidence interval [CI], 36.1-80.9) and three partial responses (15%; 95% CI, 3.2-37.9). The other five patients showed stable disease (25%; 95% CI, 8.7-49.1). The median duration of the progression-free survival was 6.5 months (range, 3-20). Myelosuppression was the main toxicity, with leukopenia being the most prominent (grade 3/4 toxicity in 35% patients), followed by thrombocytopenia in 20% patients. In addition, 35% patients had grade 3 anemia. All the toxicities were manageable and the patients recovered fully. Among non-hematological toxicities, the only notable one was grades 2 and 3 hepatic toxicity seen in two and one patients, respectively, necessitating a decrease in the paclitaxel dose in two patients. CONCLUSIONS: GCP combination is an effective salvage chemotherapy in patients with heavily pretreated and relapsed ovarian and peritoneal cancer. The significant side effects of myelosuppression and hepatic toxicity were of moderate severity and manageable.     

卡铂联合紫杉醇方案中不同药物剂量对骨髓抑制的影响

目的 探讨卡铂联合紫杉醇(TC)方案中不同药物剂量对卵巢癌患者骨髓抑制的影响.方法 回顾性分析2002年1月至2007年12月间在北京妇产医院妇瘤科采用TC方案化疗的卵巢癌患者62例(共196个疗程)的骨髓抑制情况.卡铂剂量的确定:以血浆浓度-时间曲线下面积(AUC)4～6为卡铂低剂量(147个疗程),AUC>6～7为卡铂高剂量(49个疗程);紫杉醇剂量的确定:以135～<150 mg/m2为紫杉醇低剂量(37个疗程),150～175 mg/m2为紫杉醇高剂量(159个疗程).根据每个疗程后血常规检查结果 确定骨髓抑制程度,采用x2检验(单因素分析)及logistic回归法(多因素分析)分析影响骨髓抑制的相关因素,包括年龄、身高、体质量、体表面积、病理分化程度、病理类型、手术病理分期、血清肌酐浓度、内生肌酐清除率、出现骨髓抑制的疗程序列数(疗程数)、卡铂剂量、紫杉醇剂量;并采用x2检验分析TC方案中不同卡铂和紫杉醇剂量对骨髓抑制的影响.结果 (1)骨髓抑制情况:轻度骨髓抑制(0～Ⅱ度)共159个疗程,占81.1%;重度骨髓抑制(Ⅲ～Ⅳ度)共37个疗程,占18.9%.(2)影响骨髓抑制的相关因素:单因素分析显示,疗程数、年龄、手术病理分期、血清肌酐浓度、内生肌酐清除率、卡铂剂量是影响骨髓抑制程度的因素(P值分别为0.000、0.000、0.018、0.033、0.001、0.000);而身高、体质量、体表面积、病理分化程度、病理类型和紫杉醇剂量与骨髓抑制程度无关(P均>0.05).多因素分析显示,疗程数、年龄、卡铂剂量是影响骨髓抑制程度的独立危险因素(P值分别为0.030、0.043、0.009).(3)紫杉醇低剂量的疗程中,卡铂高剂量者重度骨髓抑制的发生率(4/14)高于卡铂低剂量者(0),差异有统计学意义(P=0.015);紫杉醇高剂量的疗程中,卡铂高剂量者重度骨髓抑制的发生率(45.7%,16/35)高于卡铂低剂量者(13.7%,17/124),差异有统计学意义(P=0.000).结论 疗程数、年龄、卡铂剂量是影响卵巢癌TC方案化疗患者骨髓抑制的独立危险因素.卡铂剂量选择AUC为4～6、紫杉醇剂量选择135～<150 mg/m2时会明显减少骨髓抑制特别是重度骨髓抑制的发生.

Abstract：

Objective To analyze the relative factors of bone marrow suppression after chemotherapy with different-dose carboplatin and paclitaxel (TC) on the patients with ovarian cancer.Methods Sixty-two patients with ovarian cancer admitted in Beijing Obstetrics and Gynecology Hospital from January 2002 to December 2007, using TC regimen ,a total of 196 cycles of chemotherapy ,were divided into two groups by the doses of carboplatin [area under concentration-time curve(AUC) 4 -6 for low-dose,AUC >6 -7 for hight-dose, the carboplatin dose calculated with AUC] or by the doses of paclitaxel (135 -< 150 mg/m2 low-dose,150 - 175 mg/m2 hight-dose). After each TC cycle, the routine blood was test to determine the graduation of the marrow suppression, and then the correlation factors were analyzed with logistic regression. Results (1) The occurrence rate of bone marrow suppression:there were 159 cycles (81.1%) grade 0 - Ⅱ bone marrow suppression, while 37 cycles (18.9%) of grade Ⅲ - Ⅳ. (2) Factors related to bone marrow suppression:the results shown that there were not related to bone marrow suppression,which incluced cellular differentiation, tumor type, height, weight and paclitaxel dose(P>0.05). While,the different cycle, age, the later stages of tumor, serum creatinine concentration, endogenous creatinine clearance rate, AUC values were the relative factors of bone marrow suppression(P =0.000,0.000,0.018,0.033,0.001,0.000). Seven variables were conducted into the logistic regression and the results shown that the different cycles, the age, AUC grades were independent risk factors (P = 0.030,0.043,0.009).(3) When low-dose of paclitaxel was given, the occurrence of bone marrow suppression was related to the carboplatin dose AUC. The higher AUC values for carbopaltin were chosen, the higher of severe bone marrow suppression would happen. (4/14 vs 0,P=0.015). When the dose of high grade of paclitaxel was given, the occurrence of bone marrow suppression in cases with hight-dose carboplatin was statistically significant than that in cases treated with low-dose carboplatin [45.7%(16/35) vs 13.7% (17/124), P=0.000]. Conclusions The independent risk factors of myelosuppression after chemotherapy with TC regime on the patients with ovarian cancer including the cycles, age and AUC values. The carboplatin dose calculating with AUC is related to the occurrence of bone marrow suppression, the higher AUC values for carbopaltin would chosen,the higher of severe bone marrow suppression would be happen.     

A phase I study of paclitaxel, topotecan, cisplatin and Filgrastim in patients with newly diagnosed advanced ovarian epithelial malignancies: a Gynecologic Oncology Group study

OBJECTIVES: To determine a recommended dose level (RDL) of paclitaxel, cisplatin and topotecan in women with previously untreated epithelial ovarian or peritoneal cancer as a possible experimental arm in a future Gynecologic Oncology Group phase III study. METHODS: Patients with newly diagnosed stage III or IV disease were treated with paclitaxel 175 mg/m2/3 h, followed 2 h later by cisplatin 50 mg/m2 on day 1. Topotecan was administered on consecutive days as a 30-minute infusion, beginning after cisplatin on day 1, receiving either 5 days beginning at 0.3 mg/m2 (cohort 1), or 3 days beginning at 0.5 mg/m2 (cohort 2). Treatment was given every 21 days for a maximum of 8 cycles. RESULTS: Forty-five evaluable patients were enrolled in the two cohorts. Thrombocytopenia and prolonged neutropenia were the major dose-limiting toxicities. Dose-limiting neutropenia was seen at the first dose level, thus all subsequent dose escalations included Filgrastim. The RDL of cohort 1 was paclitaxel 175 mg/m2/3 h, cisplatin 50 mg/m2 and topotecan 0.5 mg/m2 daily x 5 with Filgrastim. The RDL of cohort 2 was paclitaxel 175 mg/m2/3 h, cisplatin 50 mg/m2 and topotecan 0.75 mg/m2 daily x 3 with Filgrastim. CONCLUSION: In women with previously untreated epithelial ovarian or peritoneal cancer the combination of paclitaxel, cisplatin and topotecan is feasible. However, this treatment requires the use of Filgrastim and attenuated dosing of topotecan in both a 5-day and 3-day topotecan infusion schedule.     

High-dose topotecan, melphalan, and cyclophosphamide (TMC) with stem cell support: a new regimen for the treatment of advanced ovarian cancer

OBJECTIVE: The goal of this study was to determine the optimal dose of topotecan when used in combination with high-dose melphalan and cyclophosphamide (TMC), and to assess the toxicity and efficacy of the regimen in patients with advanced ovarian cancer. METHODS: Fifty-three patients with persistent or recurrent ovarian cancer were treated. Disease status at study entry included: platinum-sensitive recurrent disease (15 patients), platinum-resistant or refractory recurrent disease (15 patients), positive second-look surgery (16 patients), failure to achieve a primary clinical complete response (CR) (7 patients). Following stem cell mobilization and collection, patients were given cyclophosphamide 1 g/m(2)/day on Days -6, -5, -4; melphalan 70 mg/m(2)/day on Days -3, -2; and topotecan at escalating doses from 1.25 to 4.0 mg/m(2)/day on Days -6 to -2. Peripheral blood stem cells were infused on Day 0. RESULTS: The optimal topotecan dose selected for future trials was 4.0 mg/m(2)/day x 5 days. The regimen had acceptable toxicity with no regimen-related death. Toxicity (Bearman toxicity criteria) was limited mostly to grade 1-2 mucositis and diarrhea. The overall response rate of patients with measurable or evaluable disease was 93%. Median survival has not yet been reached, but with a median follow up of 18 months (range: 11-37) 77% of patients are alive. CONCLUSION: With a topotecan dose of 4.0 mg/m(2)/day x 5 days, the TMC regimen has acceptable toxicity and produces high response rates. In the setting of ovarian cancer, high-dose chemotherapy should be administered only as part of well-designed clinical trials. TMC should be considered a potential regimen for future randomized trials in patients with advanced ovarian cancer.     

Phase 2 evaluation of topotecan administered on a 3-day schedule in the treatment of platinum- and paclitaxel-refractory ovarian cancer

PURPOSE; The aim of this study was to investigate the toxicity and efficacy of a more convenient topotecan administration schedule (in contrast to the "standard" 1.5 mg/m(2)/day x 5 days q 21 days) in the management of platinum- and paclitaxel-refractory ovarian cancer. METHODS: Patients with clinically defined platinum- and paclitaxel-refractory ovarian cancer participating in this phase 2 trial conducted by the Gynecologic Cancer Program of the Cleveland Clinic Taussig Cancer Center received topotecan at a dose of 1.5 mg/m(2)/day x 3 days on a 21-day schedule. Both dose escalations and reductions were permitted in the protocol design. RESULTS: A total of 29 patients (median age: 61; range: 43-80) were treated with this modified topotecan schedule. These individuals had received a median of two prior regimens (range: 1-4) (retreatment with a platinum agent or paclitaxel considered a single regimen). The median number of topotecan courses delivered was 3 (range: 1-7). Major toxicity included grade 4 neutropenia (24% of patients); neutropenic fever (10%); grade 3 thrombocytopenia (10%); and requirement for blood transfusion (14%). Dose escalation was possible, and dose reductions required, in 14 and 28% of patients, respectively. Two patients exhibited evidence of a clinically relevant response to treatment. CONCLUSION: This 3-day topotecan program is more convenient and less toxic than the standard 5-day regimen. The limited level of activity observed is not inconsistent with that previously reported for the 5-day topotecan infusion schedule in platinum/paclitaxel-refractory ovarian cancer. Further investigation will be required to document the clinical utility of a 3-day topotecan schedule in a less heavily pretreated and more chemosensitive patient population.     

Prolonged topotecan infusion with cisplatin in the first-line treatment of ovarian cancer: an NYGOG and ECOG study

OBJECTIVE: To determine the toxicity and efficacy of combined therapy with cisplatin and prolonged infusion topotecan as front line therapy in women with epithelial ovarian cancer. PATIENTS AND METHODS: Women with previously untreated, measurable and non-measurable epithelial ovarian cancer, stages Ic-IV were eligible. Patients were treated with cisplatin 75 mg/m(2) on day 1, followed by topotecan 0.3 to 0.4 mg/m(2)/day given as a continuous infusion over 14-21 days, every 28 days. Dose levels and duration of infusion were adjusted for toxicity as appropriate. Patients were evaluated for response to treatment and treatment toxicity by standard NYGOG criteria. RESULTS: Sixty patients were enrolled. Among the 20 patients with post-surgical residual disease >2 cm, 80% [95% CI (56.3%, 94.3%)] demonstrated an objective response to therapy. The median progression-free survival for all 60 patients enrolled was 19.3 months with a median overall survival of 45.6 months given the median follow-up of 55 months (range 6-81 months). Five year survival is estimated to be 41%. Toxicity was observed in the first four patients treated with topotecan (0.4 mg/m(2)/day x 21 days) and dosing was continued at 0.3 mg/m(2)/day x 14 days thereafter. Of the 56 patients treated at the amended dose level, marrow suppression continued to be dose-limiting, with 86% of patients experiencing grade 3 or 4 neutropenia, 55% experiencing grade 3 or 4 thrombocytopenia and 50% of patients experiencing grade 3 or 4 anemia. Nonetheless, only 11/245 cycles administered were associated with febrile neutropenia and/or infection (8 port-related). Other non-hematologic toxicity was as expected. There were no treatment-related deaths. CONCLUSION: This large, multicenter phase II study of prolonged infusion topotecan in combination with cisplatin demonstrated similar response, time to progression and survival compared with reported results of taxane and platinum combinations. Hematologic toxicity was greater but tolerated. Further studies investigating topotecan in combination with platinum therapy as a first line agent are warranted.