Phase III trial of observation versus six courses of paclitaxel in patients with advanced epithelial ovarian cancer in complete response after six courses of paclitaxel/platinum-based chemotherapy: final results of the After-6 protocol 1.

PURPOSE: To assess whether six courses of paclitaxel are effective as consolidation treatment in patients with advanced epithelial ovarian cancer who are in complete response after first-line paclitaxel/platinum-based chemotherapy. PATIENTS AND METHODS: Patients with stages IIb to IV disease in clinical or pathologic complete response after six courses of paclitaxel/platinum-based chemotherapy were randomly allocated to either observation (ie, control) or six courses of paclitaxel 175 mg/m(2) every 3 weeks (ie, maintenance). RESULTS: Two hundred patients were randomly assigned from March 1999 to July 2006. Because of the low accrual rate, an unplanned interim analysis of futility according to the Bayesian approach was performed. Grade 2 or greater motor neurotoxicity and sensory neurotoxicity were reported in 11.3% and 28.0% of the paclitaxel-arm patients, respectively. After a median follow-up of 43.5 months, 107 patients (53%) had experienced relapse, and 48 patients (24%) had died. Two-year progression-free survival rates were 54% (95% CI, 43% to 64%) and 59% (95% CI, 49% to 69%; P = not significant) in the control and maintenance arms, respectively. Corresponding 2-year overall survival rates were 90% (95% CI, 84% to 97%) and 87% (95% CI, 80% to 94%; P = not significant), respectively. The Cox model showed that residual disease after initial surgery (macroscopic v no macroscopic residuum; hazard ratio [HR], 1.91; 95%CI, 1.21 to 3.03) and stage (IIIc to IV v others; HR, 3.10; 95% CI, 1.13 to 8.48) were independent prognostic factors for progression-free survival, whereas the treatment arm (maintenance v control) had no prognostic relevance. CONCLUSION: A consolidation treatment with six cycles of paclitaxel does not prolong progression-free survival or overall survival in patients in complete response after first-line paclitaxel/platinum-based regimens.

Extending the platinum-free interval with a non-platinum therapy in platinum-sensitive recurrent ovarian cancer. Results from the SOCRATES Retrospective Study.

BACKGROUND: It has been proposed that extending the platinum-free interval with intervening non-platinum therapy increases the efficacy of a later re-treatment with platinum in platinum-sensitive recurrent ovarian cancer. This hypothesis is based on data from small series and although it has not been validated prospectively, this strategy has entered general practice in Italy in the last years. The SOCRATES study retrospectively assessed the pattern of care of a cohort of patients with recurrent platinum-sensitive ovarian cancer observed in the years 2000-2002 in 37 Italian centres. Data were collected between April and September 2005. METHODS: Patients with recurrent ovarian cancer with a platinum-free interval >6 months were eligible. 493 patient files were collected and 428 were eligible and analyzed. RESULTS: The interval from the end of the 1st line to relapse was 6-12 months in 164 patients (39.5%) and >12 months in 251 cases (60.5%). Patients received a 2nd (100%), 3rd (80.1%), 4th (50.2%), 5th (28.3%), and 6th (11.9%) line of chemotherapy. At 2nd line 282 (65.9%) received platinum (group A), while 146 (34.1%) received non-platinum chemotherapy (group B). In the latter group, 67 patients received platinum at later progression (group B1), while 79 never received platinum (group B2). Median time to platinum re-treatment was 20 and 23.1 months in patients of groups A and B1, respectively. The response rate to the first platinum received was 74.4 and 57.4% in groups A and B1, respectively (p = 0.02). Group B2 was characterized by the worst response rate and survival. At multivariate analysis time of first platinum re-treatment (2nd line vs. later; p = 0.0132; OR = 2.34) and age (p = 0.0029; OR = 2.41) was independently associated with a higher possibility of response to platinum. CONCLUSIONS: With the limits of a retrospective study, our data question the hypothesis that extending the platinum-free interval with an intervening non-platinum therapy in patients with recurrent platinum-sensitive ovarian cancer improves the response rate of a further platinum re-treatment.

Systematic aortic and pelvic lymphadenectomy versus resection of bulky nodes only in optimally debulked advanced ovarian cancer: a randomized clinical trial.

BACKGROUND: The role of systematic aortic and pelvic lymphadenectomy in patients with optimally debulked advanced ovarian cancer is unclear and has not been addressed by randomized studies. We conducted a randomized clinical trial to determine whether systematic aortic and pelvic lymphadenectomy improves progression-free and overall survival compared with resection of bulky nodes only. METHODS: From January 1991 through May 2003, 427 eligible patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIB-C and IV epithelial ovarian carcinoma were randomly assigned to undergo systematic pelvic and para-aortic lymphadenectomy (n = 216) or resection of bulky nodes only (n = 211). Progression-free survival and overall survival were analyzed using a log-rank statistic and a Cox multivariable regression analysis. All statistical tests were two-sided. RESULTS: After a median follow-up of 68.4 months, 292 events (i.e., recurrences or deaths) were observed, and 202 patients had died. Sites of first recurrences were similar in both arms. The adjusted risk for first event was statistically significantly lower in the systematic lymphadenectomy arm (hazard ratio [HR] = .75, 95% confidence interval [CI] = 0.59 to 0.94; P = .01) than in the no-lymphadenectomy arm, corresponding to 5-year progression-free survival rates of 31.2 and 21.6% in the systematic lymphadenectomy and control arms, respectively (difference = 9.6%, 95% CI = 1.5% to 21.6%), and to median progression-free survival of 29.4 and 22.4 months, respectively (difference = 7 months, 95% CI = 1.0 to 14.4 months). The risk of death was similar in both arms (HR = 0.97, 95% CI = 0.74 to 1.29; P = .85), corresponding to 5-year overall survival rates of 48.5 and 47%, respectively (difference = 1.5%, 95% CI = -8.4% to 10.6%), and to median overall survival of 58.7 and 56.3 months, respectively (difference = 2.4 months, 95% CI = -11.8 to 21.0 months). Median operating time was longer, and the percentage of patients requiring blood transfusions was higher in the systematic lymphadenectomy arm than in the no-lymphadenectomy arm (300 versus 210 minutes, P<.001, and 72% versus 59%; P = .006, respectively). CONCLUSION: Systematic lymphadenectomy improves progression-free but not overall survival in women with optimally debulked advanced ovarian carcinoma.

Interval debulking surgery in advanced epithelial ovarian cancer.

Cytoreductive surgery and chemotherapy are the mainstay for the treatment of advanced epithelial ovarian cancer. In order to minimize the tumour burden before chemotherapy, cytoreductive surgery is usually performed first. The importance of the amount of residual disease as the main prognostic factor for patients suffering from advanced disease has been almost universally accepted even in the absence of prospective randomized trials addressing the benefit of cytoreductive surgery. In the last decade, the value of debulking surgery after induction chemotherapy - interval debulking surgery, IDS - has been widely debated, especially after the completion of a prospective randomized study from the EORTC addressing the introduction of a surgical procedure with debulking intent preceded and followed by cytoreductive chemotherapy. The rationale of such a strategy in the context of the primary treatment of advanced ovarian cancer lies in a higher cytoreductibility to the 'optimal' status forwarded, and possibly facilitated, by chemotherapy. The results demonstrated a prolongation of both progression-free survival and median survival in favour of patients randomized to IDS (5 and 6 months, respectively). Multivariate analysis revealed IDS to be an independent prognostic factor which reduced the risk of death by 33% at 3 years and by 48% in subsequent re-evaluation after more than 6 years of observation. Despite the above, results have been questioned by many, leading the GOG to perform a similar study which has been concluded very recently. Nevertheless, the main concern regarding the application of IDS in all instances relates to the morbidity of two major surgical procedures integrated within a short period during which cytotoxic chemotherapy is also administered. Neoadjuvant chemotherapy has been recently proposed to avoid a non-useful surgical procedure in patients considered 'optimally unresectable' after diagnosis of advanced ovarian cancer. Whether or not this newer approach will translate into a longer survival with a better quality of life is going to be addressed by a novel EORTC study. Finally, the concept of a 'chemical' cytoreduction preceding and facilitating a subsequent 'surgical' effort has been recently introduced also in the treatment of recurrent disease. The EORTC has recently initiated a prospective randomized study (LOROCSON - Late Onset Recurrent Ovarian Cancer: Surgery or Not) to validate the importance of such an approach to be balanced with medical treatment alone not only in terms of survival but also as far as quality of life is concerned.