Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer--results from two randomised studies. International Collaborative Ovarian Neoplasm trial 1: a randomized trial of adjuvant chemotherapy in women with early-stage ovarian cancer. Importance of delivered cycles and nomogram for intraperitoneal chemotherapy in ovarian cancer. Medical Research Council study on chemotherapy in advanced ovarian cancer. Medical Research Council's Working Party on ovarian cancer. Secondary surgical cytoreduction for advanced ovarian carcinoma. Survival of premenopausal women with metastatic breast cancer. Long-term follow-up of Eastern Cooperative Group and Cancer and Leukemia Group B studies. A pilot study of a supervised group exercise programme as a rehabilitation treatment for women with breast cancer receiving adjuvant treatment. The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. Gynecological Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer. Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study.
Endometrial cancer patients with high grade tumours, deep myometrial invasion or advanced stage disease have a poor prognosis. Randomised studies have demonstrated the prevention of loco-regional relapses with radiotherapy (RT) with no effect on overall survival (OS). The possible additive effect of chemotherapy (CT) remains unclear. Two randomised clinical trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III) were undertaken to clarify if sequential combination of chemotherapy and radiotherapy improves progression-free survival (PFS) in high-risk endometrial cancer. The two studies were pooled.
                Patients (n=540; 534 evaluable) with operated endometrial cancer International Federation of Obstetrics and Gynaecology (FIGO) stage I-III with no residual tumour and prognostic factors implying high-risk were randomly allocated to adjuvant radiotherapy with or without sequential chemotherapy.
                In the NSGO/EORTC study, the combined modality treatment was associated with 36% reduction in the risk for relapse or death (hazard ratio (HR) 0.64, 95%confidence interval (CI) 0.41-0.99; P=0.04); two-sided tests were used. The result from the Gynaecologic Oncology group at the Mario Negri Institute (MaNGO)-study pointed in the same direction (HR 0.61), but was not significant. In the combined analysis, the estimate of risk for relapse or death was similar but with narrower confidence limits (HR 0.63, CI 0.44-0.89; P=0.009). Neither study showed significant differences in the overall survival. In the combined analysis, overall survival approached statistical significance (HR 0.69, CI 0.46-1.03; P=0.07) and cancer-specific survival (CSS) was significant (HR 0.55, CI 0.35-0.88; P=0.01).
                Addition of adjuvant chemotherapy to radiation improves progression-free survival in operated endometrial cancer patients with no residual tumour and a high-risk profile. A remaining question for future studies is if addition of radiotherapy to chemotherapy improves the results.
                Copyright 2010 Elsevier Ltd. All rights reserved. The question of whether platinum-based adjuvant chemotherapy can improve outcomes in patients with early-stage epithelial ovarian cancer is an important one. We carried out a multicenter, open randomized trial to determine whether adjuvant chemotherapy would improve overall survival and prolong recurrence-free survival in women with early-stage epithelial ovarian cancer.
                Between August 1991 and January 2000, 477 patients in 84 centers in five countries were randomly assigned to receive either adjuvant chemotherapy immediately following surgery (n = 241) or no adjuvant chemotherapy until clinically indicated (n = 236). Kaplan-Meier curves of overall survival and recurrence-free survival were compared using the Mantel-Cox version of the log-rank test. All statistical tests were two-sided.
                Women who received adjuvant chemotherapy had better overall survival than women who did not (hazard ratio [HR] of 0.66, 95% confidence interval [CI] = 0.45 to 0.97; P =.03). These results translate into 5-year survival figures of 70% for women who did not receive adjuvant chemotherapy and 79% for women who did receive adjuvant chemotherapy, a difference of 9% (95% CI = 1% to 15%). Adjuvant chemotherapy also improved recurrence-free survival (HR = 0.65; 95% CI = 0.46 to 0.91; P =.01). These results translate into 5-year recurrence-free survival figures of 62% for women who did not receive adjuvant chemotherapy and 73% for women who did receive adjuvant chemotherapy, a difference of 11% (95% CI = 3% to 18%).
                These results suggest that platinum-based adjuvant chemotherapy improves survival and delays recurrence in patients with early-stage ovarian cancer. Intraperitoneal (IP) chemotherapy has gained enthusiasm in the treatment of ovarian cancer. Despite having a better survival advantage than intravenous (IV) chemotherapy, IP chemotherapy still poses significant morbidity and complications. Identifying the subset of patients who could best benefit from IP chemotherapy, and those who would least benefit from this treatment, thus avoiding potential complications, is critical.
                Between January 2001 and December 2007, 367 patients with stage III epithelial ovarian cancer underwent randomized trial for IP/IV chemotherapy were recruited to construct a nomogram, which is a graphical representation of Cox proportional hazards model adopting six weighted risk factors including age, CA125, IP/IV delivery, stage, histology, and upper abdominal metastases. The nomogram was internally validated for discrimination and calibration. The concordance index was used for quantifying the predictive ability of overall survival with bootstrapping to correct for bias.
                The cycles of completed IP chemotherapy had an impact on overall survival (> or =5 vs. < or =4 cycles, P=0.02). A nomogram for predicting median survival and 5-year survival probability was constructed with a concordance index of 0.72. Upper abdominal tumor metastases (P<0.001) and colon resection (P=0.02) predicted increased chances for early discontinuation of IP chemotherapy.
                At least five IP cycles are needed to achieve better survival. Nomogram can help to identify the subset of patients who can least benefit from IP chemotherapy, thus avoiding potential IP complications and help to facilitate discussion between patient and physician, risk stratification, and help to guide clinical care. A total of 264 eligible patients with advanced ovarian cancer were randomised to single or triple agent cytotoxic therapy; 261 were available for analysis. The treatments were continuous oral cyclophosphamide (arm S), and a combination of oral cyclophosphamide, hexamethylmelamine and methotrexate on a pulsed basis (arm T). Mortality attributed to cancer was slightly lower on arm T (p = 0.06), but this was offset by the greater toxicity of this regimen, and overall survival and activity index were similar on the two arms. There was thus little evidence of greater clinical benefit on the triple agent regimen. Tumour mass removed at operation, extent of remaining tumour and age all showed significant correlation with prognosis. Survival was longer in patients whose disease responded to either therapeutic regimen. We evaluated the effect of adding secondary cytoreductive surgery to postoperative chemotherapy on progression-free survival and overall survival among patients who had advanced ovarian cancer and residual tumor exceeding 1 cm in diameter after primary surgery.
                Women were enrolled within six weeks after primary surgery. If, after three cycles of postoperative paclitaxel plus cisplatin, a patient had no evidence of progressive disease, she was randomly assigned to undergo secondary cytoreductive surgery followed by three more cycles of chemotherapy or three more cycles of chemotherapy alone.
                We enrolled 550 women. After completing three cycles of postoperative chemotherapy, 216 eligible patients were randomly assigned to receive secondary surgical cytoreduction followed by chemotherapy and 208 to receive chemotherapy alone. Surgery was declined by or medically contraindicated in 15 patients who were assigned to secondary surgery (7 percent). As of March 2003, 296 patients had died and 82 had progressive disease. The likelihood of progression-free survival in the group assigned to secondary surgery plus chemotherapy, as compared with the chemotherapy-alone group, was 1.07 (95 percent confidence interval, 0.87 to 1.31; P=0.54), and the relative risk of death was 0.99 (95 percent confidence interval, 0.79 to 1.24; P=0.92).
                For patients with advanced ovarian carcinoma in whom primary cytoreductive surgery was considered to be maximal, the addition of secondary cytoreductive surgery to postoperative chemotherapy with paclitaxel plus cisplatin does not improve progression-free survival or overall survival.
                Copyright 2004 Massachusetts Medical Society. In premenopausal women with metastatic breast cancer, differences in survival curves early during follow-up can be misleading. The authors therefore analyzed long-term survival in 378 patients, entered in three randomized trials, started between 1973 and 1978. Combined data from the three trials were used to increase the power for identifying prognostic variables. Cancer and Leukemia Group B (CALGB) trial 7382 randomized patients to oophorectomy plus either cyclophosphamide or combination chemotherapy or observation. Eastern Cooperative Oncology Group (ECOG) 2174 randomized patients who had not progressed 3 months after oophorectomy to combination chemotherapy or combination chemotherapy or observation. Trial ECOG 2177 randomized estrogen receptor (ER) positive or ER-unknown patients to oophorectomy plus combination chemotherapy or immediate combination chemotherapy, and ER-negative patients were directly assigned to combination chemotherapy. Hence ER-negative patients need not have been healthy enough to be randomized to oophorectomy. With only 14% of the patients still alive, median survival on the three studies was 30, 24, and 28 months. The median survival of individual treatments changed noticeably in ECOG 2174 and ECOG 2177 with long-term follow-up. At this time there are no differences in survival between randomized regimens in any of the three trials. In a multivariate model, factors associated with significantly poorer survival were visceral-dominant disease, nodal metastases, breast metastases, age younger than 45 years, ER negativity, and not receiving chemotherapy immediately after oophorectomy. This treatment difference was thus not due to imbalances in the prognostic variables used in the model, but it may be due to imbalances of unknown prognostic factors or differences in patient selection. This pilot study examined whether exercise as an adjunctive rehabilitation therapy could benefit women who have early stage breast cancer and are currently receiving chemotherapy/radiotherapy. The study was designed as a randomised controlled trial (RCT). Physical functioning, fatigue and Quality of Life (QoL) outcomes were evaluated pre and post a 12-week intervention. The results showed that after 12 weeks the women who participated in the exercise programme (n = 12) displayed significantly higher levels of physical functioning and reported higher QoL scores than the controls (n = 10). Changes in fatigue and satisfaction with life favoured the intervention group but did not reach significance. These results are encouraging and suggest that a structured group exercise programme during adjuvant treatment is a safe, well tolerated and effective way of providing physical and psychological health benefits to women during treatment for early stage breast cancer. Since this was a pilot study the numbers did not allow appropriately powered analyses of some variables of interest and favoured relatively young and socio-economically advantaged women. Future studies need to address these issues and determine if these short-term benefits can be sustained. Although the value of primary cytoreductive surgery for epithelial ovarian cancer is beyond doubt, the value of debulking surgery after induction chemotherapy has not yet been defined. In this randomized study we investigated the effect on survival of debulking surgery.
                Eligible patients had residual lesions measuring more than 1 cm in diameter after primary surgery. After three cycles of cyclophosphamide and cisplatin, these patients were randomly assigned to undergo either debulking surgery or no surgery, followed by further cycles of cyclophosphamide and cisplatin. The study end points were progression-free and overall survival. At surgery 65 percent of the patients had lesions measuring more than 1 cm. In 45 percent of this group, the lesions were reduced surgically to less than 1 cm.
                Of the 319 patients who underwent randomization, 278 could be evaluated (140 patients who underwent surgery and 138 patients who did not). Progression-free and overall survival were both significantly longer in the group that underwent surgery (P = 0.01). The difference in median survival was six months. The survival rate at two years was 56 percent for the group that underwent surgery and 46 percent for the group that did not. In the multivariate analysis, debulking surgery was an independent prognostic factor (P = 0.012). Overall, after adjustment for all other prognostic factors, surgery reduced the risk of death by 33 percent (95 percent confidence interval, 10 to 50 percent; P = 0.008). Surgery was not associated with death or severe morbidity.
                Debulking surgery significantly lengthened progression-free and overall survival. The risk of death was reduced by one third, after adjustment for a variety of prognostic factors. To determine whether GnRHa administration before and during combination chemotherapy for breast cancer could preserve posttreatment ovarian function in young women or not.
                Prospective randomized controlled study.
                Department of Obstetrics and Gynecology, Mansura University Hospital, Mansura, Egypt.
                Eighty patients with unilateral adenocarcinoma of the breast and with no metastasis who had undergone modified radical mastectomy or breast-conserving surgery plus full axillary lymph node dissection were included in the study. Patients were assigned randomly to receive combined GnRHa and chemotherapy or chemotherapy alone. One woman in each group dropped out.
                Return of spontaneous menstruation and ovulation. Hormonal changes (FSH, LH, E(2), P) during and after the course of treatment.
                In the study group, 89.6% resumed menses and 69.2% resumed spontaneous ovulation within 3-8 months of termination of the GnRHa/chemotherapy cotreatment; 11.4% experienced hypergonadotrophic amenorrhoea and ovarian failure 8 months after treatment. In the control group (chemotherapy without GnRHa), 33.3% resumed menses and 25.6% resumed normal ovarian activity. The median FSH and LH concentrations, 6 months after completion of the GnRHa/chemotherapy cotreatment group, were significantly less than the control group. During the GnRHa/chemotherapy cotreatment the concentrations of FSH, LH, and P decreased to almost prepubertal levels. However, within 1-3 months after the last GnRHa injection, an increase in LH and FSH concentrations was detected, followed several weeks later in by an increase in P concentrations to within normal levels.
                GnRHa administration before and during combination chemotherapy for breast cancer may preserve posttreatment ovarian function in women <40 years. Long-term studies are required.
We found no conclusive evidence to determine whether IDS between cycles of chemotherapy would improve or decrease the survival rates of women with advanced ovarian cancer, compared with conventional treatment of primary surgery followed by adjuvant chemotherapy. IDS appeared to yield benefit only in women whose primary surgery was not performed by gynaecologic oncologists or was less extensive. Data on QoL and adverse events were inconclusive.