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 II trial of weekly docetaxel for patients with relapsed ovarian cancer who have previously received paclitaxel--ANZGOG 02-01

OBJECTIVE: To determine the response rate of weekly docetaxel in women with relapsed epithelial ovarian cancer previously treated with paclitaxel and at least one line of platinum-based chemotherapy. METHODS: In this multi-center phase II trial, 37 patients with relapsed disease were enrolled and treated with weekly docetaxel at 35 mg/m for 5 out of 6 consecutive weeks. Two patient cohorts were considered, those who progressed or relapsed within 4 months (N=7) or at greater than 4 months (N=30) from the time of completing their last course of paclitaxel. RESULTS: Patients in both cohorts received a median of 2 cycles of treatment (range; 1-4). In evaluable patients, the combined overall response rate, using both CA125 and RECIST response criteria was 18.9% (7/37; 95% CI; 10-34%). The combined overall progression-free survival was 3.1 months (95% CI; 2.5-3.8), and the combined overall survival was 12.3 months (95% CI; 8.2-16.4). Treatment was generally well tolerated with the only grade 4 toxicity being skin toxicity (3%). The most common grade 3 toxicities were fatigue (14%) and watery eyes (8%) with grade 3 neutropenia observed in only 5% of patients. CONCLUSION: Weekly docetaxel is well tolerated and has activity in patients with relapsed ovarian cancer previously treated with platinum and paclitaxel.     

Phase 2 trial of single agent docetaxel in platinum and paclitaxel-refractory ovarian cancer, fallopian tube cancer, and primary carcinoma of the peritoneum

OBJECTIVE: Previously reported data have suggested the lack of complete cross-resistance between docetaxel and paclitaxel in ovarian cancer. We wished to evaluate the biological and clinical activity of docetaxel in a patient population with well-characterized platinum and paclitaxel-refractory ovarian cancer. METHODS: In this single-institution phase 2 trial, 30 women with advanced ovarian cancer whose disease had either failed to respond to primary platinum-paclitaxel chemotherapy or where the cancer had progressed within 3 months of their last treatment with both a platinum agent and paclitaxel were treated with single agent docetaxel (75 mg/m(2) q 3 weeks). Due to a prior history of excessive chemotherapy-induced neutropenia, 3 patients initiated treatment at a dose of 60 mg/m(2). RESULTS: The median number of courses of docetaxel delivered on this protocol was 3 (range 1-7), with 7 patients requiring dose reductions due to treatment-related side effects. The most common toxicities included grade 4 neutropenia, neutropenic fever, and grade >/=2 fatigue experienced by 9 (30%), 2 (7%), 5 (17%) patients, respectively. Three patients (10%) achieved both an objective response (by CA-125 criteria) and symptomatic improvement (e.g., decrease in pain and ascites). The durations of responses were 3, 4, and 6 months. CONCLUSION: Single-agent docetaxel has modest, but definite activity in patients with well-characterized platinum and paclitaxel-resistant ovarian cancer. Use of this drug should be considered a rational management approach in appropriately selected patients in this clinical setting.     

A phase II trial of high-dose hydroxyurea administered parenterally in patients with epithelial ovarian carcinoma refractory to platinum

Verschraegen CF, Kudelka AP, Loyer E, Edwards CL, Freedman RS, Kavanagh JJ. A phase II trial of high-dose hydroxyurea administered parenterally in patients with epithelial ovarian carcinoma refractory to platinum. Int J Gynecol Cancer 1998; 8 : 494–498.
This phase II study was designed to analyze the efficacy and toxicity of an intravenous infusion of hydroxyurea in patients with ovarian cancer in which previous chemotherapy with platinum failed. Another phase II study of paclitaxel was run in the same patient population. Twenty-six patients with measurable ovarian cancer were entered in the hydroxyurea phase II study at The University of Texas M. D. Anderson Cancer Center. Treatment consisted of a loading dose of 2,100 mg/m² of hydroxyurea followed by a continuous intravenous infusion of 16,800 mg/m² over 24 h repeated every 3 weeks. Patients with disease unresponsive to hydroxyurea could then be crossed over to paclitaxel. Disease in one patient responded, but the patient refused further treatment with hydroxyurea. Disease in 3 was stable. The median survival time was 8.8 months. The main toxic effect was neutropenia, with 31% of patients experiencing grade 3 or 4 neutropenia. No episodes of neutropenic fever were observed. Twenty seven percent of patients presented with anemia and thrombocytopenia. Other side effects were all lower than grade 2 and included gastrointestinal dysfunction (35% of patients), alopecia (12%), dermatitis (12%), headache (8%), and stomatitis (4%). We conclude that high-dose hydroxyurea administered parenterally as a single agent over 24 h is not active in patients with platinum-refractory ovarian cancer but is subjectively well tolerated.     

Activity of weekly paclitaxel in patients with advanced endometrial cancer previously treated with both a platinum agent and paclitaxel

PURPOSE: The aim of this report is to describe the potential clinical utility of the weekly administration of paclitaxel in patients with endometrial cancer previously treated with a platinum agent and paclitaxel (delivered on an every 3-week schedule). METHODS: We briefly describe the clinical courses of three women with recurrent endometrial cancer who had prior exposure to platinum and paclitaxel, and who were subsequently treated with weekly paclitaxel in an effort to relieve significant cancer-related symptoms. RESULTS: In these individuals, the weekly administration of paclitaxel was reasonably well tolerated. There was evidence of both objective and subjective improvement in the status of the malignant process. CONCLUSION: The weekly administration of paclitaxel is a rational management approach in women with metastatic or recurrent endometrial cancer who have previously received treatment with both a platinum agent and paclitaxel. This delivery strategy should be further explored through the conduct of well-designed clinical trials, both in the primary and secondary chemotherapeutic management of this malignancy.     

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

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

Current standards of care for chemotherapy of optimally cytoreduced advanced epithelial ovarian cancer

There has been limited change in evidence-based primary chemotherapeutic management of optimal residual advanced ovarian cancer for more than a decade. The backbone of therapy remains a platinum agent (generally carboplatin) and a taxane (generally paclitaxel). Phase 3 randomized trial data provide support for the use of weekly paclitaxel in this setting (compared to the traditional every 3-week schedule) and the addition of bevacizumab as a component of primary management. Recently available data provide increasingly solid support for a role of regional platinum administration in at least a subset of patients with optimal residual advanced ovarian cancer and an important retrospective analysis has suggested a novel biomarker that may predict for the utility (or lack thereof) of this method of drug delivery.     

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

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

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

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

白蛋白结合型紫杉醇联合铂类或异环磷酰胺治疗复发性卵巢癌的疗效及安全性分析

目的:观察白蛋白结合型紫杉醇联合铂类或异环磷酰胺治疗复发性卵巢癌的临床疗效及毒副反应。方法:回顾分析我院46例复发性卵巢癌患者接受含不同制剂紫杉醇的联合化疗的疗效及安全性。26例铂敏感复发患者分别采用白蛋白结合型紫杉醇或溶剂型紫杉醇联合铂类化疗,20例铂耐药复发患者采用白蛋白结合型紫杉醇或溶剂型紫杉醇联合异环磷酰胺方案,每21天为1疗程,直至完全缓解后再巩固2个疗程或疾病进展或出现不可耐受的不良反应。比较患者间临床效果、毒副作用及预后差异。结果:铂敏感复发患者中,白蛋白结合型紫杉醇组的完全缓解率显著高于溶剂型紫杉醇组(60%vs 18.8%,P0.05);两组的客观缓解率分别为90%、75%。铂耐药复发患者中,白蛋白结合型紫杉醇组的完全缓解率显著高于溶剂型紫杉醇组(16.7%vs 0%,P0.05);两组的客观缓解率分别为66.7%、57.1%。铂敏感复发患者中,白蛋白结合型紫杉醇组及溶剂型紫杉醇组的中位无进展生存时间(PFS)分别为10.25、7.5个月(P0.05);铂耐药复发患者中白蛋白结合型紫杉醇组及溶剂型紫杉醇组的中位PFS分别为7.8、5.6个月(P0.05)。4组患者的不良反应主要表现为骨髓抑制和胃肠道反应,铂敏感、铂耐药患者中白蛋白结合型紫杉醇组及溶剂型紫杉醇组各种严重不良反应的发生率均无显著差异。结论:与溶剂型紫杉醇比较,含有白蛋白结合型紫杉醇的联合化疗方案治疗铂敏感或铂耐药复发性卵巢癌均有更高的完全缓解率,可有效延长PFS,且不额外增加严重毒副反应的发生率。     

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.     

Phase II study of gemcitabine and weekly paclitaxel in recurrent platinum-resistant ovarian cancer

OBJECTIVE: The purpose of this study is to evaluate the activity of gemcitabine and weekly paclitaxel in patients with platinum-resistant ovarian cancer. METHODS: Thirty-five patients with platinum-resistant disease and prior treatment with paclitaxel received treatment with paclitaxel 80 mg/m(2) IV over 60 min, followed by gemcitabine 1000 mg/m(2) IV administered on days 1, 8, and 15. Cycles were repeated every 4 weeks. RESULTS: All patients had platinum-resistant disease and all had received prior treatment with paclitaxel. Patients were heavily pretreated as the median number of chemotherapy regimens for recurrent disease was 2 (0-3). The overall response rate was 40% (95% confidence intervals (24%, 58%) and 37% of patients achieved stable disease. The median time to progression was 5.7 months (95% CI, 4.6, 8.5) and median overall survival 13.1 months (95% CI, 10.6, 15.9). More than 50% of patients were alive at 12 months, including six patients (17%) who were alive at 24 months. Treatment was well tolerated. Grades 3-4 neutropenia occurred in 17 patients (48.5%), grade 3 thrombocytopenia in 7 (20%), grade 3 anemia in 3 (8.5%). The most common serious non-hematological toxicities were nausea (14%), vomiting (14%), and fatigue (34%). CONCLUSIONS: The regimen of weekly paclitaxel and gemcitabine exhibits significant activity in heavily pretreated patients, is well tolerated, and is associated with encouraging survival. This regimen should be considered as a treatment option in patients with chemotherapy-resistant ovarian cancer.     

A randomized phase II study of cabozantinib versus weekly paclitaxel in the treatment of persistent or recurrent epithelial ovarian,fallopian tube or primary peritoneal cancer: An NRG Oncology/Gynecologic Oncology Group study

IntroductionCabozantinib is a receptor tyrosine kinases inhibitor that targets MET (c-MET), VEGF receptor 2 (VEGFR2), RET, AXL, KIT, FLT-3, and TIE-2 and previously showed promising single agent activity in recurrent ovarian cancer.MethodsThis was an open label, 1:1 randomized study of cabozantinib 60 mg orally (PO) daily versus weekly paclitaxel 80 mg/m² given 3 out of 4 weeks (NCT01716715); 111 patients were enrolled. Eligibility included persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma and at least one but no >3 prior chemotherapy regimens.ResultsMedian PFS was similar for both treatment groups and was 5.3 months for cabozantinib and 5.5 months for weekly paclitaxel (HR 1.11 (90% CI 0.77–1.61, p = 0.64)). Secondary analyses of overall survival (OS) and event free survival (EFS) showed that cabozantinib did not perform as well as weekly paclitaxel. Median OS for cabozantinib was 19.4 months and was not reached for weekly paclitaxel (HR 2.27 (90% CI 1.17–4.41, p = 0.04). EFS was also worse in the cabozantinib arm, 3.5 months, compared to weekly paclitaxel at 5.0 months (HR 1.81 (90% CI 1.24–2.63, p = 0.01). Overall response rate (ORR) was less for cabozantinib compared to weekly paclitaxel (7% versus 24.1%). Gastrointestinal toxicities, specifically nausea, diarrhea, and abdominal pain were worse in the cabozantinib arm.ConclusionsMedian PFS was similar for cabozantinib and weekly paclitaxel. However, OS, EFS, and ORR were worse for cabozantinib compared to weekly paclitaxel. Cabozantinib given at this dose and schedule cannot be recommended as a treatment for recurrent ovarian cancer.     

Gemcitabine in epithelial ovarian cancer treatment: current role and future perspectives

Newer agents and combinations are needed in order to improve current results in ovarian cancer treatment. Gemcitabine is a novel agent that has shown consistent activity as a single agent in the treatment of platinum-resistant ovarian cancer and a favorable toxicity profile. Because of its clinical and preclinical synergism with platinum analogs, gemcitabine has been combined with carboplatin as a convincing approach in the treatment of platinum-sensitive recurrent ovarian cancer patients. Further combination of gemcitabine and other agents, including paclitaxel, is also feasible and has been actively studied in order to establish the role of gemcitabine in the management of treated and untreated ovarian cancer patients.     

A phase II study of pegylated liposomal doxorubicin oxaliplatin and cyclophosphamide as second-line treatment in relapsed ovarian carcinoma

Abstract.   Valerio MR, Tagliaferri P, Raspagliesi F, Fulfaro F, Badalamenti G, Arcara C, Cicero G, Russo A, Venuta S, Guarneri G, Gebbia N. A phase II study of pegylated liposomal doxorubicin oxaliplatin and cyclophosphamide as second-line treatment in relapsed ovarian carcinoma. Int J Gynecol Cancer 2006; 16(Suppl. 1): 79–85
We carried out a phase II nonrandomized study to examine the level of activity of oxaliplatin, pegylated liposomal doxorubicin, and cyclophosphamide in a patient population with relapsed ovarian cancer pretreated with platinum derivatives and paclitaxel. Patients received oxaliplatin (85 mg/m²), pegylated liposomal doxorubicin (30 mg/m²), and cyclophosphamide (750 mg/m²). A total of 49 patients (39 assessable for toxicity and response) were enrolled in this trial. Neutropenia grade 3 was observed in six patients (15%) and anemia grade 3 in one patient (0.2%). Fatigue grade 1–2 occurred in 26 patients (66%), nausea/vomiting grade 1 in 23 patients (58%), and alopecia grade 1–2 in 19 patients (48%). Twenty-one (53%) patients experienced grade 1–2 peripheral neuropathy. The overall response rate was 46% (95% CI 23.6–68.7). Median progression-free survival was 28 weeks (range 12–52 weeks) and median survival was 45 weeks (range 26–136+ weeks). The mean duration of response was 34 weeks (range 16–52 weeks). In platinum-resistant and -refractory ovarian cancer patients, the overall response rate was 37% (CI 95% 14.4–60.8) with a progression-free survival of 28 weeks (range 12–52 weeks) and a median survival of 42 weeks (range 28–84 weeks). This combination chemotherapy is generally well tolerated and is an active second-line regimen against ovarian cancer.     

Multi-institutional phase 2 study of TLK286 (TELCYTA™, a glutathione S-transferase P1-1 activated glutathione analog prodrug) in patients with platinum and paclitaxel refractory or resistant ovarian cancer

The purpose of this study was to determine the safety and efficacy of TLK286 (TELCYTA(TM)), a glutathione analog prodrug, in patients with platinum and paclitaxel refractory or resistant ovarian carcinoma. Thirty-six patients with measurable disease were enrolled. TLK286 was administered at 1000 mg/m2 intravenously every 3 weeks. The endpoints were objective response rate assessed by Response Evaluation Criteria in Solid Tumors (RECIST) and survival. Adverse events were graded using the National Cancer Institute Common Toxicity Criteria. Thirty-four platinum refractory or resistant patients (94%) were evaluable for objective tumor response. Five patients (15%) had objective tumor responses, including one durable complete response (CR) of greater than 3 years and continuing. The disease stabilization rate was 50%, including one CR (3%), four partial responses (12%), and 12 durable disease stabilizations (35%). Responses were accompanied by improvement in clinical symptoms and Eastern Cooperative Oncology Group Performance Status (ECOG PS) and decline in CA125 levels. Median survival was 423 days with survival of 60% at 1 year and 40% at 18 months. TLK286 was well tolerated in this population. TLK286 is an active agent in chemotherapy-resistant ovarian cancer. Further studies of TLK286 in platinum and paclitaxel refractory or resistant ovarian cancer are in progress.     

Preliminary experience with salvage weekly paclitaxel in women with advanced recurrent ovarian carcinoma

PURPOSE OF INVESTIGATION: To assess the role of palliative chemotherapy with weekly paclitaxel in patients with recurrent ovarian cancer. METHODS: Thirty-two patients with paclitaxel- and platinum-resistant ovarian cancer were treated with weekly paclitaxel at 80 mg/m2 as a 1-hour intravenous infusion weekly for six weeks every eight weeks (1 cycle). This schedule was considered to be given for three cycles. Evaluation of radiographically measurable disease was used in the assessment of response. CA-125 was used to classify responses only in the absence of a measurable lesion. RESULTS: Thirty-two patients were all assessable for response. Of these, nine patients (28.1%) achieved a partial response and one patient achieved a complete response, leading to an overall response rate of 31.2%. Stable disease occurred in six patients (18.8%), and 16 patients (50%) had progressive disease. Nine patients died of progressive disease while on treatment. The median survival for the entire group was 10.5 months (range 2.5-22 months). Grade 3 or 4 leukopenia and neutropenia occurred in eight and six patients, respectively. Four of these patients developed febrile neutropenia without infection. Grade 1 and 2 peripheral neuropathies were observed in 50% of the patients without causing any premature drop out. Severe (grade 3 or 4) peripheral neuropathy was not observed. There were 11 patients with grade 1 or 2 myalgias. CONCLUSION: Weekly paclitaxel regimen is well tolerated with acceptable toxicity. The favorable toxicity profile and the encouraging antitumor activity observed in this study makes this regimen an option for the salvage treatment of patients with recurrent ovarian cancer.     

Phase 2 trial of single-agent gemcitabine in platinum-paclitaxel refractory ovarian cancer

OBJECTIVE: There is a need to find agents with activity in platinum and taxane refractory ovarian cancer to be employed as second-line therapy in the malignancy. Limited clinical trial experience has suggested that gemcitabine possesses activity in this clinical setting. We wished to further define the level of activity of gemcitabine in women with well-characterized platinum/taxane refractory disease. METHODS: Patients with ovarian or fallopian tube cancer or primary carcinoma of the peritoneum, whose disease had either failed to respond to a platinum and taxane treatment, or had responded but the "treatment free interval (TFI)" was < or =3 months, or if the TFI was >3 months and they had been retreated with the agents and not responded (or experienced a TFI of <3 months), were eligible for treatment on this phase 2 single institution protocol. Gemcitabine was administered weekly (as a 1-h infusion) for 3 weeks, followed by 1-week break. RESULTS: A total of 51 patients were treated on this trial. The initial dose level (1250 mg/m(2)/week) resulted in excessive toxicity (fatigue, fever/chills, bone marrow suppression). The modified starting dose (1000 mg/m(2)/week) resulted in a more acceptable side effect profile. Eight patients (16%) with measurable disease (n = 4) or evaluable disease by CA-125 criteria (n = 4) achieved an objective response (median duration of response: 4 months; range 2-13 months). CONCLUSION: Single agent gemcitabine possesses modest, but definite, activity in patients with well-characterized platinum/taxane resistant ovarian cancer. It is reasonable to consider this drug for second-line (or later) treatment in this clinical setting.     

Phase II trial of docetaxel and carboplatin in recurrent platinum-sensitive ovarian, peritoneal and tubal cancer

OBJECTIVE: Docetaxel and carboplatin are active in relapsed ovarian, peritoneal and tubal cancer. Recently, two prospective-randomized trials showed an advantage of carboplatin combination regimen with paclitaxel or gemcitabine over carboplatinum alone in platinum-sensitive cases. The question on the most effective combination with the best tolerable side effects still needs to be answered. METHODS: Eligible patients had recurrent ovarian, peritoneal or tubal cancer (platinum-free interval >6 months), performance status 0-2 and normal bone marrow, renal and hepatic function. 25 patients (age 18-75 years) were enrolled into this phase II trial. Patients with debulking operation of recurrence were excluded from this study. Docetaxel 75 mg/m(2) via 30-min infusion was given on day 1 followed by carboplatin (area under curve [AUC] 5) on day 1. The administration was repeated every 3 weeks over 6 courses. Primary endpoint of this trial was the response rate; secondary endpoints were progression-free survival, overall survival and toxicity. RESULTS: In the intent-to-treat population, there were 16 (64.0%) complete and 2 (8.0%) partial responses resulting in an overall response rate of 72.0%. Three patients (12.0%) showed a stable disease and other 2 patients (8.0%) a progression of cancer. Two patients (8.0%) were not evaluable for response. Neutropenia was the most frequent G3/G4 hematologic toxicity in 15/25 patients (60.0%); but no neutropenic fever occurred in this trial. Diarrhea G3 was the most frequent G3/G4 non-hematologic toxicity in only 3/25 patients (12.0%). Dose-limiting toxicities were hypersensitivity reaction in one and depressive mood alteration requiring therapy in another case. CONCLUSION: Carboplatin in combination with docetaxel is highly active and well tolerated in patients with recurrent platinum-sensitive ovarian, peritoneal and tubal cancer. Prospective-randomized trials comparing this with other carboplatin therapeutic doublets in patients with recurrent ovarian cancer are a possible option for the future to answer the question on the best combination regimen.     

Phase II study of gemcitabine in recurrent platinum-and paclitaxel-resistant ovarian cancer

OBJECTIVE: To determine the activity and tolerability of gemcitabine in the palliative treatment of ovarian cancer. METHODS: Patients affected by ovarian cancer, and with progressive disease after treatment with platinum/paclitaxel-based chemotherapy, were enrolled into this phase II study. Gemcitabine, 1000 mg/m(2), was administered on days 1, 8, and 15, by 30-min intravenous infusion. Cycles were repeated every 28 days. RESULTS: Fifty patients were enrolled. All the patients were platinum and/or paclitaxel resistant (median number of previous regimens, 2; range, 1-5). Median platinum-free interval was 3 (range, 1-11) months and median paclitaxel-free interval was 6 (range, 1-36) months. A total of 210 courses were evaluable for toxicity, with a median number of four cycles administered per patient (range, 1-10). A grade 3 or 4 hematological toxicity was observed in 27 patients (54%) (anemia grade 3, 16%; grade 4, 2%; neutropenia grade 3, 24%; grade 4, 18%; thrombocytopenia grade 3, 8%; grade 4, 0%). A 20-50% dose reduction was required for 36 patients (72%, 55% of cycles). Blood transfusions were necessary for 15 patients (30%), while 2 (4%) were treated with erythropoetin. Granulocyte colony-stimulating factor was necessary in 4 patients (8%). Nonhematological toxicity was mild and manageable. Only 4 patients (8%) experienced a grade 3 hepatic toxicity (elevated liver enzymes). Forty-one patients (82%) are, so far, evaluable for response. Among them, 7 partial responses (17%; 95% confidence interval [CI], 6-29), 15 disease stabilizations (>16 weeks) (36.6%; 95% CI, 21.9-51.3), and 19 progressions (46.3%; 95% CI, 31.0-61.6) have been registered. An overall clinical benefit was observed in 53.7% of patients. Thirteen patients (31.7%) had a time-to-progression exceeding 24 weeks. CONCLUSIONS: This study confirms the activity and safety of gemcitabine in heavily pretreated patients with recurrent ovarian cancer.