Phase II trial of vinorelbine for relapsed ovarian cancer: a Southwest Oncology Group study

OBJECTIVES: To assess the activity of vinorelbine in women with recurrent or resistant epithelial ovarian cancer following treatment with platinum and paclitaxel in terms of survival rate at 6 months, objective response rate (in the subset of patients with bidimensionally measurable disease), and health-related quality of life. METHODS: Seventy-nine evaluable patients with progressive ovarian cancer following platinum and taxane therapy received vinorelbine 30 mg/m(2) days 1 and 8 of a 21-day treatment cycle. RESULTS: Six-month survival rate for the entire group was 65% (95% CI: 54-75%) and median survival was 10.1 months (95% CI: 7.7-13.6 months). In the 71 women with measurable disease, 0 complete and 2 partial responses were observed (RR = 3%) (95% CI: 0.3-10%). Patients reported substantial symptom-related distress at baseline, which persisted, but did not worsen, during treatment. Patients also had impaired physical functioning at baseline and this continued to decline during treatment. CONCLUSIONS: The 6-month survival rate achieved with salvage vinorelbine is comparable to the results obtained with other salvage therapies in patients with relapsed ovarian cancer. During the initial 10 weeks of treatment, vinorelbine did not appear to be effective in alleviating the symptom-related distress or progressive impairment of physical functioning associated with this disease.     

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

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

Survival outcomes in patients with recurrent ovarian cancer who were treated with chemoresistance assay-guided chemotherapy

OBJECTIVE: The purpose of this study was to determine the outcome of patients with recurrent ovarian carcinoma after extreme drug resistance assay-directed therapy. STUDY DESIGN: Fifty women who were treated with chemotherapy based on extreme drug resistance assay guidance were compared with 50 well-balanced control subjects who were treated empirically. RESULTS: In the platinum-sensitive group, patients with extreme drug resistance-directed therapy had an overall response rate of 65% compared with 35% in the patients who were treated empirically (P=.02). The overall and progression-free median survival were 38 and 15 months in the extreme drug resistance assay group compared with 21 and 7 months in the control group, respectively (P=.005, overall; P=.0002, progression free). In the platinum-resistant group, there was no improved outcome in the patients who underwent assay-guided therapy. In multivariate analysis, platinum-sensitive disease, extreme drug resistance-guided therapy and early stage of disease were independent predictors for improved survival. CONCLUSION: In this retrospective analysis, our results indicate an improved outcome in patients with recurrent ovarian carcinoma who have platinum sensitive disease and who underwent extreme drug resistance-directed chemotherapy. Randomized, prospective, controlled trials are needed.     

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

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

Phase II trial of weekly paclitaxel (80 mg/m2) in platinum and paclitaxel-resistant ovarian and primary peritoneal cancers: a Gynecologic Oncology Group study

OBJECTIVE: To evaluate the activity of single agent weekly paclitaxel in patients with both platinum and paclitaxel (delivered every 3 weeks)-resistant ovarian cancer. METHODS: Forty-eight patients with platinum and paclitaxel-resistant ovarian cancer (defined as progression during, or recurrence < 6 months following, their prior treatment with both agents) received single agent weekly paclitaxel (80 mg/m2/week) until disease progression (assuming acceptable toxicity). Following the initial 12 weekly doses, treatment could be given for 3 weeks, with a 1 week break. RESULTS: In this chemoresistant population, the objective response rate was 20.9%. Serious adverse events were relatively uncommon (neuropathy-grade 2: 21%; grade 3: 4%; and grade 3 fatigue: 8%). CONCLUSION: The weekly administration of paclitaxel can be a useful management approach in women with both platinum and paclitaxel (given every 3 weeks)-resistant ovarian cancer. It would be appropriate to directly compare weekly to every 3-week paclitaxel delivery in the setting of primary chemotherapy of advanced ovarian cancer.     

Efficacy and safety of AEZS-108 (INN: Zoptarelin Doxorubicin Acetate) an LHRH agonist linked to doxorubicin in women with platinum refractory or resistant ovarian cancer expressing LHRH receptors: A multicenter Phase II trial of the ago-study group (AGO GYN 5)

Objectives

To evaluate the activity and toxicity of AEZS-108 (Zoptarelin Doxorubicin Acetate) an LHRH agonist linked to doxorubicin in women with platinum refractory or resistant ovarian cancer expressing LHRH receptors.

Methods

Women with epithelial ovarian, fallopian tube or primary peritoneal cancer, expressing LHRH receptors were eligible for this trial, when they had progression during treatment with a platinum based regimen or within 6 months after receiving a platinum based regimen and a previous taxane treatment. At least one measurable target lesion (RECIST) or CA-125 levels higher than twice the upper limit of normal range (GCIG-criteria) were required. Patients received AEZS-108 (267 mg/m² equimolar to 76.8 mg/m² of free doxorubicin) every 3 weeks as a two hour i.v. infusion.

Results

Fifty-five of 59 (93%) of ovarian cancer samples screened expressed LHRH receptors. 42 patients were enrolled in this study and received at least 1 infusion of AEZS-108 (ITT population). Of these 42 patients 6 (14.3%) had a partial response, 16 (38%) stable disease, 16 (38%) progressive disease and 4 patients were not evaluable. Median time to progression was 12 weeks (95% CI: 8–20 weeks), and median overall survival was 53 weeks (95% CI: 39–73 weeks). Toxicity profile was favorable.

Conclusion

AEZS-108 has a clinical activity in platinum refractory/resistant ovarian cancer which seems to be comparable to that of pegylated liposomal doxorubicin or to topotecan. Toxicity was comparably low. These data support the concept of a targeted chemotherapy for tumors expressing LHRH receptors.     

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.     

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

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

Role of salvage cytoreductive surgery in the treatment of patients with recurrent ovarian cancer after platinum-based chemotherapy

OBJECTIVES: The role of cytoreductive surgery, which is well established in the primary treatment for epithelial ovarian cancer, is controversial in recurrent disease. The aim of this study was to assess the clinical benefit of salvage surgical cytoreduction in patients with recurrent ovarian cancer after platinum-based chemotherapy. METHODS: We conducted a retrospective analysis of 46 patients with recurrent epithelial ovarian cancer treated at our department between 1988 and 2003. Twenty-three patients underwent salvage cytoreductive surgery (cytoreductive group), and the other 23 patients were treated without surgery (control group). RESULTS: Patients in cytoreductive group had a median survival of 41.7 months after recurrence, which was significantly longer than control group (18.8 months; P < 0.01). The duration of stay at home and the period oral intake was preserved were significantly longer in the cytoreductive group. In the cytoreductive group, survival was influenced by the residual disease after surgery (residual tumor diameter, <2 cm vs >2 cm; median survival, 50 months vs 35.2 months; P < 0.05). However, the number of recurrent sites (solitary vs multiple) and the lengths of treatment-free intervals after primary treatment (<6 months vs >6 months) showed no significant influence on survival. CONCLUSIONS: The application of cytoreductive surgery might improve the prognosis of patients with recurrent ovarian cancer if the tumor was resectable. Preserved prognoses of platinum-resistant disease with short treatment-free interval demonstrated in this study suggest that the concept of maximum cytoreduction might be introduced in the treatment of recurrent disease in the future.     

Phase II trial of combination intraperitoneal cisplatin and 5-fluorouracil in previously treated patients with advanced ovarian cancer: long-term follow-up

OBJECTIVES: This trial was performed to determine the response rate and progression-free and overall survivals of patients with advanced recurrent ovarian cancer who were treated with intraperitoneal cisplatin and 5-fluorouracil. METHODS: Twenty-four patients with ovarian cancer were entered on this trial and treated with intraperitoneal (ip) cisplatin (DDP) and ip 5-fluorouracil, every 3 weeks for eight cycles. Following iv hydration, the cisplatin and 5-fluorouracil were administered through an ip catheter in 2 liters of 0.9% normal saline with a 4-h dwell. RESULTS: All patients were evaluable for progression-free and overall survival and toxicity analysis, and 22 patients for response. The median age was 59 (range, 35-71); initial disease status included 9 patients with residual disease following chemotherapy prior to entry on this study; 5 patients had progressed, and 10 patients had recurrent disease more than 6 months following initial chemotherapy. Of the 9 patients with residual disease, 1 complete response and 3 partial responses were observed; of 10 patients with recurrent disease, 1 complete and 1 partial response were observed for an overall response rate of 27%. No objective responses were seen in the 7 patients who were platinum-refractory on protocol entry. The median progression-free and overall survivals are 7.0 (range, 0.5-137) and 15.5 (range, 3-147) months, respectively. Toxicity included hypomagnesemia, vomiting, abdominal pain, and mild anemia. Only one patient required a dosage adjustment of cisplatin for a serum creatinine elevation >2.0 mg/dl. CONCLUSIONS: We conclude that the combination of ip cisplatin and 5-FU is an effective regimen for patients with residual or relapsed epithelial ovarian cancer with survival durations, response rates, and toxicity profiles that compare favorably with those of other second-line ovarian cancer regimens. Patients who are primarily platinum-refractory are unlikely to benefit from these agents administered into the peritoneal cavity.     

Primary chemotherapy and adjuvant tumor debulking in the management of advanced-stage epithelial ovarian cancer

The aim of this article was to review the experience with neoadjuvant chemotherapy and interval surgical debulking in patients with metastatic epithelial ovarian cancer. A retrospective chart review was carried out to identify patients treated with neoadjuvant platinum/Taxol chemotherapy and interval debulking. Cox regression modeling was used to identify significant predictors of progression-free interval. The Kaplan-Meier method was used to estimate the survival statistic for the study group. Sixty-one patients were identified after being treated with neoadjuvant chemotherapy and interval debulking surgeries. All surgeries were performed after three cycles of platinum/Taxol combination chemotherapy. Eighty percent of patients had a residual disease status of 2 cm or less after surgery. Suboptimal debulking was statistically associated with tumor involvement of the upper abdominal organs (P < 0.001) and non-normalization of CA125 before surgery (P= 0.03). The perioperative complication rate was 7%. At a mean follow-up time of 19 months, 77% of patients were still alive. Cox regression modeling identified the microscopic tumor residual status as the only significant predictor of progression-free interval. The estimated median survival for the group was 41.70 months (95% confidence interval = 13.84-69.56 months). Neoadjuvant chemotherapy with interval debulking surgery appeared to be safe and feasible in patients with metastatic epithelial ovarian carcinoma.     

First-line intraperitoneal carboplatin-based chemotherapy for 165 patients with epithelial ovarian carcinoma: results of long-term follow-up

OBJECTIVE: Currently, no long-term follow-up data are available on intraperitoneal (IP) carboplatin-based chemotherapy for ovarian carcinoma. In this study we evaluated retrospectively the survival and recurrence of a retrospective cohort of patients with epithelial ovarian cancer treated with first-line IP carboplatin-based therapy. METHODS: Records were reviewed of 174 patients with epithelial ovarian cancer who received IP carboplatin-based therapy between 1990 and 2000. All patients underwent surgical staging, and implantable port systems were placed regardless of residual tumor size. The pathological slides were submitted and reviewed, and then nine patients were excluded because of borderline malignancies (n = 8), and wrong histology (n = 1). Therefore, the records of 165 patients were analyzed for survival. Tumor grade was determined by the Universal grading system. Statistical analysis included tests for association between potential prognostic factors, and between prognostic factors and survival. Survival probabilities were estimated by Kaplan-Meier methods, and prognostic factors for survival were evaluated by a Cox regression model. RESULTS: The mean age of the patients was 53.7 years (range 21-83). The median follow-up was 41 months. The distribution by stage and histology was as follows: high risk (grade 2/3, clear cell, capsule rupture) stage I, 54; II, 21; III, 72; IV, 18; and serous, 75; clear cell, 30; mucinous, 27; endometrioid, 20; others, 13. The chemotherapy regimen was either carboplatin alone (n = 22) or in combination with cyclophosphamide (n = 116) or paclitaxel (n = 27). Catheter-related complications occurred in 16 (9.7%) cases. The chemotherapeutic response in 54 patients with measurable disease was 66.4%. The 5-year survival was 94.4% for stage I, and 87.9% for stage II. The median survival for optimal and suboptimal stage III/IV patients was 51 months and 34 months, respectively. The median survival of patients with stage III/IV disease was 51 months with carboplatin doses of 400 mg/m(2) or more, but it was only 25 months with carboplatin doses smaller than 400 mg/m(2). Poor prognostic factors, determined by Cox regression multivariate analysis, were clear cell histology (P < 0.001) and a carboplatin dose smaller than 400 mg/m(2) (P = 0.002). CONCLUSIONS: Survival of patients who underwent carboplatin-based IP chemotherapy was excellent when the dose of carboplatin was higher than 400 mg/m(2). A prospective evaluation of IP carboplatin therapy with modern combination is warranted.     

FaFEC: a novel regimen for advanced ovarian cancer

A palliative combination chemotherapy regimen (FaFEC) was developed for patients with relapsed epithelial ovarian cancer in particular patients relapsing after, or ineligble to enter, phase II trials, usually due to lack of evaluable disease. Forty-six patients were enrolled. Patients had received a mean of 2.3 previous drug regimens and nine (19%) had intestinal obstruction at the start of FaFEC. The majority of patients were inevaluable by WHO criteria so objective response data was obtained from serial serum CA125 evaluations. A serological response was demonstrated in 8/44 (18%). The responders included 6/27 women who had a prior relapse-free interval of less than 3 months, four who were resistant to platinum chemotherapy and three patients who had previously received paclitaxel. The major (WHO grade 3/4) toxicities included leucopenia (six patients), anemia (three patients), thrombocytopenia (two patients), nausea and vomiting (four patients) and severe infections (five patients). Following FaFEC the median time to failure was 0.48 years and the median survival was 0.66 years. FaFEC was effective in this group of very poor prognosis patients. The serological response rate of 18% is noteworthy considering the multiple prior treatments that patients had received and the short treatment free intervals. FaFEC may be useful second line therapy in epithelial ovarian cancer patients ineligible for phase II studies and should be considered for a randomized comparison with paclitaxel.     

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。     

A pilot study of three-cycle consolidation chemotherapy with paclitaxel and platinum in epithelial ovarian cancer patients with clinical complete response after paclitaxel and platinum chemotherapy

The aim of this study is to evaluate the efficacy of three additional cycles of paclitaxel and platinum chemotherapy in epithelial ovarian cancer patients with clinical complete response (CR). Patients with histologically confirmed epithelial ovarian cancer stages II-IV with clinical CR after primary surgery and six cycles of chemotherapy with paclitaxel/platinum entered into the study. Three cycles of paclitaxel/platinum (cisplatin, carboplatin) were administered as a consolidation chemotherapy only in patients who agreed to the informed consent. Patients without further treatment served as controls. A total of 81 patients entered into the study. According to the informed consent, 42 patients were treated by the consolidation chemotherapy, and 39 patients were followed up without further treatment. The median actuarial disease-free survival for the patients with and without consolidation chemotherapy was 25.0 months and 26.0 months, respectively (P= 0.80). The median overall survival is not reached. World Health Organization grade 3-4 toxicities in the consolidation arm were increased but showed no significant differences statistically. Although the sample size is small and not randomized, these results suggest that three cycles of consolidation chemotherapy with paclitaxel/platinum might not provide a favorable outcome in patients with a clinical CR.     

Retrospective review: re-treatment of patients with ovarian cancer with carboplatin after platinum resistance

The objective of the analysis was to determine the effectiveness of re-treating patients with ovarian cancer, primary peritoneal cancer, and fallopian tube cancer with carboplatin after being deemed platinum resistant. From a database period January 1, 1996, to December 12, 2002, 34 patients were identified who received nonplatinum agents before resuming treatment with carboplatin. The median age was 65 years, and a median of two nonplatinum chemotherapy (range 1-5) prior to re-treatment with carboplatin was received. The median platinum-free interval from the time platinum was last received to re-treatment with carboplatin was 15.2 months (95% confidence interval [CI] 12.6-17.9; range 6.2-47.0). A median number of four cycles of carboplatin (range 1-11) was received. Two patients (5.9%) achieved partial response, while 21 patients (61.7%) achieved stable disease. The median time to progression for these 23 patients after re-treatment with carboplatin was 5.7 months (95% CI 5.2-6.3; range 1.8-15.3). Twenty-seven patients have died, and all patients have progressed. Seven patients are still receiving salvage therapy. The median overall survival from the time deemed to be platinum resistant is 23.2 months (95% CI 20.1-26.4). Patients who have been deemed platinum resistant may still benefit from platinum re-treatment after an interval of treatment with nonplatinum agents.     

The Retrospective Study of Second-line Chemotherapy in Ovarian Cancer

Objective:  To evaluate the efficacy of Second-line Chemotherapy for ovarian cancer not from short term efficacy but from the survival rate.
Patients and Methods:  Eighty-seven patients with epitherial ovarian cancer treated with Second-line chemotherapy from 1993 were examined retrospectively. All the patients were treated with platinum as first line chemotherapy (≥ 3 courses). Paclitaxel was used for Second-line Chemotherapy in 25 patients. The Kaplan-Meier Method and Log-Rank Test were carried out for the cumulative survival rate and analysis.
Results:  The Median Survival Time of all patients after Second-line Chemotherapy was 23.6 months. Any significant difference in the survival rate was recognized only by the histological diagnosis (p < 0.0001). There was no significant difference in the survival rates whether patients were treated with paclitaxel as second line chemotherapy or not (p = 0.1915). The disease free survival period of the Second Look Laparotomy (SLL) negative group (23.9 months) is longer than that of SLL positive group (6.2 months).
Conclusions:  The survival rate after Second-line Chemotherapy was influenced only by histological diagnosis.
ACTA OBST GYNAEC JPN Vol. 54, No. 9, pp. 1429–1436, 2002     

Platinum-based neoadjuvant chemotherapy and interval surgical cytoreduction for advanced ovarian cancer: a meta-analysis

OBJECTIVE: To determine the overall survival and relative effect of multiple prognostic variables in cohorts of patients with advanced-stage ovarian cancer treated with platinum-based neoadjuvant chemotherapy in lieu of primary cytoreductive surgery. METHODS: Twenty-two cohorts of patients with Stage III and IV ovarian cancer (835 patients) were identified from articles in MEDLINE (1989-2005). Linear regression models, with weighted correlation calculations, were used to assess the effect on median survival time of the proportion of each cohort undergoing maximum interval cytoreduction, proportion of patients with Stage IV disease, median number of pre-operative chemotherapy cycles, median age, and year of publication. RESULTS: The mean weighted median overall survival time for all cohorts was 24.5 months. The weighted mean proportion of patients in each cohort undergoing maximal interval cytoreduction was 65.0%. Each 10% increase in maximal cytoreduction was associated with a 1.9 month increase in median survival time (p=0.027). Median overall survival was positively correlated with platinum-taxane chemotherapy (p<0.001) and increasing year of publication (p=0.004) and negatively correlated with the proportion of Stage IV disease (p=0.002). Each incremental increase in pre-operative chemotherapy cycles was associated with a decrease in median survival time of 4.1 months (p=0.046). CONCLUSIONS: Neoadjuvant chemotherapy in lieu of primary cytoreduction is associated with inferior overall survival compared to initial surgery. Increasing percent maximal cytoreduction is positively associated with median cohort survival; however, the negative survival effect of increasing number of chemotherapy cycles prior to interval surgery suggests that definitive operative intervention should be undertaken as early in the treatment program as possible.     

A phase II trial of capecitabine in heavily pre-treated platinum-resistant ovarian cancer

OBJECTIVE: To determine the activity of capecitabine in women with platinum-resistant ovarian cancer. METHODS: In this multi-centre phase II trial, 35 patients with platinum-resistant ovarian, primary peritoneal or fallopian tube carcinomas were treated with capecitabine 1250 mg/m(2) twice daily for 14 days every 21 days. Platinum resistance was defined as progression within 4 months of completing the last platinum and all patients had previously received a taxane. Response was assessed by both RECIST criteria for patients with measurable disease and CA125 criteria. Responders were defined as patients with measurable disease who achieved a CR or PR according to RECIST criteria, patients without measurable disease who met the CA125 criteria for response and patients with stable measurable disease who met the CA125 criteria for response. RESULTS: Patients had received a median of four prior chemotherapy regimens (range 1-9). The median number of cycles of capecitabine administered was 3 (range 1-10). The response rate using the combined RECIST and CA125 criteria was 9% (95% CI 2-25%). In patients evaluable using RECIST criteria, the response rate was 5% (95% CI 0-25%). In patients evaluable for CA125 response, the response rate was 7% (95% CI 1-22%). The median progression-free survival was 2.3 months, and the median survival was 7.1 months. Treatment was generally well tolerated with most frequent grade 3 toxicities being hand-foot syndrome (17%) and diarrhea (9%). CONCLUSION: Capecitabine is well tolerated but has limited activity in patients with heavily pre-treated platinum-resistant ovarian cancer.     

A new therapeutical approach: topotecan plus gemcitabine in the treatment of patients with relapsed ovarian cancer after failure of first-line chemotherapy with paclitaxel and platinum

AIM: Topotecan and gemcitabine have demonstrated mono-activity against recurrent ovarian cancer. Both drugs affect DNA replication; in addition, topotecan inhibits DNA repair. Based on the efficacy profiles and different mechanisms of action, a phase-I study was conducted to determine the maximum tolerated dose (MTD) of topotecan (day 1-5) and the dose-limiting toxicities (DLT) in combination with gemcitabine (day 1 + 8) every 21 days. METHODS: Three to six patients were treated per dose-level. Patients with ovarian cancer who had failed a platinum and paclitaxel-containing therapy were enrolled. No individual dose escalation or use of cytokines were allowed. RESULTS: Twenty-three patients were recruited. Fifty percent of all patients were pretreated with at least two platinum-containing therapies. Eighty courses were assessable for toxicity. The MTD was reached at a dosage of 0.75 mg/m2 topotecan in combination with 800/600 mg/m2 gemcitabine. Thrombocytopenia and leucopenia were the major DLTs. The dose for phase-II trials is 0.50 mg/m2 topotecan given with 800/600 mg/m2 gemcitabine. In this dose-level only one related non-haematological adverse event > grade 2 was observed (grade 3 mycotic stomatitis) and one grade 4 thrombocytopenia occurred. Responses were observed in six patients and stable disease in four out of 12 assessable patients. Median survival time was 15.3 (95% CI: 13.21-28.64) months. CONCLUSION: The results demonstrate feasibility and the tolerability of topotecan in combination with gemcitabine in recurrent ovarian cancer patients. Based on these results a phase-II study was conducted to evaluate the efficacy of this new combination.