Pilot study evaluating the efficacy and toxicity of irinotecan plus oral etoposide for platinum- and taxane-resistant epithelial ovarian cancer

OBJECTIVES: To evaluate the efficacy and toxicity of combination chemotherapy with intravenous irinotecan and oral etoposide in women with platinum- and taxane-resistant epithelial ovarian cancer. METHODS: Between October 2002 and September 2005, we studied 27 women with platinum- and taxane-resistant epithelial ovarian cancer. Irinotecan was administered in an intravenous dose of 70 mg/m(2) as a 90-min infusion on days 1 and 15 of a 28-day cycle, and etoposide was administered in an oral dose of 50 mg/day on days 1 to 21. For heavily pretreated patients, the initial dose of irinotecan was lowered to 60 mg/m(2). Treatment cycles were repeated until disease progression or unacceptable toxicity. RESULTS: All 27 patients were eligible and assessable. There were 11 partial responses and 1 complete response for an overall response rate of 44.4%. The median durations of overall response and of stable disease were 11 months and 8 months, respectively. The major toxicity was neutropenia (grade 3, 22.2%; grade 4, 37.1%). Diarrhea was infrequent and mild, and gastrointestinal toxicity was moderate and manageable. Acute myeloid leukemia (M5) developed as a secondary malignancy in 1 patient. CONCLUSIONS: The results of our pilot study suggest that a combination of irinotecan and oral etoposide is effective and tolerable in women with platinum- and taxane-resistant epithelial ovarian cancer.     

Weekly topotecan in heavily pretreated patients with recurrent epithelial ovarian carcinoma

OBJECTIVE: To investigate weekly topotecan in heavily pretreated patients with recurrent ovarian cancer. METHODS: The records of patients with recurrent epithelial ovarian cancer who were treated with weekly topotecan after failure of > or =1 prior regimen were reviewed. Patients received topotecan (median starting dose approximately 2.5 mg/m(2)) on days 1, 8, and 15 of a 28-day cycle. Antitumor response was assessed after 2 cycles by serial CA-125 levels. RESULTS: Thirty-five heavily pretreated patients received a mean of 5 cycles of topotecan (range, 1-13 cycles). Thirty-two patients had definable platinum sensitivity (16 sensitive, 8 resistant, 8 refractory). Median age was 56 years. A total of 177 cycles (534 weeks) of topotecan was administered. Hematologic toxicity was generally mild, and no grade 4 toxicities were observed. Grade 3 hematologic toxicity, including leukopenia, neutropenia, thrombocytopenia, and anemia, was observed in 2, 2, 1, and 0 patients, respectively. No patients experienced grade 3 or 4 nonhematologic toxicity. Based on serial CA-125 measurements, there were 1 (3%) complete and 5 (15%) partial responses, with 1 of the partial responses in a patient with platinum-refractory disease. Stable disease was reported in 13 (38%) patients, including 5 patients with platinum-resistant/refractory disease. CONCLUSION: Weekly topotecan demonstrates activity and is well tolerated compared with historical data with the standard 5-day schedule. Higher doses may be warranted because of the high tolerability shown for weekly topotecan. Weekly topotecan may be an appropriate treatment option for patients with recurrent ovarian cancer, especially heavily pretreated patients who might require dosing schedules with improved tolerability.     

A phase IIA study of the topoisomerase I inhibitor, exatecan mesylate (DX-8951f), administered at two different dose schedules in patients with platinum- and taxane-resistant/refractory ovarian cancer

OBJECTIVES: There is an urgent need for new agents with activity in platinum- and taxane-resistant epithelial ovarian cancer. Exatecan mesylate is a novel topoisomerase I inhibitor with potent activity against ovarian cancer in vitro. A multicentre phase IIA study was conducted in patients with platinum- and taxane-resistant epithelial ovarian cancer. PATIENTS AND METHODS: Fifty-seven patients with bidimensionally measurable ovarian cancer, previously exposed to platinum and taxanes, whose disease had relapsed within 6 months of platinum-containing chemotherapy were randomised to one of two intravenous schedules of exatecan mesylate; 0.3 mg/m(2) daily for 5 days every 3 weeks (Arm A) or 2.1 mg/m(2) weekly for 3 weeks out of 4 (Arm B). RESULTS: There were no responses in the weekly arm and a radiological response rate of 5.3% (95% CI 0.3-21.8%) in the daily arm. Principal toxicities were myelosuppression and emesis. Grade 3/4 neutropenia occurred in 29% of patients in Arm A and 6% patients in Arm B. Seventy-one percent of patients in Arm A required red cell transfusions while on treatment. CONCLUSIONS: Exatecan is well tolerated in this poor prognosis group of patients but only has modest single agent activity when administered in a daily regimen.     

Salvage chemotherapy with a combination of irinotecan hydrochloride and mitomycin C in platinum- and paclitaxel-resistant epithelial ovarian cancer: case reports

INTRODUCTION: The efficacy and toxicity of salvage chemotherapy with a combination of irinotecan hydrochloride (CPT-11) and mitomycin C (MMC) for platinum-and paclitaxel-resistant epithelial ovarian cancer are reported. CASE REPORT: Three consecutive patients with platinum- and paclitaxel- resistant epithelial ovarian cancer were treated with 120 mg/m2 of CPT-11 (days 1 and 15) and 7 mg/m2 of MMC (days 1 and 15) every four weeks. In all three cases partial responses were achieved and overall survivals were 17 months or longer. Most of the adverse side-effects were manageable. CONCLUSIONS: This regimen could be administered even in heavily pretreated patients with platinum- and paclitaxel- resistance. Phase I and II studies are needed to confirm the feasibility of this treatment. The efficacy of most salvage treatments for platinum- and paclitaxel-resistant epithelial ovarian cancer is disappointing, and our cases might be of interest from the perspective of treating platinum- and paclitaxel-resistant ovarian cancer.     

Bevacizumab and weekly taxane chemotherapy demonstrates activity in refractory ovarian cancer

OBJECTIVE: To determine the ability of patients to be treated with biweekly bevacizumab and weekly taxane chemotherapy in women with advanced, refractory ovarian cancer. METHODS: Ten patients with advanced, recurrent, and refractory ovarian cancer who were treated with biweekly bevacizumab (10 mg/kg) and weekly taxane (paclitaxel or docetaxel) chemotherapy days 1, 8, 15, and 22 every 28 days were identified retrospectively. All patients were followed with serial CA125 measurements prior to each cycle of therapy; cross-sectional imaging was not used to follow response to therapy. Toxicities were assessed prior to each cycle of treatment. RESULTS: Of the 10 patients treated with weekly taxane and biweekly bevacizumab therapy, all 9 that were evaluable had a decrease in CA125. Five patients have had an increase in CA125 after therapy after a median of three cycles (range 1-4), while 3 patients experienced normalization of CA125 and another with continued improvement in CA125. All symptomatic patients experienced rapid palliation of pain, nausea, and ascites. Side effects have been mild, with no grade 3 or 4 toxicities noted. No treatment delays or discontinuations have been necessary. CONCLUSION: Treatment of advanced, recurrent, refractory epithelial ovarian cancer with bevacizumab and weekly taxane chemotherapy leads to significant, albeit temporary, improvement in the cancer-related symptoms in women treated on this regimen, and short-term exposure to these agents is not associated with significant toxicity. Thus, continued investigation of bevacizumab with weekly scheduling of cytotoxic chemotherapy is imperative.     

Phase II study of irinotecan plus doxorubicin for early recurrent or platinum-refractory ovarian cancer: interim analysis

The aim of this study was to evaluate the efficacy and toxicity of irinotecan and doxorubicin in the treatment of patients with early recurrent or platinum-refractory ovarian cancer. Nineteen woman from five different institutions were treated. Two patients had platinum-refractory cancer, 11 had platinum-resistant disease, and 6 had platinum-sensitive tumors. An intravenous infusion of Irinotecan (50 mg/m(2)) was given on days 1, 8, and 15, while doxorubicin (40 mg/m(2)) was administered as an intravenous bolus on day 3. This treatment schedule was repeated every 4 weeks. Among the 13 patients defined as having platinum-refractory/platinum-resistant disease, 4 patients achieved a clinical response (30.8%, 95% CI: 9.1-61.4), while only one of 6 patients defined as having platinum-sensitive disease achieved a clinical response (16.7%, 95% CI: 0.4-64.1). Leukopenia and neutropenia were the major dose-limiting toxicities. Grade 3 or 4 leukopenia and neutropenia were noted in 24 (48%) and 33 (66%) of the courses, while febrile neutropenia occurred in 2 courses. Five patients (26%) had grade 2 or worse diarrhea during 7 courses. Our data demonstrated that this regimen might be comparable to standard approved agents in patients with early recurrent or platinum refractory ovarian cancer.     

Phase 2 trial of carboplatin, paclitaxel, and irinotecan in ovarian, fallopian tube, and primary peritoneal cancers

OBJECTIVE: Our goal in this nonrandomized phase 2 trial was to evaluate the toxicity and obtain preliminary data on the potential efficacy of a novel three-drug combination regimen (carboplatin-paclitaxel-irinotecan) when employed as initial therapy of advanced ovarian cancer or as second-line treatment in the setting of a prolonged (>or=12 months) treatment-free interval. METHODS: Patients with a histologically confirmed diagnosis of advanced ovarian cancer, primary adenocarcinoma of the peritoneum, or fallopian tube cancer were enrolled in the study. Patients received carboplatin (AUC 5), paclitaxel (150 mg/m(2) over 3 h), and irinotecan (100 mg/m(2) over 90 min). The three-drug combination was initially administered on an every 21-day schedule, but due to toxicity was subsequently changed to a 28-day program. RESULTS: A total of 30 patients were enrolled into this phase 2 trial. Twenty-three patients were chemotherapy naive, while 7 had received prior chemotherapy. Seventeen patients completed all six cycles of treatment. Eight patients (27%) were removed from the study after a median of three cycles due to toxicities. Seventeen patients (57%) experienced grade 4 neutropenia, with three individuals requiring hospitalization for neutropenic fever and dehydration. Grades 3 and 4 thrombocytopenia were experienced by three patients each. The principal nonhematologic toxicities were diarrhea (grade 3: three patients) and fatigue. The overall objective clinical response rate was 83%. CONCLUSIONS: The combination of carboplatin-paclitaxel-irinotecan can be administered to women with advanced ovarian cancer with significant, but overall acceptable toxicity. Modification of the regimen from a 3-week to a 4-week schedule permits a greater percentage of patients to complete the program without experiencing excessive toxicity. The overall objective response rate observed in this trial is comparable to other combination regimens employed in this setting. Defining a place for this three-drug program in the standard management of ovarian cancer will require the conduct of an appropriately designed randomized trial.     

A phase I study of Adp53 (INGN 201; ADVEXIN) for patients with platinum- and paclitaxel-resistant epithelial ovarian cancer

PURPOSE: Adenoviral p53 (Adp53) is a replication-deficient adenovirus containing human p53 cDNA. This phase I study was designed as a toxicity study of multiple dosing of Adp53 administered by intraperitoneal (IP) delivery to patients with ovarian cancer. EXPERIMENTAL DESIGN: Eligibility criteria included patients with platinum- and paclitaxel-resistant metastatic epithelial ovarian cancer; a Zubrod performance status of 0, 1, or 2; and adequate bone marrow, liver, and renal function. Patients underwent laparoscopy, washings, biopsies, and placement of an IP catheter within 10 days of Adp53 administration. Adp53 was given daily for 5 days every 3 weeks at one of the following four dose levels: 3 x 10(10), 3 x 10(11), 1 x 10(12), or 3 x 10(12) viral particles (vp). RESULTS: Seventeen patients were enrolled in the trial. Fifteen (88%) patients are evaluable for toxicity. The mean age of the study group was 51 years (range 32-67). All but one patient received two or more chemotherapy regimens before study entry. No dose-limiting toxicities (DLT) were observed. Grade 3 toxicities included fatigue (six patients), fever (two patients), chills (one patient), abdominal pain (three patients), nausea (two patients), and sinus congestion (one patient). One patient had Grade 3 edema and headache. There were no hematologic toxicities. Eleven patients (65%) are evaluable for response. Two of 17 patients (12%) had a mixed response. Four patients (24%) had stable disease for up to four courses. Five patients (29%) had progressive disease after one to two courses. CONCLUSIONS: Multiple dosing of IP Adp53 was well tolerated in this group of heavily pretreated patients; however, the dosing schedule and the amount cannot be concluded from this study. With a negative randomized trial of ovarian cancer in front-line treatment that included an adenovirus p53 plus chemotherapy, we feel that further refinement of gene therapy is required before additional trials are undertaken. OVERVIEW SUMMARY: Ovarian cancer is the most lethal of the gynecologic malignancies. It also tends to recur and progress within the abdominal cavity. Because of this, regional intraperitoneal therapy for ovarian cancer is attractive. Mutation and/or deletion of the p53 gene are common in advanced ovarian cancer. In this study, we have tested the safety and practicality of using an adenovirus-mediated delivery of the p53 gene to patients with chemo-refractory ovarian cancer via an intraperitoneal catheter. Fifteen patients were treated. Common toxicities were abdominal pain, fever, and chills. Several patients also had catheter infections. One patient had prolonged decrease in CA125 and stable disease. The best mechanism of delivery of gene therapy for patients is unclear, however, no severe toxicities were found using an adenovirus-mediated p53 gene in this group heavily pretreated patients with recurrent ovarian cancer.     

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.     

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 Study of 96-hr Continuous-Infusion Etoposide and Doxorubicin with Bolus Cyclophosphamide in Refractory Epithelial Ovarian Cancer

Effective salvage chemotherapy for patients with ovarian cancer who have failed platinum- and taxane-based regimens has not been identified. It has been reported that prolonged infusions of chemotherapy may be active in some malignancies which have become refractory to bolus treatments. We evaluated a regimen of 96-hr continuous-infusion doxorubicin (10 mg/m²/24 hr), etoposide (50 mg/m²/24 hr), and bolus cyclophosphamide (750 mg/m²) administered every 21 days to patients with ovarian cancer who had previously been treated with paclitaxel and a platinum compound. Nineteen women were treated, 15 of whom had platinum-refractory cancer. Six of the first 9 experienced a neutropenic fever after the first treatment cycle, and therefore all subsequent patients received prophylactic granulocyte-colony-stimulating factor. Other significant toxicities included hand and foot syndrome (1 patient) and mucositis (4 patients). There was one partial response in a patient with platinum-sensitive disease. We conclude that this regimen causes significant myelosuppression and does not have major activity in heavily pretreated patients with ovarian cancer.     

A phase I trial of gemcitabine and topotecan in previously treated ovarian or peritoneal cancer: a Gynecologic Oncology Group study

OBJECTIVE: To determine the maximum tolerated dose (MTD) of the combination of gemcitabine and topotecan in women with previously treated epithelial ovarian, peritoneal, or fallopian tube cancer. METHODS: Patients with recurrent or persistent cancer after treatment with a platinum and paclitaxel-containing regimen were eligible for this study. Initial treatment was gemcitabine at a dose of 800 mg/m(2) on days 1, 8, and 15 and topotecan at a dose of 0.5 mg/m(2) on days 2-5, with cycles repeated every 28 days. Dose escalations were planned first for topotecan (Cohort I, Dose Levels 1-5) then for gemcitabine (Cohort II, Dose Levels 6-9) until the MTD was reached. RESULTS: Ten patients received a total of 29 cycles. When none of the first four patients could complete therapy as prescribed due to toxicity, doses for each drug were reduced by 1 day. The next six patients were treated at the modified schedule of gemcitabine days 1 and 8 and topotecan days 2-4 (Dose Level -1). Despite this modification, dose-limiting toxicities including neutropenia, thrombocytopenia, and stomatitis occurred at Dose Level -1, and the study was closed early. CONCLUSIONS: At both the initial dose schedule and an attenuated schedule, the combination of gemcitabine and topotecan produced dose-limiting toxicities in women with previously treated epithelial ovarian or peritoneal cancer.     

Is age a barrier to the aggressive treatment of ovarian cancer with paclitaxel and carboplatin?

OBJECTIVE: The objective of this study was to determine whether the toxicities associated with chemotherapy are age related in women treated for ovarian cancer. METHODS: Patients with stage II-IV epithelial ovarian cancer underwent cytoreductive surgery. Adjunctive therapy was given to each patient consisting of intravenous (IV) paclitaxel 175 mg/m(2) over 3 h with a subsequent 30-min IV infusion of carboplatin. Carboplatin dose was calculated to achieve a targeted area under the curve (AUC) of 5.0-7.5. Treatment was repeated at 21- to 28-day intervals for six cycles. Toxicities were graded after each dose of chemotherapy. Results were analyzed using the Wilcoxon rank sum test and log likelihood ratio to compare toxicities in women age <60 years old to women >/=60 years old. RESULTS: Fifty-three women, 22 of whom were >/=60 years old, were treated with 309 cycles of chemotherapy. Forty-eight patients (92%) completed all six cycles. AUC dosing of carboplatin was equivalent for both groups. Carboplatin dose reduction occurred in 75% of patients for grade 4 neutropenia or thrombocytopenia. No patient required a reduction in the paclitaxel dose. Neutropenia was less frequent in women >/=60 years old than in women <60 years old (P = 0.02). There was no difference between women <60 years old and women >/=60 years old in the incidence of anemia, thrombocytopenia, or the use of growth factors. A 68% complete clinical response rate was observed in women >/=60 years old compared to a 74% complete response rate for women under age 60 (P = 0.22). CONCLUSION: Age is not a barrier to the aggressive treatment of ovarian cancer with this regimen of paclitaxel and carboplatin.     

Retrospective analysis of weekly topotecan as salvage therapy in relapsed ovarian cancer

OBJECTIVE: To retrospectively investigate the safety and efficacy of weekly topotecan in heavily pretreated patients with ovarian cancer. METHODS: Data were collected by retrospective review of patient records. Eligible patients had received > or =2 prior regimens for ovarian cancer before treatment with weekly topotecan. Efficacy was determined by measurable disease or CA 125 levels. Adverse event and growth factor support data were also collected. RESULTS: Fifty patients (median age, 61 years) were evaluable for safety and received a total of 244 4-week cycles of therapy (median, 3; range, 1-21 cycles). Most patients (84%) had measurable disease, and 30% had performance status of > or =2. Patients had received two to six prior treatments for ovarian cancer. Median weekly dose per patient was topotecan 3.7 mg/m(2). Grade 4 hematologic toxicities (generally manageable) occurred in 4% of patients. One patient had febrile neutropenia. Grade 3/4 nonhematologic toxicities were fatigue in two (4%) patients. Forty-two patients were evaluable for response. Of 35 evaluable patients with measurable disease, 11 (31%) had a partial response (median duration, 3 months), and 15 (43%) patients had stable disease (median duration, 3.5 months). Of 41 evaluable patients with elevated CA 125 (median, 154 U/l; range, 47-7200 U/l), 11 (27%) had > or =50% decreases or normalization of CA 125 levels. Median time to progression in all patients with stable disease has not been reached (follow-up range, 1.5-17.3 months). CONCLUSIONS: Weekly topotecan is active and well tolerated in heavily pretreated patients with relapsed ovarian cancer. Prospective studies of this regimen are warranted.     

Safety and efficacy of lenalidomide (Revlimid) in recurrent ovarian and primary peritoneal carcinoma

OBJECTIVES: To conduct a phase I trial to determine the safety and toxicity profile of a novel immunomodulatory drug, lenalidomide, in recurrent ovarian and primary peritoneal cancer. The secondary objective is to evaluate the efficacy profile and quality of life (QOL) parameters in patients receiving this treatment. METHODS: Patients with recurrent ovarian or peritoneal cancer who received standard staging surgery and at least one prior platinum-based chemotherapy regimen were treated with single-agent oral lenalidomide 25 mg daily for 21 days of a 28-day cycle. Toxicities were monitored by patient report, physical exam, and laboratories. Response was assessed by imaging, physical exam, and CA-125. Therapy was discontinued with disease progression and/or unacceptable toxicity. RESULTS: 20 patients with recurrent ovarian or peritoneal cancer were enrolled and received 70 completed 28-day cycles and 10 partial cycles of lenalidomide therapy. The majority of adverse events were grades 1-2, including fatigue (25/80 cycles), nausea/vomiting (23/80), constipation (13/80), abdominal pain (17/80), rash (12/80), neutropenia (12/80), and anemia (12/80). Grade 3 toxicities occurred in 12 of 80 cycles (14%) and no grade IV toxicities were observed. Eleven patients completed > or = 2 cycles and were evaluable for response. Nine achieved stable disease (SD) of at least 3 months, with four patients maintaining SD for > 6 months. The mean time to progression was 5.8 months (range 2-12 months). CONCLUSION: Overall, oral lenalidomide was well tolerated and may have some activity as a single agent in this heavily pre-treated population. Further studies combining lenalidomide with cytotoxic treatments may be warranted in this disease setting.     

Three-consecutive-day topotecan is an active regimen for recurrent epithelial ovarian cancer

OBJECTIVE: The aim was to determine the response rate and toxicity of topotecan administered Days 1-3 every 21 days for recurrent epithelial cancers of the ovary, peritoneum, or fallopian tube. A 3-day regimen may be more convenient and less expensive than a 5-day schedule. METHODS: Patients with recurrent epithelial cancer of the ovary, peritoneum, or fallopian tube who had adequate hepatic, renal, and hematologic function were eligible for participation. Topotecan (2 mg/m(2)) was administered for 3 consecutive days every 21 days. Response was measured clinically and serologically. Granulocyte colony stimulating factors (GCSF) were not utilized prophylactically, but could be added under specific conditions. RESULTS: Thirty-one patients with recurrent ovarian cancer whose median age was 63 (range 32-84) received 165 cycles of topotecan (median = 6; range 2-8) and are evaluable for toxicity. The median number of prior regimens was 1. Topotecan was administered on schedule in 96.6% of cycles. Grade 3/4 neutropenia was seen in 29.1 and 23.6% of courses, respectively; but only 3.4% of cycles required GCSF support (6 cycles for 2 patients). Grade 4 thrombocytopenia was rare (1% of cycles). Nonhematologic toxicity was mild. The response rate for 28 evaluable patients was 32.1% (10.7% complete response (CR) and 21.4% partial response (PR)); stable disease was seen in 17.9% of patients. The median progression-free interval (PFI) for all patients was 15.5 weeks (range 5-40). Eighteen platinum-sensitive patients demonstrated a 43.4% response rate (12.5% CR and 31.3% PR); stable disease was documented in 18.8%. The median PFI for platinum-sensitive patients was 18.5 weeks (range 5-40). CONCLUSION: Topotecan is an effective regimen with acceptable toxicity for recurrent ovarian cancer when administered for 3 consecutive days (2 mg/m(2)) every 21 days. It can be delivered on schedule without GCSF support in the vast majority of patients.     

A phase I trial of oxaliplatin and topotecan in recurrent ovarian carcinoma

OBJECTIVE: Oxaliplatin and topotecan have demonstrated activity as single agents against recurrent platinum-sensitive and -resistant ovarian cancer, as well as synergy in vitro. This was a dose-finding study of combination therapy with weekly topotecan and alternating-week oxaliplatin in patients with recurrent epithelial ovarian cancer. METHODS: Eligible patients had a diagnosis of recurrent ovarian or primary peritoneal carcinoma, a performance status of 0-2, and normal bone marrow, renal, and hepatic function. On days 1 and 15 of a 28-day cycle, patients received a fixed dose of oxaliplatin (85 mg/m2) via intravenous infusion. On days 1, 8, and 15, patients received an escalating dose of intravenous topotecan (2.0-4.0 mg/m2). Five dose levels were planned with a minimum cohort of 3 patients at each level. RESULTS: Thirteen patients were enrolled and received a total of 50 cycles of chemotherapy. The maximum tolerated dose was 85 mg/m2 of oxaliplatin and 3.0 mg/m2 of topotecan, and grade 3 neutropenia was the dose-limiting toxicity. Four of nine (44%) evaluable patients had stable disease or a partial response to the drug combination as assessed by cancer antigen-125 levels. CONCLUSIONS: A 28-day schedule of oxaliplatin and topotecan is safe and well tolerated. Because of the in vitro synergy observed between topoisomerase I inhibitors and platinum derivatives and the tolerability reported in the current study, this regimen warrants further investigation.     

以吉西他滨为基础的联合化疗治疗复发性铂类耐药卵巢上皮性癌的临床观察

目的 评价以吉西他滨为基础联合异环磷酰胺和蒽环类药物治疗复发性铂类耐药卵巢上皮性癌(卵巢癌)的近期疗效及毒副反应.方法 对60例复发性铂类耐药卵巢癌患者应用吉西他滨、异环磷酰胺和蒽环类药物联合化疗方案[吉西他滨800 mg/m2,第1、8天;异环磷酰胺1.5 g/m2,第1～3天;多柔比星(其他名称:阿霉素)40 mg/m2或表柔比星(其他名称:表阿霉素)60 mg/m2(第1天),或米托蒽醌10 mg/m2(第1、8天);21～28 d重复],回顾性分析其临床病理资料.结果 60例患者共接受172个疗程的化疗.完全缓解0例,部分缓解22例(37%,22/60),稳定23例(38%,23/60),疾病进展15例(25%,15/60),临床总获益率75%(45/60);中位无疾病进展生存期为7个月,中位总生存期为20个月.主要不良反应为骨髓抑制,白细胞减少发生率达82%(49/60),其中Ⅲ～Ⅳ度占31%(15/49);消化道反应均为Ⅰ、Ⅱ度,占42%(25/60).结论 以吉西他滨为基础的联合化疗可作为铂类耐药的复发性卵巢癌的治疗方案之一,毒副反应可以耐受.     

Consolidation therapy with weekly paclitaxel infusion in advanced epithelial ovarian cancer and primary peritoneal cancer: an extended follow-up

OBJECTIVE: To determine the impact of weekly paclitaxel consolidation on progression-free survival (PFS) of women undergoing treatment for ovarian cancer. METHODS: All women with advanced epithelial ovarian or primary peritoneal carcinoma, treated with paclitaxel consolidation therapy from August 1997 to March 2002, were identified. Patients received weekly paclitaxel infused at a median dose of 80 mg/m(2) (range: 60-80 mg/m(2)) for a maximum of 12 weeks. A chart review was performed to assess disease status and chemotherapy-related toxicities. PFS was calculated from the date of initiation of induction chemotherapy until the date of documented disease recurrence. RESULTS: 31 women received paclitaxel consolidation therapy over the study period (29 stage III and 2 stage IV). 24 women had epithelial ovarian carcinoma and 7 were diagnosed with primary peritoneal carcinoma. The median PFS was 27 months (range: 12-62 months). The overall 2-year survival was 94%, where 17 women (55%) were without evidence of disease and 12 (39%) were alive with disease. The median follow-up was 41 months (range: 15-77 months). Over 337 weeks of consolidation therapy, 1 patient experienced Grade 3 neuropathy and 1 patient developed Grade 3 neutropenia. CONCLUSION: Consolidation therapy with weekly paclitaxel infusion is a well-tolerated regimen that resulted in a median PFS of 27 months in women who obtained a complete clinical response following induction therapy. Given the lack of side effects and the potential for extending the PFS of those treated, a prospective randomized study of weekly paclitaxel should be considered.     

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.