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.     

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 case of prolonged carboplatin therapy in a patient with carboplatin hypersensitivity

OBJECTIVES: Platinum-containing chemotherapeutic drugs have high response rates yet are known to cause hypersensitivity reactions. Attempts have been made to rechallenge allergic patients with prolonged desensitization infusion regimens. CASE: A female with advanced peritoneal cancer went into remission after six cycles of paclitaxel/cisplatin. Her cancer recurred 17 months later and she was treated with paclitaxel/carboplatin. A hypersensitivity reaction to carboplatin occurred during the fourth cycle and further carboplatin was withheld. With the second recurrence carboplatin was resumed using a prolonged desensitization regimen. The patient had a third recurrence and has recently completed cycle 15 of carboplatin for a total of 56 cycles. CONCLUSIONS: A carboplatin desensitization regimen may allow patients with platinum-sensitive ovarian or peritoneal cancer to continue to benefit from its efficacy.     

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。     

Paclitaxel and carboplatin combination chemotherapy in a hemodialysis patient with advanced ovarian cancer.

BACKGROUND: There are few reports on the pharmacokinetics of paclitaxel combined with carboplatin or on the dose schedule of carboplatin in combination use during hemodialysis in patients with ovarian cancer. CASE: A 40-year-old woman with chronic renal failure on hemodialysis who had FIGO stage III ovarian cancer was treated with debulking surgery and carboplatin/paclitaxel combination chemotherapy. Paclitaxal was administered at 150 mg/m(2) as a 3-h intravenous infusion followed by a 30-min infusion of carboplatin on a nondialysis day. The carboplatin dose was chosen to produce a target area under the concentration/time curve (AUC) of 5.0 microg-min/ml according to the Calvert formula. The pharmacokinetic study showed that the AUCs of free platinum and paclitaxel were 4.43 microg-min/ml and 15.9 microg-h/ml, respectively. Dosing of carboplatin based on the AUC produced an acceptable degree of thrombocytopenia and neutropenia. After the completion of five cycles of the combination chemotherapy, the tumor showed complete response, and the patient remained disease free for 8 months. CONCLUSION: Paclitaxel and carboplatin combination chemotherapy can be given to patients undergoing hemodialysis, with dialysis performed 16 h after the administration and with a dose adjustment of carboplatin to reach a target AUC. In these conditions, tumor response can be obtained.     

Weekly low-dose carboplatin and paclitaxel in the treatment of recurrent ovarian and peritoneal cancer

OBJECTIVES: Weekly paclitaxel alone has moderate activity in the salvage treatment of recurrent ovarian cancer and is associated with a favorable toxicity profile. Combination paclitaxel and carboplatin is a well-established first-line regimen for ovarian cancer. The purpose of this study was to evaluate weekly low-dose paclitaxel and carboplatin in recurrent ovarian or peritoneal cancer. METHODS: Patients with recurrent ovarian or peritoneal cancer previously treated with between one and four chemotherapeutic regimens were eligible. Patients had measurable or assessable disease defined by clinical exam, radiographic studies, or serum CA-125 greater than 75 U/ml. One cycle of treatment consisted of carboplatin at an area under the curve of 2 and paclitaxel at 80 mg/m(2) on days 1, 8, and 15 on a 28-day cycle. Clinical responses were defined by established criteria. RESULTS: Twenty-nine patients were included in this intent-to-treat study. The median number of prior treatment regimens was 2 (range 1 to 4). The overall response rate was 82.8% (16 complete clinical responses, 8 partial responses). Among 8 platinum-refractory patients, the response rate was 37.5%, while 21 platinum-sensitive patients had a 100% response rate. Median time to progression was 13.7 months among platinum-sensitive patients and 3.2 months among platinum-refractory patients. Overall median time to progression was 11.5 months and median-duration of response was 9.9 months. Hematologic toxicity was common (32% grade 3 neutropenia, no grade 4 neutropenia, 14.2% grade 3 or 4 thrombocytopenia) and managed by treatment delay, dose reduction of paclitaxel, or discontinuation of carboplatin. CONCLUSION: Weekly low-dose carboplatin and paclitaxel has significant activity in both platinum-sensitive and platinum-resistant recurrent ovarian cancer with acceptable toxicity that is easily managed by dose adjustment.     

Safety of paclitaxel in a patient with ovarian cancer and hyperbilirubinemia due to Rotor's syndrome

BACKGROUND: Rotor's syndrome is a rare congenital disorder characterized by functional hyperbilirubinemia. Treatment decision may be challenging in a cancer patient with Rotor's syndrome, since the majority of the antineoplastic agents are metabolized in the liver and excreted via the biliary system. We report the first case of paclitaxel administration in a patient with ovarian cancer and elevated bilirubin levels due to Rotor's syndrome. CASE: A 50-year-old woman with Rotor's syndrome had an exploratory laparotomy and was diagnosed to have stage IIIC epithelial ovarian cancer. The baseline serum bilirubin value was 15.3 mg/dL. She was started on a 50% dose of 87.5 mg/m(2) paclitaxel by 3-h infusion plus carboplatin AUC-6. The paclitaxel dose was increased by 25% at consecutive cycles until the standard dose of 175 mg/m(2)/3 h was achieved. Six cycles were administered without any metabolic derangement. The patient was rendered disease free with this treatment. CONCLUSION: Paclitaxel appears to be safe to administer to cancer patients with functional hyperbilirubinemia.     

Devastating effects of chemotherapy: deafness and acute renal failure in a patient with epithelial ovarian cancer

Abstract.   Ozguroglu M, Sari O, Turna H. Devastating effects of chemotherapy: deafness and acute renal failure in a patient with epithelial ovarian cancer. Int J Gynecol Cancer 2006; 16(Suppl. 1): 394–396.
Paclitaxel and platinum combination is the standard chemotherapy regimen for patients with advanced epithelial ovarian cancer. The dose-limiting toxicity effects of this combination are myelosuppression and neuropathy. Herein, we report a case of a 71-year-old female with advanced epithelial ovarian cancer who developed bilateral total loss of hearing and acute renal failure related with paclitaxel- and carboplatin-based chemotherapy. Acute renal failure accompanied by complete loss of hearing in patients treated with carboplatin and paclitaxel combination has not been previously reported. This uncommon adverse effect of carboplatin and paclitaxel combination was discussed, and all the literature in English related with the toxicity of paclitaxel and carboplatin were reviewed.     

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.     

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.     

Dose-Dense Paclitaxel With Carboplatin for Advanced Ovarian Cancer: A Feasible Treatment Alternative

ObjectiveEpithelial ovarian cancer is the leading cause of death from gynaecologic cancers in the Western world. If possible, initial cytoreductive surgery is the treatment of choice, followed by adjuvant chemotherapy, usually with a platinum/taxane combination. Increased survival has been recently reported in women who were given adjuvant chemotherapy weekly rather than at three-week intervals, which has been the standard. At our centre, we have been treating patients with advanced ovarian cancer with a dose-dense protocol since March 2010. Treatment is given in an outpatient setting on days 1, 8, and 15 of a 21-day cycle for six cycles. Carboplatin for an AUC of 5 mg/mL/min and paclitaxel 80 mg/m² are given on day 1, followed by paclitaxel 80 mg/m² on days 8 and 15. Our objective was to determine whether this protocol is a feasible alternative treatment in our population and whether or not the toxicity profile is acceptable.MethodsWe performed a chart review of 46 patients undergoing treatment with dose-dense chemotherapy for advanced ovarian cancer. Demographic information, patient characteristics, adverse events, and treatment endpoints were recorded.ResultsSixty-one percent of women completed the six-cycle protocol as planned with minimal interruption, which is comparable to the only previously reported trial using this regimen. The most common side effects of treatment were fatigue, neuropathy, and neutropenia. Supplementation with regular magnesium and granulocyte colony-stimulating factor reduced delays.ConclusionDose-dense paclitaxel with carboplatin chemotherapy for the treatment of advanced ovarian cancer shows promise in terms of progression-free and overall survival. We have shown this protocol to be practical and feasible in our population.     

Discordance of clinical symptoms and electrophysiologic findings in taxane plus platinum-induced neuropathy

Paclitaxel combined with carboplatin is currently accepted as the first-line treatment for ovarian carcinoma, frequently associated with neuropathy. Due to its frequent association with neuropathy, combination of docetaxel and carboplatin has been suggested as an alternative. A 47-year-old woman developed paresthesia after the first cycle of paclitaxel/carboplatin for ovarian cancer. Her nerve conduction study (NCS) showed only sural neuropathy after completion of six cycles, which returned to normal in 6 months. She had fewer neuropathy symptoms when treatment was changed to docetaxel/carboplatin for recurrent cancer. NCS revealed generalized sensory neuropathy following docetaxel/carboplatin treatment, which normalized after 12 months. Our observation indicated that there is a disparity between clinical symptoms and electrophysiologic examination in taxane-induced neuropathy. Although docetaxel was tolerated well by the patient, evidence of generalized sensory neuropathy was present in NCS.     

A phase II trial of weekly paclitaxel and every 3 weeks of carboplatin in potentially platinum-sensitive ovarian and peritoneal carcinoma

OBJECTIVE: Paclitaxel administered weekly in equal cumulative doses is associated with less hematologic and non-hematologic toxicity than an every 3-week administration. We studied weekly paclitaxel and 3-week carboplatin in potentially platinum-sensitive recurrent ovarian and peritoneal carcinoma. METHODS: Paclitaxel at a dose of 80 mg/m(2) over 1 h in combination with carboplatin at an AUC of 5 was administered on day 1. Subsequent paclitaxel doses, modified based on the day of treatment ANC, were administered on days 8 and 15. Paclitaxel dose reductions to 75% of prior dose were performed for chemotherapy delays or toxicity. RESULTS: Twenty-eight patients were studied. The median age was 59 (range 42-80). The median platinum-free interval was 12 months (range 7-129 months). A median of six courses (range 1-13) was administered. Paclitaxel dose reductions to 60 mg/m(2) were required in 85% of the patients. Grades 3 and 4 thrombocytopenia were seen in 5 and 0 patients, respectively. Grades 3 and 4 neutropenia were seen in 14 and 1 patients, respectively. One patient was hospitalized for neutropenic fever. Twenty of 26 (77%) evaluable patients have responded with 15 patients (58%) achieving a complete response. CONCLUSIONS: Weekly paclitaxel at a dose of 60 mg/m(2) in combination with carboplatin at an AUC of 5 is well tolerated and active in potentially platinum-sensitive recurrent ovarian and peritoneal carcinoma.     

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.     

The integration of anthracyclines in the treatment of advanced ovarian cancer

Abstract. Lück H-J, du Bois A, Weber B, Pfisterer J, Goupil A, Kuhn W, Barats JC, Blohmer J, Mousseau M, Schröder W, Meier W, Möbus V, Richter B, AGO-GINECO Intergroup. The integration of anthracyclines in the treatment of advanced ovarian cancer.
Since the publication of the Gynecologic Oncology Group (GOG) protocol 111 in 1996, and the results of the Arbeitgemeinschaft Gyna kologische Onkologie (AGO) trial Ovar-3 and the GOG protocol 158, the combination of platinum and paclitaxel has been adopted as the standard therapy in advanced ovarian cancer.
One option for achieving further progress in the first-line treatment of advanced ovarian cancer might be the addition of noncross-resistant drugs to the two-drug regimen. Meta-analysis showed a survival benefit for platinum-anthracycline based combinations as compared to platinum-based combinations without anthracyclines.
An AGO phase I/II trial compared epirubicin in combination with carboplatin and paclitaxel in untreated patients with gynecological malignancies. Based on the results of this study a randomized phase III trial together with the French GINECO group was conducted. The trial started 11/97 and was closed 11/99. All 1281 patients were randomized. Currently, 1132 end-of-therapy reports have been issued. Nine hundred eighty nine (87%) patients completed six cycles of treatment. Treatment and toxicity data are available for these patients. Three hundred thirty five patients had a measurable residual tumor after initial debulking surgery. Response data of 228 patients (111 ET-Carbo, 117 Carbo-T) are available.     

Case ReportWeekly carboplatin in a frail elderly woman with advanced peritoneal carcinoma

Introduction Standard chemotherapy for ovarian, peritoneal and fallopian tube carcinoma has been a combination of carboplatin (AUC=6) and paclitaxel 175 mg/m² every 3 weeks. For frail and elderly patients who may not tolerate the toxicity associated with combination chemotherapy there is the option of omitting paclitaxel and giving carboplatin (AUC=6) as a single agent every 3 weeks. The toxicity may be reduced further, without decreasing effectiveness, by giving single-agent carboplatin at a reduced dose (AUC=2) every week. Case report A frail 79-year-old woman with advanced peritoneal carcinoma had first-line and second-line chemotherapy with single-agent carboplatin on day 1 every 7 days. This has resulted in disease stabilization, CA-125 partial response and improved quality of life. Toxicity has been negligible. Conclusion Weekly carboplatin is an attractive option for the treatment of frail and elderly patients with ovarian, peritoneal and fallopian tube carcinoma.     

Hypersensitivity reactions and the utility of oral and intravenous desensitization in patients with gynecologic malignancies

OBJECTIVES: The aims of this study were to characterize hypersensitivity reactions to chemotherapy in patients with gynecologic malignancies and to determine the utility of oral and intravenous desensitization. METHODS: We retrospectively reviewed patients with hypersensitivity reactions identified by direct physician query and by review of charts with ICD9 code E933.1 (Adverse Effect Anti-Neoplastic). RESULTS: Thirty-two patients were identified: 27 with ovarian cancer, 4 with primary peritoneal cancer, and 1 with cervical cancer. Nine patients experienced hypersensitivity reactions during the primary regimen and 23 during chemotherapy for recurrent disease. Hypersensitivity occurred following an average of nine courses. Hypersensitivity occurred secondary to paclitaxel (10) carboplatin (16), cisplatin (4), bleomycin (1), and paclitaxel/carboplatin combination therapy (1). Patients had previously received the agent in 93.8% of carboplatin reactions, in 54.5% of paclitaxel reactions, and in all other agent reactions. Hypersensitivity reactions most commonly included flushing, dyspnea/bronchospasm, back pain, chest discomfort, pruritus, erythema, and nausea and occasionally included alterations in blood pressure or pulse rate. Reactions were successfully treated in 96.9% of patients by interrupting the infusion and administering steroids, antihistamines, benzodiazepines, nebulized beta-agonists, and/or pressors. Seventeen patients underwent desensitization, one to two agents, with 94% success. Nine of ten patients had successful iv desensitization, and 8/10 patients had successful oral desensitization. One failure on the oral regimen had previous successful iv desensitization. CONCLUSIONS: Hypersensitivity reactions to chemotherapeutic agents do not necessarily require exclusion of a compound from the treatment regimen. Intravenous and oral desensitization protocols are useful for successful and safe administration of paclitaxel and platinum compounds in patients with prior hypersensitivity reactions.     

Repetitive high-dose topotecan, carboplatin, and paclitaxel with peripheral blood progenitor cell support in previously untreated ovarian cancer: results of a Phase I study

OBJECTIVE: In view of the significant activity of topotecan in ovarian cancer with dose-limiting toxicity (DLT) of myelosuppression, we evaluated the addition of topotecan to carboplatin and paclitaxel with peripheral blood progenitor cell (PBPC) support. METHODS: Patients with previously untreated stage IIIC or IV ovarian cancer with macroscopic residual disease following primary debulking surgery were eligible. Patients received two cycles of carboplatin AUC = 5 and 175 mg/m(2) of paclitaxel with collection of PBPCs after the second cycle. Patients subsequently received three cycles of high-dose therapy (HDT) with topotecan on a daily x5 schedule, paclitaxel (250 mg/m(2) over 24 h), and carboplatin (AUC = 12-16). RESULTS: Nineteen patients with a median age of 49 years (range 21-63) were enrolled and topotecan was escalated in 6 patient cohorts up to a dose of 4.5 mg/m(2)/day. Fifty-two of the planned 57 treatment cycles were delivered with no treatment-related deaths. Neutrophil and platelet recovery was rapid and the interval between HDT was 28 days. Febrile neutropenia occurred following 57% of all HDT cycles. DLTs of mucositis and diarrhea were observed at topotecan (4.5 mg/m(2)/day), paclitaxel (250 mg/m(2)) and carboplatin (AUC = 12). The protocol was subsequently modified to administer topotecan (2.5 mg/m(2)/day) with carboplatin (AUC = 16); however, 2 patients developed grade 4 diarrhea (1 with grade 3 mucositis and 1 with grade 4 mucositis). The clinical CR rate was 73% (14/19) with an overall clinical response rate of 95% (18/19). Of the 14 patients with a CCR, 13 of these underwent a second-look laparotomy with 8 (61%) achieving a pathological CR. With a median follow-up of 28 months (range 11-40 months), the median PFS is 36 months and OS has not been reached. CONCLUSION: When combined with carboplatin (AUC = 12) and paclitaxel (250 mg/m(2)), the recommended topotecan dose is 3.5 mg/m(2)/day for 5 days. This outpatient HDT regimen combines three of the most active drugs in ovarian cancer with acceptable toxicity and promising activity.     

Phase 2 trial of intraperitoneal carboplatin and etoposide as salvage treatment of advanced epithelial ovarian cancer

To evaluate the efficacy of intraperitoneal (IP) carboplatin-based therapy as salvage treatment of ovarian cancer, 46 patients with persistent or recurrent ovarian cancer following initial systemic chemotherapy were treated with a regimen of carboplatin (200-300 mg/m2) and etoposide (100 mg/m2) administered on a monthly schedule. A maximum of six courses of therapy was delivered, followed by a response laparotomy. The treatment program was well tolerated, except for bone marrow suppression, with one-quarter of patients developing platelet count depressions to < or = 50,000/mm3, and one-third experiencing hemoglobin levels of < or = 8 g/dl during treatment. Twelve (38%) of 32 patients evaluable for efficacy of the treatment program achieved a surgically documented response, including 8 (25%) complete responses. Of 25 patients whose largest tumor mass at the initiation of therapy measured < or = 0.5 cm, 11 (44%) responded, including 8 (32%) complete responses. We conclude that the IP administration of carboplatin can result in surgically documented responses when used in the salvage setting in patients with advanced ovarian cancer. The relative efficacy of carboplatin versus cisplatin when administered by the IP route to patients with ovarian cancer previously treated with platinum-based systemic therapy remains to be defined.     

A phase II study of paclitaxel, carboplatin, and gemcitabine in previously untreated patients with epithelial ovarian cancer FIGO stage IC-IV (AGO-OVAR protocol OVAR-8)

PURPOSE: A multicenter, nonrandomized, phase II study was initiated to evaluate the tolerability, toxicity, and activity of paclitaxel, carboplatin, and gemcitabine combination in previously untreated ovarian cancer. PATIENTS AND METHODS: Chemonaive patients who had radical debulking surgery for primary epithelial ovarian cancer International Federation of Gynecology and Obstetrics (FIGO) IC-IV received sequentially paclitaxel 175 mg/m(2), carboplatin AUC 5, and gemcitabine 800 mg/m(2) on day 1 and gemcitabine 800 mg/m(2) on day 8, every 3 weeks. RESULTS: From October 2001 to July 2002, 55 patients were treated and evaluated. Main toxicities were hematological with NCI-CTC grade 3/4 anemia 12.7%, leukopenia 70.9%, neutropenia 76.3%, and thrombocytopenia 45.5. However, febrile neutropenia occurred only in 1.8%. Grade 3/4 nonhematological toxicities were rare and occurred in less than 10% of patients. Toxicity-induced treatment delays occurred in 3.1% of cycles and resulted in early treatment cessation in four patients. Dose intensity reached 90.8% for carboplatin and paclitaxel, and 73.3% for gemcitabine. Objective response was observed in 10 of 14 patients with measurable disease. CONCLUSIONS: The triplet combination of paclitaxel-carboplatin-gemcitabine is feasible and active, with manageable hematological toxicity and no unexpected nonhematological toxicity. This regimen has proceeded to phase III evaluation.