Gavin Stuart

Gemcitabine Plus Carboplatin Compared With Carboplatin in Patients With Platinum-Sensitive Recurrent Ovarian Cancer: An Intergroup Trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG

PURPOSE Most patients with advanced ovarian cancer develop recurrent disease. For those patients who recur at least 6 months after initial therapy, paclitaxel platinum has shown a modest survival advantage over platinum without paclitaxel; however, many patients develop clinically relevant neurotoxicity, frequently resulting in treatment discontinuation. Thus, an alternative regimen without significant neurotoxicity was evaluated by comparing gemcitabine plus carboplatin with single-agent carboplatin in platinum-sensitive recurrent ovarian cancer patients. METHODS Patients with platinum-sensitive recurrent ovarian cancer were randomly assigned to receive either gemcitabine plus carboplatin or carboplatin alone, every 21 days. The primary objective was to compare progression-free survival (PFS). RESULTS Three hundred fifty-six patients (178 gemcitabine plus carboplatin; 178 carboplatin) were randomly assigned. Patients received a median of six cycles in both arms. With a median follow-up of 17 months, median PFS was 8.6 months (95% CI, 7.9 to 9.7 months) for gemcitabine plus carboplatin and 5.8 months (95% CI, 5.2 to 7.1 months) for carboplatin. The hazard ration (HR) for PFS was 0.72 (95% CI, 0.58 to 0.90; P = .0031). Response rate was 47.2% (95% CI, 39.9% to 54.5%) for gemcitabine plus carboplatin and 30.9% (95% CI, 24.1% to 37.7%) for carboplatin (P = .0016). The HR for overall survival was 0.96 (95% CI, 0.75 to1.23; P = .7349). While myelosuppression was significantly more common in the combination, sequelae such as febrile neutropenia or infections were uncommon. No statistically significant differences in quality of life scores between arms were noted. CONCLUSION Gemcitabine plus carboplatin significantly improves PFS and response rate without worsening quality of life for patients with platinum-sensitive recurrent ovarian cancer.

Phase III Trial Comparing Radical Radiotherapy With and Without Cisplatin Chemotherapy in Patients With Advanced Squamous Cell Cancer of the Cervix

PURPOSE To test the hypothesis that cisplatin (CDDP) administered concurrently with standard radiotherapy (RT) would improve pelvic control and survival in patients with advanced squamous cell cancer of the cervix. PATIENTS AND METHODS A total of 259 patients with International Federation of Gynecology and Obstetrics stage IB to IVA squamous cell cervical cancer with central disease greater-than-or-equal 5 cm or histologically confirmed pelvic lymph node involvement were randomized to receive RT (external-beam RT plus brachytherapy) plus weekly CDDP chemotherapy (40 mg/m(2)) (arm 1) or the same RT without chemotherapy (arm 2). RESULTS A total of 253 patients were available for analysis. Median follow-up was 82 months. No significant difference was found in progression-free survival (P =.33). No significant difference in 3- and 5-year survival rates was found (69% v 66% and 62% v 58%, respectively; P =.42). The hazard ratio for survival (arm 2 to arm 1) was 1.10 (95% confidence interval, 0.75 to 1.62). CONCLUSION This study did not show a benefit to either pelvic control or survival by adding concurrent weekly CDDP chemotherapy in a dose of 40 mg/m(2) to radical RT as given in this trial. Careful attention to RT details is important for achieving optimum outcome for patients with this disease.

2010 Gynecologic Cancer InterGroup (GCIG) Consensus Statement on Clinical Trials in Ovarian Cancer Report From the Fourth Ovarian Cancer Consensus Conference

2010 Gynecologic Cancer InterGroup (GCIG) consensus statement on clinical trials in ovarian cancer. This report provides the outcomes from the Fourth Ovarian Cancer Consensus Conference.

Cisplatin-cyclophosphamide versus carboplatin-cyclophosphamide in advanced ovarian cancer: a randomized phase III study of the National Cancer Institute of Canada Clinical Trials Group.

PURPOSE Given the potential for improved tolerance, a trial was initiated to compare the toxicity and efficacy of a standard regimen of cisplatin-cyclophosphamide (75 mg/m2 and 600 mg/m2, respectively) with an experimental regimen of carboplatin-cyclophosphamide (300 mg/m2 and 600 mg/m2, respectively) in women with postoperative macroscopic residual ovarian cancer. PATIENTS AND METHODS Between 1985 and 1989, 447 (417 eligible) patients were randomized. Treatment arms were well balanced; most patients had stage III (82%), grade 3 (54%) tumors with bulky residual (greater than 2 cm in 59%), and good performance status (Eastern Cooperative Oncology Group [ECOG] 0 or 1, 77%). Response was assessed after six 4-week cycles. RESULTS The treatments were equally deliverable, with 76% of patients completing their allocated regimen. The reported reasons for failure to complete treatment differed; toxicity/refusal predominated on the cisplatin arm, and progressive disease predominated on the carboplatin arm (P = .0092). Cisplatin-treated patients were more likely to develop neuropathy and nephropathy, and carboplatin patients experienced myelosuppression, particularly thrombocytopenia. Efficacy was similar, with no significant differences for the cisplatin and carboplatin arms in clinical response rate (57% v 59% in those with measurable disease), pathologic response rate (52% v 54% in those suitable for relaparotomy), time to progression (median, 56 v 58 weeks), or overall survival (median, 100 weeks v 110 weeks). Time to progression and survival were predicted by residual disease size, performance status, and treatment center (with those treated at centers that accrued more patients doing better). CONCLUSION Neither regimen is optimal in that relapse remains the norm. It may be inappropriate to expect that any single regimen can be an effective therapy for all patients with advanced ovarian cancer. Both cisplatin and carboplatin are likely to have a role in future treatment strategies.

Clinical trials in recurrent ovarian cancer.

The 4th Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup was held in Vancouver, Canada, in June 2010. Representatives of 23 cooperative research groups studying gynecologic cancers gathered to establish international consensus on issues critical to the conduct of large randomized trials. Group C, 1 of the 3 discussion groups, examined recurrent ovarian cancer, and we report the consensus reached regarding 4 questions. These included the following: (1) What is the role of cytoreductive surgery for recurrent ovarian cancer? (2) How do we define distinct patient populations in need of specific therapeutic approaches? (3) Should end points for trials with recurrent disease vary from those of first-line trials? (4) Is CA-125 progression alone sufficient for entry/eligibility into clinical trials?

Comparison of CA-125 and Standard Definitions of Progression of Ovarian Cancer in the Intergroup Trial of Cisplatin and Paclitaxel Versus Cisplatin and Cyclophosphamide

PURPOSE A definition for progression of ovarian cancer has been proposed based on either a confirmed doubling of CA-125 levels from the upper limit of normal or from the nadir level if levels are persistently elevated. Retrospectively, we determined whether the use of this CA-125 definition in a randomized trial would have shown the same magnitude of difference between the treatment arms as was shown when the standard progression definition was used. PATIENTS AND METHODS A retrospective analysis was performed on 680 patients in the Taxol Intergroup Trial with advanced epithelial ovarian carcinoma, of whom 628 were assessable according to CA-125. The date of progression according to clinical or radiologic criteria was compared with the date of progression according to CA-125. RESULTS Of the 628 patients assessable for both definitions, 556 clinical or radiologic progressions were determined compared with 389 according to the CA-125 definition. There was a highly significant difference in the hazard of progression between the paclitaxel and cisplatin arm (TP) compared with the cyclophosphamide and cisplatin arm (CP) when either standard or CA-125 criteria were used to define progression (standard, P = .002; CA-125, P = .011). The hazard ratio of TP/CP over time was similar when comparing the different methods of defining progression. CONCLUSION The results of this analysis show that the magnitude of the therapeutic benefit was similar whether CA-125 or standard criteria were used to define progression.

Advanced Ovarian Cancer: Phase III Randomized Study of Sequential Cisplatin–Topotecan and Carboplatin–Paclitaxel vs Carboplatin–Paclitaxel

BACKGROUND Topotecan has single-agent activity in recurrent ovarian cancer. It was evaluated in a novel combination compared with standard frontline therapy. METHODS Women aged 75 years or younger with newly diagnosed stage IIB or greater ovarian cancer, Eastern Cooperative Oncology Group Performance Status of 1 or less, were stratified by type of primary surgery and residual disease, treatment center, and age; then randomly assigned to one of the two 21-day intravenous regimens. Patients in arm 1 (n = 409) were administered four cycles of cisplatin 50 mg/m(2) on day 1 and topotecan 0.75 mg/m(2) on days 1-5, then four cycles of paclitaxel 175 mg/m(2) over 3 hours on day 1 followed by carboplatin (area under the curve = 5) on day 1. Patients in arm 2 (n = 410) were given paclitaxel plus carboplatin as in arm 1 for eight cycles. We compared progression-free survival (PFS), overall survival, and cancer antigen-125 normalization rates in the two treatment arms. A stratified log-rank test was used to assess the primary endpoint, PFS. All statistical tests were two-sided. RESULTS A total of 819 patients were randomly assigned. At baseline, the median age of the patients was 57 years (range = 28-78); 81% had received debulking surgery, and of these, 55% had less than 1 cm residual disease; 66% of patients were stage III and 388 (47.4%) patients had measurable disease. After a median follow-up of 43 months, 650 patients had disease progression or died without documented progression and 406 had died. Patients in arm 1 had more hematological toxicity and hospitalizations than patients in arm 2; PFS was 14.6 months in arm 1 vs 16.2 months in arm 2 (hazard ratio = 1.10, 95% confidence interval = 0.94 to 1.28, P = .25). Among patients with elevated baseline cancer antigen-125, fewer in arm 1 than in arm 2 had levels return to normal by 3 months after random assignment (51.6% vs 63.3%, P = .007) CONCLUSIONS Topotecan and cisplatin, followed by carboplatin and paclitaxel, were more toxic than carboplatin and paclitaxel alone, but without improved efficacy. Carboplatin plus paclitaxel remains the standard of care for advanced epithelial ovarian cancer.

First-line treatment regimens and the role of consolidation therapy in advanced ovarian cancer

Current first-line management for advanced ovarian cancer consists of cytoreductive surgery followed by chemotherapy, usually with a platinum/taxane combination. Although this approach has been shown to achieve overall response rates of 70-80% in clinical trials, the majority of patients relapse. A number of different approaches have been investigated to improve the efficacy of therapy, including the introduction of newer agents, such as topotecan, into chemotherapy regimens and the use of consolidation therapy. Encouraging results have been obtained in clinical trials of topotecan administered using a variety of different approaches, including replacement regimens, triplet regimens, and sequential doublet regimens. Other treatment modalities have included the use of drug resistance modifiers and intraperitoneal delivery of treatment. A variety of approaches to consolidation therapy have also been investigated, including radiotherapy, cytotoxic therapy, and intraperitoneal therapy. The use of topotecan has also shown promise in this setting, although further data from large, controlled trials are required. In summary, while good response rates are obtained using current first-line treatments, the high relapse rate indicates the need to develop more effective and durable treatment regimens including new agents with, perhaps, an increased emphasis on maintaining remission through the use of consolidation therapy.

First-line therapy in ovarian cancer trials

At the 4th Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup (GCIG) held in Vancouver, Canada, in June 2010, representatives of 23 cooperative research groups studying gynecologic cancers gathered to establish international consensus on issues critical to the conduct of large randomized trials. The process focused on 13 predetermined questions. Group A, 1 of the 3 discussion groups, addressed the first 5 questions, examining first-line therapies in newly diagnosed ovarian cancer patients. A1: What are the appropriate end points for different trials (maintenance, upfront chemotherapy trials including molecular drugs)? A2: Are there any subgroups defined by tumor biology who need specific treatment options/trials? A3: Is the 2004 GCIG-recommended standard comparator arm still valid? A4: What is the role of modifying dose, schedule, and delivery of chemotherapy? A5: What role does surgery play today?

Quality of Life in Ovarian Cancer Patients: Comparison of Paclitaxel Plus Cisplatin, With Cyclophosphamide Plus Cisplatin in a Randomized Study

PURPOSE Formal quality-of-life (QOL) assessments may contribute important information on patient symptoms. Despite many trials of systemic chemotherapy in ovarian cancer, reports of its effect on QOL are few. PATIENTS AND METHODS QOL was assessed in an Intergroup randomized trial comparing paclitaxel plus cisplatin to cyclophosphamide plus cisplatin in women with advanced ovarian cancer. One hundred fifty-two eligible patients accrued in Canada completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 and a trial-specific checklist at baseline (after surgical debulking) and at regular intervals during and after chemotherapy. Mean change scores over time in the two arms were calculated. RESULTS Compliance with QOL questionnaire completion was excellent (81% to 93%). In general, deterioration was seen in the QOL domains immediately after chemotherapy (day 8 of cycle 1), followed by clinically meaningful improvements compared with baseline (change scores > or = 10) in both arms during the treatment period in a number of domains and items, including global QOL, emotional function, social function, fatigue, pain, sleep, constipation, appetite, abdominal swelling, and abdominal cramps. Improvements in global QOL persisted for the duration of follow-up. More neurosensory effects and myalgia were documented in the paclitaxel arm; however, this did not adversely affect global or other domains of QOL and improved once chemotherapy was completed. CONCLUSION Improvement from baseline in QOL measures was seen in both treatment arms. The greater neurologic and muscle toxicity of paclitaxel did not adversely influence QOL. QOL data can contribute useful information on the experience of symptoms and their time course, which may assist patients and physicians in their discussion about the anticipated effects of therapy.