The role of topotecan as second-line therapy in patients with recurrent ovarian cancer

INTRODUCTION: Up to 80% of patients with advanced ovarian cancer will recur following first-line platinum containing chemotherapy. Topotecan has recently been used as a second-line agent in treatment of advanced ovarian disease. The aim of the study was to evaluate the effect of topotecan on response rate and progression-free interval on patients with recurrent ovarian cancer who had been treated with platinum-containing first-line chemotherapy. METHODS: A retrospective review of all cases of recurrent ovarian cancer treated with topotecan was done. Response was determined using radiologic reports (CT scans, ultrasound scans), CA-125 level and the clinical evaluation. Response type was determined using World Health Organization (WHO) criteria. RESULTS: Between 1998-2000, a total of 43 patients were treated with topotecan. Median age was 57 (range 41-80), 40/43 patients had stage III and IV, 37/43 patients had Grade 3 tumors. Seventeen of 43 patients (39.5%) demonstrated stable disease and 9/43 (21%) patients demonstrated partial response. Median time to response was eight weeks, median progression-free interval was 31 weeks and median time of follow-up and survival was 48 weeks. CONCLUSION: Topotecan is considered a reasonable option for treatment of patients with recurrent ovarian cancer that have failed previous treatment with platinum-containing chemotherapy.     

Phase II evaluation of 3-day topotecan with cyclophosphamide in the treatment of recurrent ovarian cancer

OBJECTIVE: The aim of this trial was to investigate the toxicity and efficacy of a 3-day topotecan administration schedule in combination with cyclophosphamide in the management of recurrent ovarian cancer. METHODS: Patients with recurrent measurable ovarian cancer who had up to two prior chemotherapy regimens for the management of their disease participating in this phase II trial were to receive topotecan at a dose of 1.25 mg/m(2)/day x 3 days in combination with cyclophosphamide at 600 mg/m(2) on Day 1 every 21 days. Dose escalation and reductions were permitted. RESULTS: A total of 36 patients (median age = 65; range 37-84) were treated with this combination regimen. Seventeen were platinum-sensitive and 19 were platinum-resistant. A total of 169 cycles of chemotherapy was administered (median = 4; range 1-10). Major toxicity included grade 4 neutropenia (68.6%), neutropenic fever (7.1%), grade 3 thrombocytopenia (18.3%), and requirement for blood transfusion (19.5%). Dose escalation was possible in 3 (8.3%), and dose reduction was required in 14 (38.9%) patients. Overall response rate was 25 and 44.5% stable disease. Median progression-free interval and overall survival was 5.4 and 23.5 months, respectively, independent of platinum sensitivity. CONCLUSION: The 3-day topotecan schedule in combination with cyclophosphamide appears to have good activity in recurrent ovarian cancer regardless of platinum sensitivity. Neutropenia was the only severe toxicity and was less prevalent than other reported trials of topotecan. This tolerable regimen offers patients more convenience and appears to have moderate activity.     

Topotecan and ifosfamide as salvage treatment in advanced ovarian cancer

OBJECTIVE: The purpose of the study was to evaluate activity and toxicity of the combination of topotecan and ifosfamide as salvage treatment in patients with advanced ovarian cancer refractory to or relapsing after platinum compound-based chemotherapy. METHODS: Thirty-nine patients entered the trial. Inclusion criteria were: previous platinum compound-based chemotherapy with or without paclitaxel, age /=50% reduction of baseline CA-125 was recorded. Significant higher response rate was observed in platinum-sensitive population (11/15 patients) compared to resistant disease (8/24 patients). CONCLUSIONS: Chemotherapy with topotecan and ifosfamide (IT) in pretreated advanced ovarian cancer patients is feasible with moderate toxicity. The potential of the regimen for synergistic drug interactions deserves further evaluations.     

拓扑替康联合铂类治疗晚期卵巢癌的疗效观察

目的:评价拓扑替康联合铂类(TPT+铂类)治疗晚期卵巢癌的疗效及安全性。方法:回顾分析2000年4月至2004年12月收治的符合入选标准的晚期卵巢上皮性癌患者45例,其中初治20例,复治25例。比较初治患者与同期收治的接受紫杉醇加铂类(TP方案)及环磷酰胺加铂类(PC方案)治疗者的临床有效率、中位无进展生存时间和中位生存时间。复治患者则比较一线经铂类或经紫杉醇治疗复发者的有效率、中位无进展生存时间和中位生存时间。结果:初治患者中,TPT+铂类组有效率为75.0%,中位无进展生存时间及中位生存时间分别为17.8月及29.7月,而TP组分别为82.5%,20.9月,35.3月,PC组分别71.4%,14.6月,27.8月,TPT加铂类组与TP组、PC组相比,差异无显著性(P>0.05)。复治患者中,总有效率为28.0%,一线经铂类或经紫杉醇治疗复发患者的有效率为33.3%、23.1%,中位无进展生存时间分别为11.3月、8.4月,中位生存时间分别为18.3月,17.3月,差异无显著性(P>0.05)。非血液性毒性轻微。结论:TPT联合铂类治疗晚期卵巢癌疗效肯定,特别是对复发病例有较好疗效,耐受性良好。     

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.     

An open label evaluation of topotecan in patients with relapsed or refractory epithelial ovarian cancer – single institution experience in a developing country

Abstract. Malik IA. An open label evaluation of topotecan in patients with relapsed or refractory epithelial ovarian cancer–single institution experience in a developing country.
Investigators in developing countries rarely get an opportunity to participate in clinical drug trials in oncology. We recently participated in two clinical trials involving the use of topotecan in patients with advanced epithelial ovarian cancer who had failed initial platinum based chemotherapy. It provided us an opportunity to gain experience with the use of a rather highly myelosuppressive drug and also enabled us to compare our data with those reported from the western countries. Thirty-nine patients with good performance status and adequate bone marrow, liver, and renal functions were accrued. All patients had previously received at least one platin containing regimen of chemotherapy. The most common histologic sub type was serous adenocarcinoma. Almost half of the patients had platinum refractory disease. Mean number of cycles delivered was 7.5. Eleven patients (28%) achieved complete or partial remission. Time to progression was 4.6 months. Mean overall survival was 11.3 months. Toxicity was primarily hematologic and manageable. Performance status was the only variable predictive of response. Ability to obtain informed consent, data management, and availability of adequate radiologic and laboratory facilities were important limitations. Our results confirm the applicability of results obtained in the western countries to other patient groups and ability to conduct clinical trials in oncology in the developing countries.     

Lack of efficacy of 24-h infusional topotecan in platinum-refractory ovarian cancer: A Gynecologic Oncology Group trial

BACKGROUND: The aim of this study was to evaluate the efficacy of a more convenient topotecan administration schedule in the second-line treatment of advanced platinum-refractory ovarian cancer. METHODS AND MATERIALS: The Gynecologic Oncology Group conducted a Phase II trial of 24-h infusional topotecan (8.5 mg/m(2)), repeated every 3 weeks in 26 patients with platinum-refractory ovarian cancer (failure to respond to initial platinum-based treatment or development of recurrent disease within 6 months of completion of chemotherapy). RESULTS: Grade 4 neutropenia (85% of patients) and thrombocytopenia (12%) were the major toxicities encountered. Of the 25 patients evaluable for response, only a single patient experienced an objective response (4%). CONCLUSIONS: When employed at this dose and schedule (24-h infusion every 3 weeks), topotecan has minimal second-line activity in platinum-refractory ovarian cancer.     

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

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

UCN-01 in combination with topotecan in patients with advanced recurrent ovarian cancer: a study of the Princess Margaret Hospital Phase II consortium

BACKGROUND AND OBJECTIVE: UCN-01 is a staurosporine analogue shown to abrogate the G2 checkpoint through inhibition of cyclin-dependent kinases. Preclinical evidence suggests synergy between UCN-01 and cytotoxic chemotherapy. Topotecan is an active agent in ovarian cancer. This phase II study was conducted to investigate the safety and efficacy of topotecan and UCN-01 in patients with advanced ovarian cancer. METHODS: A two-stage phase II trial was designed for patients with advanced ovarian cancer with progressive disease despite prior treatment with platinum and paclitaxel. Patients with advanced ovarian cancer were treated with topotecan, 1 mg/m(2) IV, days 1 to 5, and UCN-01 70 mg/m(2) on day 1 of the first cycle, and 35 mg/m(2) on day 1 of all subsequent cycles. Treatment was repeated on a 3-week cycle. The primary objective of this study was objective response rate while secondary objectives included rates of stable disease, duration of response, progression-free and overall survival, as well as toxicity. Tumor biopsy specimens were also collected where possible for molecular correlative studies. RESULTS: Twenty-nine patients are evaluable for toxicity and efficacy. Three patients (10%) achieved a partial response. The median time to progression was 3.3 months (95% CI 1.5-NA), and the median overall survival was 9.7 months (95% CI: 7.5-15.3). The most common grade 3-4 toxicities were neutropenia (79%), anemia (41%), thrombocytopenia (14%), hyperglycemia (10%), and pain (10%). CONCLUSION: The combination of UCN-01 and topotecan is generally well tolerated, however, this combination is not considered to have significant antitumor activity against advanced ovarian cancer.     

Phase II evaluation of 24-h continuous infusion topotecan in recurrent, potentially platinum-sensitive ovarian cancer: A Gynecologic Oncology Group study

OBJECTIVES: The aim of this study was to develop an alternative effective and more convenient administration schedule for intravenous topotecan when used as palliative treatment in ovarian cancer. METHODS: The Gynecologic Oncology Group conducted a Phase II trial of 24-h infusional topotecan (8.5 mg/m(2)) with treatment repeated every 3 weeks in 29 patients with platinum-sensitive recurrent ovarian cancer (prior response to platinum-based chemotherapy with a minimum treatment-free interval >/=6 months). RESULTS: The major toxicities of therapy were grade 4 neutropenia and thrombocytopenia which developed in 86 and 14% of patients, respectively. Other severe side effects were uncommon. Only 2 partial responses (7%) were observed in the 28 patients evaluable for response. CONCLUSIONS: Despite the relatively favorable ovarian cancer patient population treated in this trial (platinum-sensitive recurrent disease), the response rate was disappointingly low. Considering the three- to fivefold higher objective response rates observed in other trials employing topotecan in individuals with platinum-sensitive ovarian cancer utilizing a 5-day treatment program (delivered every 3 weeks), the results of the current study provide strong support for the conclusion that clinically relevant antineoplastic activity of this agent is highly schedule dependent.     

Own experiences in salvage chemotherapy of ovarian cancer--a preliminary report

OBJECTIVE: To compare the efficacy and side effects of the ovarian cancer salvage treatment. MATERIALS AND METHODS: 28 patients from 2nd Department of Gynecology of Wroc?aw Medical University, treated for recurrent ovarian cancer in stage III and IV were analyzed. First line treatment after complete debulking operation was based on platinum analogue (CAP). Platinum-sensitive patients were administered carboplatin with paclitaxel in the second line treatment. Platinum-resistant cases were treated with paclitaxel, topotecan or liposomal doxorubicin only. RESULTS: The effectiveness of the salvage chemotherapy was similar. Side effects depended on used agent. CONCLUSIONS: We conclude that the results of salvage treatment in ovarian cancer remain unsatisfactory. Introducing new agents into the therapy slightly improved the overall survival time.     

No rules without exception: long-term complete remission observed in a study using a LH-RH agonist in platinum-refractory ovarian cancer

OBJECTIVE: Second-line chemotherapy in platinum/paclitaxel-resistant ovarian cancer induces an objective response in <15% and third-line chemotherapy results in responses less than 10%. Chemotherapy always results in side effects with the risk of a low quality of life. Endocrine therapy is used world-wide among chemo-resistant ovarian cancer. Tamoxifen is a standard palliative treatment in many centers. LH-RH (luteinizing hormone-releasing hormone) agonists have also demonstrated activity among patients with ovarian cancer in several studies with response rates of 9-12% and disease stabilization in 15-26% of these women. METHODS: In this retrospective study 32 patients with ovarian cancer who had relapsed after platinum/paclitaxel-based first-line chemotherapy and had exhausted all standard treatments received LH-RH analogue Leuprorelin depot 3.75 mg sc once a month until tumor progression. RESULTS: One patient (3%) had a complete response, with remission time over 3 years. Two patients (6%) reached partial response with remission time of 3 and 4 months. Four patients (12%) remained stable for a mean time of 7 months (range 4-12 months). The remaining 25 patients (78%) had progressive disease. The treatment was well tolerated, and no major toxicity has been reported. CONCLUSION: This study showed that LH-RH agonist Leuprorelin has only a limited effect in patients pretreated with platinum-based chemotherapy.     

Chemotherapy for recurrent epithelial ovarian cancer previously treated with platinum--a systematic review of the evidence from randomized trials

PURPOSE: To evaluate the chemotherapeutic options for women with recurrent epithelial ovarian cancer who have received platinum-based chemotherapy. METHODS: A systematic search of the Medline, CancerLit and Cochrane Library databases was performed for the period from 1984 to June 2001 to find randomized trials comparing second- or higher-line chemotherapy regimens in patients with recurrent platinum-pretreated epithelial ovarian cancer. RESULTS: Seven randomized trials have failed to demonstrate the clear superiority of any one chemotherapy regimen in terms of improvements in long-term survival, quality of life or response rate. One trial detected a statistically significant difference between treatments in progression-free survival, which was longer with cyclophosphamide/doxorubicin/cisplatin than with paclitaxel in women with platinum-sensitive ovarian cancer. Another trial did not show a difference between liposomal doxorubicin and topotecan overall in women with recurrent ovarian cancer but a subgroup analysis detected a significant survival advantage for liposomal doxorubicin over topotecan in women with platinum-sensitive disease. CONCLUSION: The evidence available does not support firm conclusions about the preferred chemotherapy regimen for recurrent ovarian cancer. Randomized trials that compare new drugs with current standard treatments are needed.     

Weekly topotecan for recurrent endometrial cancer: a case series and review of the literature

OBJECTIVE: Topotecan, a topoisomerase 1 inhibitor, has demonstrated antitumor activity in ovarian and endometrial cancers when administered daily for 5 days every 3 weeks. Recently, topotecan has been studied on a weekly dosing schedule for the treatment of ovarian cancer and found to have efficacy with reduced toxicity. The aim of this study is to review the Memorial Sloan-Kettering Cancer Center (MSKCC) experience with weekly topotecan dosing in women with recurrent endometrial cancer. We have included a review of the literature of weekly topotecan in the treatment of patients with gynecologic cancer. METHODS: After Institutional Review Board (IRB) approval, we identified all women with recurrent endometrial cancer treated with topotecan at MSKCC from May 1996 to February 2004. Patients treated on a weekly schedule were assessed for toxicity and response. A review of the literature pertaining to weekly topotecan in the treatment of endometrial cancer was also performed. RESULTS: Eleven patients were treated with weekly topotecan during the study period, with doses ranging from 2.5-4.0 mg/m(2) on a 2- or 3-week schedule with 1 week off. The median age of the patients was 60 years old (range, 47-76 years), and the median Karnofsky performance status was 80%. Six of the 11 patients were previously treated with more than three chemotherapy regimens and eight had received prior pelvic radiation. Ninety-seven percent of treatment doses were delivered as scheduled, and only two patients required dose reductions. One patient achieved a prolonged partial response for 54 weeks, and two patients had stabilization of disease for 15 weeks each. CONCLUSIONS: Weekly topotecan has antitumor activity and is well tolerated in patients with recurrent endometrial cancer, including those patients with multiple prior treatments. Topotecan on a weekly bolus schedule should be evaluated in prospective trials to better establish its role in the treatment of recurrent endometrial cancer.     

Platinum retreatment of platinum-resistant ovarian cancer after nonplatinum therapy

OBJECTIVE: The objective was to determine the response rate to platinum retreatment of "platinum-resistant" ovarian cancer after intervening nonplatinum therapy. METHODS: We retrospectively identified 30 patients with platinum-resistant ovarian cancer who received nonplatinum chemotherapy for recurrent epithelial ovarian cancer prior to additional platinum therapy. All patients were treated between July 1, 1997, and June 30, 2001. Platinum resistance was defined as less than a partial response to platinum therapy or progression within 6 months of the last platinum therapy. RESULTS: Overall, 7 of 30 patients experienced an objective response to platinum therapy (partial response, 23%; complete response, 0%) based on CT scan (2/21) and/or CA-125 (5/9) criteria. The median time to progression for the group was 17 weeks (range, 4-59 weeks). Several predictive factors were identified. The interval since the last platinum treatment did not appear to be predictive in this group. Only 1 of 16 patients who did not have an objective response to the most recent platinum-based therapy responded to platinum rechallenge. Similarly, no patient who received more than three intervening nonplatinum treatments responded to additional platinum therapy (0/10). CONCLUSIONS: Our small retrospective series suggest that the platinum-resistant category is heterogenous and includes patients who may respond to retreatment with platinum-based agents. This group includes the patients with prior platinum responses and early progression. However, patients without an objective response to the last prior platinum therapy or more than three intervening treatments are unlikely to respond to subsequent platinum therapy.     

A dose-escalating study of weekly bolus topotecan in previously treated ovarian cancer patients

OBJECTIVE: Topotecan is an established topoisomerase I inhibitor for the treatment of relapsed ovarian cancer. Myelotoxicity and suboptimal patient convenience associated with daily topotecan, however, have prompted investigators to explore alternate regimens, including a weekly regimen of topotecan. The objective of this study was to determine the maximum tolerated dose (MTD) of topotecan given as a weekly bolus in previously treated ovarian cancer patients. METHODS: Second- and third-line ovarian cancer patients with measurable disease or elevated cancer antigen 125 received weekly bolus topotecan intravenously starting at 1.5 mg/m(2). Topotecan was escalated in dose increments of 0.5 mg/m(2) every 21 days as tolerability allowed. Dose-limiting toxicity was defined as grade 3/4 neutropenia or thrombocytopenia. RESULTS: Thirty-two of 35 patients were evaluable for safety and tolerability. No notable toxicity was observed with weekly topotecan doses < 4 mg/m(2). Additionally, there was an absence of dose-limiting myelotoxicity and thrombocytopenia with weekly topotecan. The MTD of weekly topotecan without the use of granulocyte colony-stimulating factor support was 4 mg/m(2), with grade 2 anemia, chronic fatigue, and grade 2 gastrointestinal toxicity limiting further dose escalation. Weekly topotecan also demonstrated antitumor activity at doses >2 mg/m(2). CONCLUSIONS: The establishment of a well-tolerated, weekly regimen of topotecan (4 mg/m(2), with a maximum recommended dose of 6 mg/m(2)) provides the basis for further investigation in phase II studies of single-agent and combination regimens in previously treated ovarian cancer patients.     

Topotecan in Platinum- and Paclitaxel-Resistant Ovarian Cancer

Objective:The purpose of this study was to define the response rate and toxicity of topotecan in patients with ovarian cancer resistant to first-line therapy.Methods:Twenty patients with advanced or recurrent ovarian cancer were enrolled in a phase I/II protocol, and an additional 16 patients were treated following protocol closure at Washington University Medical Center. The starting dose of topotecan was 1.25 mg/m²/day given intravenously over 30 min for 5 consecutive days. Patients were eligible for response evaluation if they completed more than one cycle of topotecan. All patients were evaluated for toxicity.Results:Of 28 patients eligible for response evaluation, 26 were resistant to both platinum and paclitaxel prior to treatment with topotecan. There were four partial responders and no complete responders for a total response rate of 14% (95% confidence interval: 4 to 33%). All responders had exhibited primary resistance to both platinum and paclitaxel. Myelotoxicity was the major toxicity, with 92% of patients experiencing Gynecologic Oncology Group (GOG) grade 3 or 4 neutropenia and 67% experiencing GOG grade 3 or 4 thrombocytopenia. Other toxicity was minimal and easily managed. Fifty percent of patients receiving more than one cycle of topotecan tolerated a dose equal or greater to the starting dose.Conclusions:Topotecan exhibits activity in patients with ovarian cancer resistant to both platinum and paclitaxel. Further study is warranted in less heavily pretreated patients and in combination with other chemotherapeutic agents.     

盐酸拓扑替康腹腔注射对大鼠腹腔器官及外周血白细胞的影响

目的 :探索拓扑替康腹腔化疗的安全性和可行性。方法 :以健康SD雌性大鼠为研究对象 ,观察拓扑替康腹腔化疗对大鼠腹腔内器官和外周血白细胞的影响。结果 :在剂量与静脉化疗总量相同和加大一倍时 ,拓扑替康腹腔化疗除引起与对照组相同的子宫炎症反应外 ,大网膜产生炎症反应 ;对卵巢和胰腺等则均无明显影响 ;当应用 4倍剂量时 ,造成胰腺实质间质部炎症反应。对外周血白细胞计数的影响与剂量有关 ,虽然各剂量腹腔化疗后第 3天 ,外周血白细胞计数都有下降 ,但仅在相当于静脉化疗剂量 2倍时 ,下降有统计学意义 ,剂量加大至 4倍时 ,虽然无统计学意义 ,但此实验组的白细胞计数在化疗后 5天无明显回升 ,直至化疗后 8天才恢复。其他实验组白细胞计数在化疗后 5天已回升至化疗前水平。结论 :拓扑替康腹腔化疗对大鼠外周血白细胞计数无严重影响 ,在适当剂量下对腹腔各正常器官也无明显刺激 ,对其一般情况等无明显作用。所以 ,在适当剂量下拓扑替康腹腔化疗是安全的 ,它为治疗卵巢肿瘤 ,特别是晚期、复发及耐药的卵巢肿瘤提供了新的途径。     

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.     

Phase II trial of lapatinib and topotecan (LapTop) in patients with platinum-refractory/resistant ovarian and primary peritoneal carcinoma

Objective

Resistance to chemotherapy is a major challenge in the treatment of ovarian/peritoneal cancer. One purported mechanism of topotecan resistance is the breast cancer resistance protein (BCRP) and P-glycoprotein (Pgp). We designed a phase II clinical trial evaluating the efficacy and adverse event profile of concomitant topotecan and lapatinib, a small molecule pan-erbB inhibitor that can block BCRP/Pgp efflux of topotecan.

Methods

Patients with platinum-refractory or resistant epithelial ovarian/peritoneal cancer were treated with topotecan 3.2 mg/m2 IV on Day 1, 8 and 15 and lapatinib 1250 mg PO daily, continuously in 28 day cycles. The primary endpoint was response rate. For correlative studies, archived tissue was assessed for expression of EGFR, HER2, HIF-1α, CD31, and BCRP.

Results

Eighteen patients were enrolled and treated. Four experienced evidence of clinical benefit: one partial response and three with stable disease. Using a two-stage Simon design, the trial was stopped after the first stage due to insufficient activity. Grades 3+ and 4+ adverse events (AE) were experienced in 14 and 4 patients, respectively. The most common grade 3/4 AE were neutropenia (56%), thrombocytopenia (28%), and diarrhea (22%).

Conclusions

The combination of lapatinib plus topotecan for the treatment of platinum refractory/resistant epithelial ovarian cancer lacks sufficient activity to warrant further investigation. In particular, hematologic adverse events were substantial. Expression of correlative study markers did not reveal patterns of predicted benefit or toxicity. Disruption of erbB signaling and BCRP/Pgp efflux with lapatinib was insufficient for overcoming topotecan resistance, suggesting alternative mechanisms of resistance are involved.