Phase II trial of oral altretamine for consolidation of clinical complete remission in women with stage III epithelial ovarian cancer: a Southwest Oncology Group trial (SWOG-9326)

OBJECTIVE: The aim of this study was to evaluate the 2-year survival rate in a group of women in complete clinical remission (cCR) from Stage III ovarian cancer following front-line therapy who were then treated with a 6-month course of altretamine. METHODS: Patients were documented to be in cCR by physical examination, computed tomography or magnetic resonance imaging scan, and serum CA-125. Treatment consisted of altretamine (Hexalen) 260 mg/m(2)/day po divided into four doses taken after meals and at bedtime for 14 of 28 days for six cycles. Based on previous experience in the Southwest Oncology Group, the treatment would be considered promising if the 2-year survival rate was > or = 65% as measured from study registration. RESULTS: From 9/1/93 and 7/1/97, 112 patients were registered and 97 were fully evaluable. The majority of patients had optimally debulked (< or = 1 cm: 63%), high-grade (Grade 3: 82%) tumors. The 2-year survival rate in this study was 75% (95% CI: 66-84%). For those patients with optimal disease, the 2-year survival rate was 82% (95% CI: 72-92%) and for those with suboptimal disease it was 64% (95% CI: 48-79%). Four patients (4%) experienced Grade 4 and 21 patients (22%) experienced Grade 3 toxicities consisting primarily of nausea/vomiting, neutropenia, fatigue, anxiety, and paresthesias. CONCLUSIONS: The 2-year survival rate in this study warrants further evaluation of consolidation therapy for women in clinical complete remission following front-line chemotherapy for Stage III ovarian cancer. Caution is advised in the interpretation of these data, however, because of the nonrandomized nature of the trial and the unknown contribution of front-line use of paclitaxel to the durability of clinical complete response.     

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.     

Whole-abdomen, single-dose consolidation radiotherapy in patients with pathologically confirmed complete remission of advanced ovarian epithelial carcinoma: a long-term survival analysis

The value of consolidation therapy in advanced epithelial ovarian carcinoma patients is controversial. The aim of the present study was to assess the long-term survival of patients with a pathologically confirmed complete remission who had consolidation by single-dose, whole-abdominopelvic radiotherapy. Of 96 histologically confirmed stage II-IV epithelial ovarian carcinoma patients who underwent cytoreductive surgery followed by high-dose, platin-based chemotherapy, 57 were in complete clinical remission at the end of therapy and 50 underwent a second-look laparotomy. The study group comprises 32 consecutive patients who had no pathological evidence of disease and who received 800 cGy single-dose, whole-abdominal radiotherapy by an 8 MEV linear accelerator in a single fraction. The absolute 5-year survival and the actuarial 10-year survival were 78.7 and 63.3%, respectively. The survival was significantly better in patients who had < or =2 cm residual disease at the completion of the original operation. No severe postradiation complications were encountered. Mild complications were seen in three (9.4%) patients. Our data indicate a favorable long-term survival of patients with a negative second-look laparotomy who had consolidation with single-dose, whole-abdominal radiotherapy. These results seem to suggest that a collaborative, prospective, randomized multiarm study is indicated to solve the controversial issue of consolidation therapy.     

Epidoxorubicin versus no treatment as consolidation therapy in advanced ovarian cancer: results from a phase II study

Abstract.   Bolis G, Danese S, Tateo S, Rabaiotti E, D'Agostino G, Merisio C, Scarfone G, Polverino G, Parazzini F. Epidoxorubicin versus no treatment as consolidation therapy in advanced ovarian cancer: results from a phase II study. Int J Gynecol Cancer 2006; 16(Suppl. 1): 74–78.
To compare the effect of epidoxorubicin given for 4 months versus no treatment in the survival of patients with advanced ovarian cancer and complete pathologic response after first-line surgery and chemotherapy with platinum-based schedules, we conducted a multicenter randomized clinical trial. Patients with histologic diagnosis of epithelial ovarian cancer FIGO stage III or IV at first diagnosis; complete pathologic response at second-look laparotomy/laparoscopy or complete clinic response; and those who have had first-line therapy including surgery and one regimen containing cisplatin or carboplatinum were eligible for the study and were randomly allocated to epidoxorubicin 120 mg/sqm or no treatment. A total of 64 women were allocated to epidoxorubicin and 74 to no treatment. There were 20 and 19 deaths, respectively, in the epidoxorubicin and no-treatment groups. The 3-year percent overall survival was 79.0% and 78.7%, respectively, in the no-treatment and epidoxorubicin groups (log-rank test, P = 0.93).     

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.     

Surgery and prognosis in stage III epithelial ovarian cancer

The results of this retrospective case study indicate that a composite of tumor grade, pattern of spread and substage at the time of opening affects the outcome most in the treatment of stage III epithelial tumors of the ovary. The poorest prognosis was associated with grade 3 histology, a pattern of spread requiring extensive and often difficult surgery for removal and a high substage. The best prognosis was usually associated with grade 1, with either very easily removed, isolated spread or low substage.
The extent of tumor defined the degree of primary cytoreduction possible. If the tumor was minimally extensive, primary cytoreduction results were excellent. The same conclusions were reached in the case of secondary cytoreduction at the time of second-look procedure. There was no statistically significant difference ( z = 1.481, P = 0.069) in 5-year survival between patients with microscopic only disease (59%) at second-look, and patients with gross disease not cytoreduced (36%).     

The impact of disease distribution on survival in patients with stage III epithelial ovarian cancer cytoreduced to microscopic residual: a Gynecologic Oncology Group study

Objective

To assess the survival impact of initial disease distribution on patients with stage III epithelial ovarian cancer (EOC) cytoreduced to microscopic residual.

Methods

We reviewed data from 417 stage III EOC patients cytoreduced to microscopic disease and given adjuvant intravenous platinum/paclitaxel on one of three randomized Gynecologic Oncology Group (GOG) trials. We subdivided patients into three groups based on preoperative disease burden: (1) minimal disease (MD) defined by pelvic tumor and retroperitoneal metastasis (2) abdominal peritoneal disease (APD) with disease limited to the pelvis, retroperitoneum, lower abdomen and omentum; and (3) upper abdominal disease (UAD) with disease affecting the diaphragm, spleen, liver or pancreas. We assessed the survival impact of potential prognostic factors, focusing on initial disease distribution using a proportional hazards model and estimated Kaplan-Meier survival curves.

Results

The study groups had similar clinicopathologic characteristics. Median overall survival (OS) was not reached in MD patients compared to 80 and 56 months in the APD and UAD groups (P < 0.05). The five-year survival percentages for MD, APD, and UAD were 67%, 63%, and 45%. In multivariate analysis, the UAD group had a significantly worse prognosis than MD and APD both individually and combined (Progression Free Survival (PFS) Hazards Ratio (HR) 1.44; P = 0.008 and OS HR 1.77; P = 0.0004 compared to MD + APD).

Conclusion

Stage III EOC patients with initial disease in the upper abdomen have a worse prognosis despite cytoreductive surgery to microscopic residual implying that factors beyond cytoreductive effort are important in predicting survival.     

Randomized phase III trial of chemoimmunotherapy in patients with previously untreated stage III, optimal disease ovarian cancer: a Southwest Oncology Group Study

Between 1979 and 1984, 98 patients considered to have stage III epithelial type ovarian cancer and optimal surgical resections (i.e., less than 2 cm residual tumor masses) were randomly assigned to treatment with 2 cm residual tumor masses) were randomly assigned to treatment with doxorubicin + cyclophosphamide + BCG (DC + BCG) vs doxorubicin + cyclophosphamide + cisplatin (DCP) vs. doxorubicin + cyclophosphamide + cisplatin + BCG (DCP + BCG). Seventeen (17%) were considered ineligible on the basis of formal histopathologic review. The pathologically proven complete response rates for DC + BCG, DCP, and DCP + BCG-treated patients were 20, 23, and 41%, respectively, and the median survival durations were 36.8, 48.2, and 57.4 months, respectively. Because of the relatively small sample size, definite conclusions concerning the response or survival impact of adding cisplatin to DC + BCG or BCG to DCP can not be drawn; nevertheless, all three groups of patients experienced prolonged survival durations with approximately 40% of all eligible patients alive at 5 years.     

Long-term survival in stage III and IV ovarian cancer

Summary A total of 104 unselected, previously untreated patients with invasive stage III or IV ovarian cancer were operated on between 1977 and 1984. Nine patients were lost in follow-up, three died from non-malignant disease. Thirteen of the 92 eligible patients (15%) were observed to survive 5 years or longer. In the 13 long-term survivors, 4 had stage IV disease, 7 positive peritoneal cytology, 3 bowel resection, and 12 residual disease <2 cm after primary surgery. Retroperitoneal lymph nodes were involved in 6/9 cases. The majority of 5-year survivors (69%) received cis-platin-containing combination chemotherapy. 5/7 long-term survivors had positive second-look. At 5 years, life-quality in 9/13 patients who were free of disease, was high. It can be concluded that only patients with optimally resected stage III or IV ovarian cancer have a realistic chance of long-term survival. It is expected that increasing radicality in surgery for ovarian cancer together with platinum-based chemotherapy regimens may improve long-term survival in the future. In addition, further studies of new chemotherapeutic approaches are needed.     

A phase II clinical trial of topotecan and carboplatin in patients with newly diagnosed advanced epithelial ovarian cancer

A phase II clinical trial conducted to evaluate the efficacy and tolerability of topotecan and carboplatin as first-line therapy for women with advanced epithelial ovarian cancer was the objective of this study. Patients had histologically confirmed ovarian epithelial cancer with at least one measurable lesion. Patients received topotecan 1.5 mg/m(2) on days 1-3 and carboplatin at an area under the curve (AUC) of 5 on day 3 every 21 days for six cycles. All 42 patients enrolled were evaluable for response and toxicity. Median number of cycles delivered was six. Overall response rate was 71%, with 19 clinical complete responses (45%) and 11 clinical partial responses (26%). Median survival time was 47 months and 5-year survival was 42%. Myelosuppression was the predominant toxicity, with grade 3 or 4 neutropenia occurring in 100% of patients. However, this toxicity was transient and easily manageable; no patients experienced febrile neutropenia. The combination of topotecan and carboplatin is active in advanced epithelial ovarian cancer. Delay of therapy by 1 week or topotecan dose reduction to 1.25 mg/m(2) is the first-choice option to reduce topotecan toxicity without affecting the efficacy. Moreover, a chemotherapy regimen using weekly topotecan, which is currently being tested, should be considered.     

A phase II study of apatinib in patients with recurrent epithelial ovarian cancer

Objective

Antiangiogenic treatments have been implicated to play a major role in epithelial ovarian cancer (EOC). Apatinib, a novel oral antiangiogenic agent targeting vascular endothelial growth factor receptor (VEGFR2), is currently being studied in different tumor types and is already used in gastric adenocarcinoma. This study was performed to assess the efficacy and safety of apatinib in patients with recurrent, pretreated EOC.

Phase II trial of imatinib mesylate in recurrent, biomarker positive, ovarian cancer (Southwest Oncology Group Protocol S0211)

Platinum-resistant ovarian cancer continues to be a difficult therapeutic problem. Clearly, molecularly targeted agents should be evaluated in this patient population. Patients were eligible for this phase II study with stage III or IV ovarian cancer, whose tumor expressed Kit (CD117) or platelet-derived growth factor receptor (PDGFR) and with relapse of measurable disease within 6 months of completing frontline, platinum- and taxane-based chemotherapy. Patients were treated daily with 400 mg of imatinib mesylate orally. It was assumed that the agent would be of no further interest if the population response rate was less than 10%. A two-stage design was used for patient accrual. A total of 34 patients were registered to the study. Of these, 15 were found to be ineligible or not evaluable (8 because their tumor samples were negative for both DC117 and PDGFR). Of 19 evaluable patients, 2 (11%) tested positively for c-Kit and 17 (89%) tested positively for PDGFR. There were no objective responders. Thirteen patients (68%) had increasing disease or symptomatic deterioration, and six (32%) went off protocol during the first month due to adverse events. Median progression-free survival was 2 months (95% CI 1-3 months) and median overall survival was 10 months (95% CI 6-18 months). Eleven percent of patients experienced grade 4 hematologic/metabolic toxicity and 37% experienced grade 3 nonhematologic toxicity. We conclude that imatinib mesylate as a single agent does not appear to have useful clinical activity in c-Kit and/or PDGFR positive, recurrent ovarian cancer in heavily pretreated patients with ovarian cancer.     

卵巢癌初次治疗后随访及巩固治疗

卵巢癌患者在经过初次肿瘤细胞减灭术和一线药物化疗后大部分能得到临床完全缓解,但是仍有很多患者特别是晚期患者将复发。文章主要对初次治疗后达到临床完全缓解患者的监测与随访,以及是否需要进一步巩固治疗以延长无进展生存期和提高总生存率的最新进展进行阐述。     

Sorafenib as a third line therapy in patients with epithelial ovarian cancer or primary peritoneal cancer: a phase II study

Purpose

New agents are required for the patients with epithelial ovarian cancer (EOC) who progress after first and second line of the treatment. Tumor vasculature targeted agents are potentially active in EOC. We aimed to assess the activity of sorafenib in patients with recurrent EOC who had received two prior therapies.

Patients and methods

A phase II non-randomized, open-label, single-arm study aimed to assess the efficacy, safety and tolerance of sorafenib monotherapy as a third line therapy in patients with EOC or primary peritoneal cancer (PPC). Sorafenib was administered as 400 mg twice daily on days 1–28 of each 4-week cycle. The primary end point of the study was to demonstrate the progression free survival (PFS).

Results

Eleven patients were enrolled. The median number of cycles was two. Among the 11 patients eligible for efficacy analysis, no patients experienced a partial response or complete response or stable disease lasting longer than 6 months according to RECIST criteria. Thus, the trial stopped at the end of the first stage of study design. The median PFS was 2.00 months (95% CI, 1,80–3,90). The median OS was 11.78 months (95% CI, 7.66 to 15.39). There were no grade 4 toxicities and few grade 3 toxicities.

Conclusion

Sorafenib fails to achieve sufficient objective response or sustained disease stabilization as third-line treatment for EOC.     

A two-stage,single-arm,phase II study of EGCG-enriched green tea drink as a maintenance therapy in women with advanced stage ovarian cancer

Objectives

A two-stage, single-arm, phase II study was conducted to assess the effectiveness and safety of an epigallocatechin gallate (EGCG)-enriched tea drink, the double-brewed green tea (DBGT), as a maintenance treatment in women with advanced stage serous or endometrioid ovarian cancer (clinicaltrials.gov, NCT00721890).

Methods

Eligible women had FIGO stage III-IV serous or endometrioid ovarian cancer. They had to undergo complete response after debulking surgery followed by 6 to 8 cycles of platinum/taxane chemotherapy at the Centre Hospitalier Universitaire de Québec. They all had to drink the DBGT, 500 mL daily until recurrence or during a follow-up of 18 months. The primary endpoint was the absence of recurrence at 18 months. Statistical analyses were done according to the principle of intention to treat. Using a two-stage design, the first stage consisted of 16 enrolled patients. At the end of the follow-up, if 7 or fewer patients were free of recurrence, the trial stopped. Otherwise, accrual would continue to a total of 46 patients.

Results

During the first stage of the study, only 5 of the 16 women remained free of recurrence 18 months after complete response. Accordingly, the clinical trial was terminated. Women's adherence to DBGT was high (median daily intake during intervention, 98.1%, interquartile range: 89.7–100%), but 6 women discontinued the intervention before the end of their follow-up. No severe toxicity was reported.

Conclusions

DBGT supplementation does not appear to be a promising maintenance intervention in women with advanced stage ovarian cancer after standard treatment.     

Randomized phase III trial of chemoimmunotherapy in patients with previously untreated stages III and IV suboptimal disease ovarian cancer: a Southwest Oncology Group Study

Between 1979 and 1984, 185 fully evaluable patients with stage III or IV epithelial type ovarian cancer and suboptimal surgical resections were randomly assigned to treatment with doxorubicin + cyclophosphamide + BCG (DC + BCG) vs doxorubicin + cyclophosphamide + cisplatin (DCP) vs. doxorubicin + cyclophosphamide + cisplatin + BCG (DCP + BCG). Patients with measurable disease (119) were analyzed separately from those with nonmeasurable disease (66). In measurable disease patients the overall clinical complete plus partial response rates for DC + BCG, DCP, and DCP + BCG-treated patients were 36, 57, and 59%, respectively. Although there were no significant patient characteristic differences between the DCP and DCP + BCG treatment groups, the addition of cisplatin to the DC + BCG regimen resulted in significantly prolonged response (P less than 0.03) and survival (P less than 0.002) durations. To the contrary, the addition of BCG to the DCP regimen did not improve objective response rates or response or survival durations. For patients with nonmeasurable, suboptimal disease there were no significant differences between the three treatments with respect to response or survival parameters; however, patients in this disease category fared generally better than those with clinically measurable disease. We conclude that cisplatin adds significantly to the efficacy of DC + BCG, but BCG does not add to the efficacy of DCP in patients with measurable, stage III or IV disease.