Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial. Adjuvant therapy in stage I and stage II epithelial ovarian cancer. Results of two prospective randomized trials. Prognostic factors of stage IV epithelial ovarian cancer: a multicenter retrospective study. Effect of cytoreductive surgery on survival of patients with recurrent epithelial ovarian cancer. A comparison of intravenous versus intraperitoneal chemotherapy for the initial treatment of ovarian cancer. 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. A Randomized Study of Epithelial Ovarian Cancer: Is Chemotherapy Useful after Complete Remission? The role of secondary cytoreduction in the management of the first relapse in epithelial ovarian cancer. Long-term survival after chemotherapy for advanced epithelial ovarian carcinoma.
Serum CA125 concentration often rises several months before clinical or symptomatic relapse in women with ovarian cancer. In the MRC OV05/EORTC 55955 collaborative trial, we aimed to establish the benefits of early treatment on the basis of increased CA125 concentrations compared with delayed treatment on the basis of clinical recurrence.
                Women with ovarian cancer in complete remission after first-line platinum-based chemotherapy and a normal CA125 concentration were registered for this randomised controlled trial. Clinical examination and CA125 measurement were done every 3 months. Patients and investigators were masked to CA125 results, which were monitored by coordinating centres. If CA125 concentration exceeded twice the upper limit of normal, patients were randomly assigned (1:1) by minimisation to early or delayed chemotherapy. Patients and clinical sites were informed of allocation to early treatment, and treatment was started as soon as possible within 28 days of the increased CA125 measurement. Patients assigned to delayed treatment continued masked CA125 measurements, with treatment commencing at clinical or symptomatic relapse. All patients were treated according to standard local practice. The primary outcome was overall survival. Analysis was by intention to treat. This study is registered, ISRCTN87786644.
                1442 patients were registered for the trial, of whom 529 were randomly assigned to treatment groups and were included in our analysis (265 early, 264 delayed). With a median follow-up of 56·9 months (IQR 37·4-81·8) from randomisation and 370 deaths (186 early, 184 delayed), there was no evidence of a difference in overall survival between early and delayed treatment (HR 0·98, 95% CI 0·80-1·20, p=0·85). Median survival from randomisation was 25·7 months (95% CI 23·0-27·9) for patients on early treatment and 27·1 months (22·8-30·9) for those on delayed treatment.
                Our findings showed no evidence of a survival benefit with early treatment of relapse on the basis of a raised CA125 concentration alone, and therefore the value of routine measurement of CA125 in the follow-up of patients with ovarian cancer who attain a complete response after first-line treatment is not proven.
                UK Medical Research Council and the European Organisation for Research and Treatment of Cancer.
                Copyright © 2010 Elsevier Ltd. All rights reserved. About a third of patients with ovarian cancer present with localized disease; despite surgical resection, up to half the tumors recur. Since it has not been established whether adjuvant treatment can benefit such patients, we conducted two prospective, randomized national cooperative trials of adjuvant therapy in patients with localized ovarian carcinoma (International Federation of Gynecology and Obstetrics Stages Ia to IIc). All patients underwent surgical resection plus comprehensive staging and, 18 months later, surgical re-exploration. In the first trial, 81 patients with well-differentiated or moderately well differentiated cancers confined to the ovaries (Stages Iai and Ibi) were assigned to receive either no chemotherapy or melphalan (0.2 mg per kilogram of body weight per day for five days, repeated every four to six weeks for up to 12 cycles). After a median follow-up of more than six years, there were no significant differences between the patients given no chemotherapy and those treated with melphalan with respect to either five-year disease-free survival (91 vs. 98 percent; P = 0.41) or overall survival (94 vs. 98 percent; P = 0.43). In the second trial, 141 patients with poorly differentiated Stage I tumors or with cancer outside the ovaries but limited to the pelvis (Stage II) were randomly assigned to treatment with either melphalan (in the same regimen as above) or a single intraperitoneal dose of 32P (15 mCi) at the time of surgery. In this trial (median follow-up, greater than 6 years) the outcomes for the two treatment groups were similar with respect to five-year disease-free survival (80 percent in both groups) and overall survival (81 percent with melphalan vs. 78 percent with 32P; P = 0.48). We conclude that in patients with localized ovarian cancer, comprehensive staging at the time of surgical resection can serve to identify those patients (as defined by the first trial) who can be followed without adjuvant chemotherapy. The remaining patients with localized ovarian cancer should receive adjuvant therapy, and with adjuvant melphalan or intraperitoneal 32P should have a five-year disease-free survival of about 80 percent. In the present study, we conducted a multicenter retrospective analysis to elucidate the prognostic factors of stage IV epithelial ovarian cancer.
                In November 1999, 24 Japanese institutions received questionnaires regarding stage IV epithelial ovarian cancer patients. Eligibility criteria included all patients with stage IV epithelial ovarian cancer who were surgically confirmed and initially treated in each institution between January 1990 and December 1997. Data were collected regarding age, performance status, tumor histologic subtype, site of metastasis, preoperative CA125, cytoreductive surgery, residual disease after cytoreductive surgery, and response to primary chemotherapy. Survival analysis and comparisons were performed by univariate and multivariate methods.
                Two hundred twenty-five patients with stage IV ovarian cancer were identified. The median age of the patients was 54 years. The most common site of extraperitoneal disease was malignant pleural effusion (39.6%). Of the 225 patients who underwent an attempt at surgical debulking, 70 (31.1%) were optimally cytoreduced. Most patients received platinum-based combination chemotherapy for primary chemotherapy. In multivariate analysis, performance status, histology, and residual disease after cytoreductive surgery were independent prognostic predictors of outcome. The overall median survival for optimally debulked patients was 32 months compared to 16 months for suboptimally debulked patients (P < 0.0001, hazard ratio: 0.415).
                Optimal surgical debulking, performance status, and histology appear to be important prognostic factors of survival in patients with stage IV epithelial ovarian cancer.
                Copyright 2001 Academic Press. The value of secondary cytoreductive surgery is still controversial, especially in patients with recurrent epithelial ovarian cancer. In this retrospective study, we investigated the effect on survival of secondary cytoreduction for recurrent disease and variables influencing redebulking surgical outcome.
                Between 1986 and 1997, 60 patients who received primary cytoreductive surgery and platinum-based chemotherapy for stage III and IV epithelial ovarian cancer experienced disease recurrence at least 6 months after completion of primary therapy, and secondary surgical cytoreduction was performed. The optimal residual disease cutoff was 1.0 cm. The Cox proportional regression model and Logistic stepwise regression were used in statistical processing of the data.
                The median progression-free interval between the two operations was 13 months (range, 6-56 months). Optimal secondary cytoreduction was achieved in 23 patients (38.33%). There was a significant difference in survival between patients who were optimally cytoreduced compared to those suboptimally cytoreduced, with an estimated median survival in the optimal group of 19 months vs. 8 months in the suboptimal group (chi(2) = 22.04, P = 0.0000). Prognosis of survival for individuals with progression-free interval >12 months was better than that of those with the interval </=12 months (chi(2) = 5.22, P = 0.0224). Patients with ascites at disease recurrence suffered a pessimistic outcome, with an estimated median survival of 6 vs. 13 months in those without ascites (chi(2) = 13.99, P = 0.0002). Multivariate analysis strongly suggested that residual disease after second operation, ascites at disease recurrence, and progression-free interval were independent prognostic factors of survival. Logistic stepwise regression revealed that recurrent ascites (P = 0.0072, relative risk = 20.36) and residual disease after the second operation (P = 0.0096, relative risk = 5.16) were important determinants of secondary surgical outcome.
                Secondary cytoreductive surgery significantly lengthened survival for patients with recurrent epithelial ovarian cancer. Patients with ascites at disease recurrence, however, were not suitable for aggressive secondary surgery, and redebulking surgery for those with residual disease of >1.0 cm after primary operation should be considered prudently.
                Copyright 2000 Wiley-Liss, Inc. A phase III study was conducted comparing intraperitoneal (ip) versus intravenous (iv) cisplatin-based therapy for patients with newly diagnosed ovarian cancer to determine if the pharmacologic advantage of ip delivery could be translated into an improved response and survival rate. Twenty-nine patients were randomized to receive six cycles of ip cisplatin 200 mg/m2 plus ip etoposide 350 mg/m2 with iv thiosulfate protection given every 4 weeks; thirty-three patients were randomized to receive six cycles of iv cisplatin 100 mg/m2 plus iv cyclophosphamide 600 mg/m2 administered every 3 weeks. Patients were stratified by stage (IIC-IV) and size of residual disease (> or < or = 1 cm). The study was conducted in a community-wide setting. The complete response in evaluable patients was 48% in the ip group and 52% in the iv group. The surgical complete response rate for all patients on study, underestimated because not all patients in complete clinical remission had a second-look laparotomy, was 31% in the ip group and 33% in the iv group. There was no difference in the response rates between the treatment arms as a function of residual disease < or = or > 1 cm. With a median follow-up of 46 months (range 21-70 months) there is no difference in response duration or survival. Both regimens were well tolerated with comparable hematologic and nonhematologic toxicity. 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 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).
                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.
                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. Objective. The aim of this study is to verify whether consolidation chemotherapy with Cisplatin improves disease-free survival and/or overall survival in patients affected by epithelial ovarian cancer.Methods. A multicenter study examined 122 randomized patients in complete remission as judged by laparoscopy or laparotomy following first-line chemotherapy consisting of ACy (Adriamycin + Cyclophosphamide), PCy (Cisplatin + Cyclophosphamide), or Mitoxantrone + Carboplatin. Sixty-one of these patients were treated with 3 cycles of 5-Fluorouracil (FU) 500 mg/m2 for 5 days followed by Cisplatin at 100 mg/m2 on the 6th or 7th day every 28 days; the other 61 received no further treatment (nihil group).Results. Sixty patients in the Cisplatin arm were evaluable. There were 36 relapses in the FU+Cisplatin arm and 30 in the nihil arm. Peritoneal relapses were 25% for Cisplatin treatment vs. 16.4 % for nihil. There were 29 deaths in the Cisplatin arm vs. 27 for nihil. Median overall survival time (95 months with Cisplatin vs. 96 months in the nihil group) and median disease-free survival (66 months with Cisplatin vs. 73 in the nihil group) were similar in both arms (p=0.66 and p=0.41, respectively). There were no significant differences in tumor stage and grade between the two arms. Seven patients presented a second neoplasm during follow-up: six in the nihil arm, but only one patient in the Cisplatin arm. Death in these patients was due to the second neoplasm and not to progression of ovarian cancer.Conclusion. Three courses of additional platinum+FU treatment after five cycles of first-line chemotherapy without FU produced no increase in overall survival or disease-free survival. The aim of this study was to investigate the benefit of secondary cytoreduction (SCR) in the first relapse in epithelial ovarian cancer and to attempt to define selection criteria for SCR.
                A retrospective population-based study on recorded information from 789 patients treated at the Norwegian Radium Hospital during 1985-2000 for their initial recurrence. In all, 217 had SCR and 572 were treated with chemotherapy alone.
                Median survival time (MST) was 1.1 years for the chemotherapy group. Complete optimal cytoreduction (COC) was achieved in 35% of all 217 patients, in 49% of the patients operated with debulking intent and in 52% if bowel surgery was done with debulking intent. MST was 4.5 versus 0.7 years for 0 versus>2 cm residual disease, respectively. Residual disease after SCR, treatment-free interval (TFI) and age were found to be prognostic factors for overall survival (OS) in multivariate analysis. Localised tumour was found to be the only significant factor to predict COC.
                SCR followed by chemotherapy gives a clear survival benefit compared with chemotherapy and should be offered when the tumour is localised. The combination of COC, TFI >24 months and age </=39 years identifies a group of patients with the best OS. Four hundred twenty-nine patients were entered into four prospective randomized clinical studies between January 1, 1973, and July 1, 1979. The records of 395 of these were analyzed to determine the proportion of patients surviving 48 months after therapy initiation. Ninety-six patients (24%) were living at 48 months, 89 of whom had second-look laparotomies. Of the 96 living patients, 53 (55%) were clinically free of disease and 43 (45%) had disease. Combination-agent chemotherapy produced a larger proportion of 48-month survivors than single-agent therapy (P = 0.001); 70% of these survivors were clinically free of disease. Patient characteristics, such as age, International Federation of Gynaecology and Obstetrics (FIGO) stage, histologic grade of tumor, and amount of residual tumor present prior to chemotherapy exerted a strong influence on length of survival. Long-term survival was not totally dependent on a complete response to chemotherapy; in fact, persistent treatment with drug regimens induced bone marrow disorders and death due to toxicity in five patients. The continued fall in survival curves after 48 months suggests that current therapy regimens are not dramatically changing long-term survival rates.
There is a lack of randomised studies on most aspects of follow-up care after treatment for epithelial ovarian cancers. Limited evidence from a single trial suggests that routine surveillance with CA125 in asymptomatic patients, with treatment at CA125 relapse, does not seem to offer survival advantage when compared to treatment at symptomatic relapse. Randomised controlled trials are needed to compare different types of follow up on the outcomes of survival, quality of Life, cost and psychological effects.