Secondary surgical cytoreduction for advanced ovarian carcinoma. Randomized trial of adjuvant intraperitoneal alpha-interferon in stage III ovarian cancer patients who have no evidence of disease after primary surgery and chemotherapy: An intergroup study. Maintenance treatment with interferon for advanced ovarian cancer: results of the Northern and Yorkshire gynaecology group randomised phase III study. International Collaborative Ovarian Neoplasm trial 1: a randomized trial of adjuvant chemotherapy in women with early-stage ovarian cancer. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. Estrogen-receptor-directed neoadjuvant therapy for breast cancer: results of a randomised trial using formestane and methotrexate, mitozantrone and mitomycin C (MMM) chemotherapy. Intervention debulking surgery in advanced epithelial ovarian cancer. Survival in ovarian cancer in Wales: Prior to introduction of all Wales guidelines. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902. Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem-cell transplantation in high-risk breast cancer.
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. Despite the improvement in progression-free and overall survival in patients with advanced ovarian cancer associated with platinum-taxane chemotherapy, strategies are needed to prevent the greater than 70% recurrence rate.
                The Southwest Oncology Group (SWOG) initiated a phase III intergroup trial of alpha-interferon (IFNalpha-26, Schering-Plough, Kenilworth, NJ) in weekly doses of 50 x 10(6) IU (for 6 doses) versus observation only in patients with no pathological evidence of residual disease at second-look surgery in 1988.
                Patient accrual was extremely slow and the trial was permanently closed in 1999 by the SWOG Data and Safety Monitoring Committee with 74 registered patients. Of these patients, 70 were evaluable for progression-free and overall survival. There was no significant difference between the two study arms in relation to median progression-free survival (P = 0.56). The median survival duration associated with intraperitoneal alpha-interferon had not been reached versus 87 months on the observation arm. In general, intraperitoneal alpha-interferon was well tolerated. There were no treatment-related deaths or grade 4 adverse events. Although no efficacy conclusions can be drawn from this prematurely closed trial, it should be noted that 57% of the patients on the observation arm recurred and all died, whereas 63% recurred and only 43% died on the intraperitoneal alpha-interferon arm.
                Although this was a negative study, there should continue to be interest in the use of biological therapy to improve survival of patients in complete remission following primary chemotherapy. A randomised phase III trial was conducted to assess the role of interferon-alpha (INFalpha) 2a as maintenance therapy following surgery and/or chemotherapy in patients with epithelial ovarian carcinoma. Patients were randomised following initial surgery/chemotherapy to interferon-alpha 2a as 4.5 mega-units subcutaneously 3 days per week or to no further treatment. A total of 300 patients were randomised within the study between February 1990 and July 1997. No benefit for interferon maintenance was seen in terms of either overall or clinical event-free survival. We conclude that INF-alpha is not effective as a maintenance therapy in the management of women with ovarian cancer. The need for novel therapeutics or strategies to prevent the almost inevitable relapse of patients despite increasingly effective surgery and chemotherapy remains. 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. Primary debulking surgery before initiation of chemotherapy has been the standard of care for patients with advanced ovarian cancer.
                We randomly assigned patients with stage IIIC or IV epithelial ovarian carcinoma, fallopian-tube carcinoma, or primary peritoneal carcinoma to primary debulking surgery followed by platinum-based chemotherapy or to neoadjuvant platinum-based chemotherapy followed by debulking surgery (so-called interval debulking surgery).
                Of the 670 patients randomly assigned to a study treatment, 632 (94.3%) were eligible and started the treatment. The majority of these patients had extensive stage IIIC or IV disease at primary debulking surgery (metastatic lesions that were larger than 5 cm in diameter in 74.5% of patients and larger than 10 cm in 61.6%). The largest residual tumor was 1 cm or less in diameter in 41.6% of patients after primary debulking and in 80.6% of patients after interval debulking. Postoperative rates of adverse effects and mortality tended to be higher after primary debulking than after interval debulking. The hazard ratio for death (intention-to-treat analysis) in the group assigned to neoadjuvant chemotherapy followed by interval debulking, as compared with the group assigned to primary debulking surgery followed by chemotherapy, was 0.98 (90% confidence interval [CI], 0.84 to 1.13; P=0.01 for noninferiority), and the hazard ratio for progressive disease was 1.01 (90% CI, 0.89 to 1.15). Complete resection of all macroscopic disease (at primary or interval surgery) was the strongest independent variable in predicting overall survival.
                Neoadjuvant chemotherapy followed by interval debulking surgery was not inferior to primary debulking surgery followed by chemotherapy as a treatment option for patients with bulky stage IIIC or IV ovarian carcinoma in this study. Complete resection of all macroscopic disease, whether performed as primary treatment or after neoadjuvant chemotherapy, remains the objective whenever cytoreductive surgery is performed. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00003636.) We wanted to determine whether neoadjuvant systemic chemoendocrine therapy guided by the estrogen receptor (ER) status of the primary breast cancer, followed by conventional surgery and/or radiotherapy, reduces local and distant recurrence and improves survival compared with adjuvant treatment given conventionally postoperatively.
                Two hundred ten patients with primary breast cancer (T1-T4, N0, N1-2) were randomised to receive treatment with neoadjuvant chemoendocrine therapy or conventional post-operative chemoendocrine therapy. Systemic therapy was based on the estrogen receptor (ER) status of the primary tumour obtained by trucut core biopsy. ER-negative patients received MMM chemotherapy (methotrexate (30 mg/m2), mitozantrone (7 mg/m2) and mitomycin (7 mg/m2) three-weekly for three months and ER-positive patients who were premenopausal received goserelin (3.75 mg monthly), and post menopausal women formestane (250 mg every two weeks) over three months.
                With a minimum of five years follow-up, there is no evidence of any survival benefit from the pretreatment neoadjuvant therapy regimen, with five year overall survival being 79% +/- 4.7% (neoadjuvant) and 87% +/- 3.4% (adjuvant). Similarly, there was no apparent benefit in terms of disease-free survival. There was, however, a significant reduction in the incidence of distant metastases in responders (4 of 51; 8%) compared with non-responders (17 of 49; 35%) (P < 0.01). There was a reduction in the need for surgery in responding patients with T1 and T2 tumours, since 10 of 74 (14%) had no detectable residual tumour, without any apparent increase in the risk of local or distant recurrence.
                In this study neoadjuvant treatment with endocrine or chemotherapy provided no obvious survival benefit to women with breast cancer. However, it does allow avoidance of surgery in some cases. Also, the patients whose tumours respond to neoadjuvant systemic therapy have a lower incidence of distant metastases after five year follow-up compared to those whose tumours fail to respond. To study whether intervention debulking surgery improves survival in patients with advanced ovarian cancer who have bulky (> 2 cm) residual disease after primary surgery.
                A prospective multicentre randomised study.
                Hospitals in the West Midlands.
                Ovarian cancer patients with bulky residual disease after primary surgery who are considered well enough to receive cis-platinum based chemotherapy and further surgery.
                Eligible patients were randomised to receive combination chemotherapy alone or combined with intervention debulking surgery.
                Survival was assessed using product limit method and log-rank test.
                Seventy-nine patients were entered into the study. Thirty-seven patients were randomised to intervention debulking surgery, 25 (67%) of whom underwent intervention debulking surgery, which was performed a median of 13 weeks after primary surgery. The median survival for the intervention debulking surgery group was 15 months (95% CI 10-20 mo) and that of those randomised to chemotherapy alone, which was 12 months (95% CI 8-16 mo), were not significantly different (hazard ratio = 0.71; 95% CI 0.44-1.13).
                Intervention debulking surgery may not improve survival in patients with advanced ovarian cancer. The objective of the study was to review referral practice, overall management, and survival in women with suspected ovarian cancer in Wales. This study was done prior to introduction of cancer management guidelines in the region. A confidential study questionnaire was sent to 20 participating hospitals. Data on 287 consecutive women with suspected ovarian cancer were collected, of which 250 women underwent primary laparotomy. Information was obtained on referral pattern, preoperative investigations, place of primary surgery, specialty of the primary surgeon, surgical parameters recorded at the time of operation, a final overall stage, adjuvant treatment, and survival outcome. There was a wide variation in referral practice and management of ovarian cancer in Wales. Stage of the disease, attempt at optimal debulking, residual disease, management by a cancer centre multidisciplinary team, and platinum-based chemotherapy were associated with improved overall survival and progression-free survival. More women were alive if managed in the cancer centre at 1 and 3 year after diagnosis (P = 0.022). This study has highlighted the acute issue of the standards of clinical care in the area of ovarian cancer management and will emphasize the implementation of better care pathways for ovarian cancers. The monoclonal antibody trastuzumab has survival benefit when given with chemotherapy to patients with early, operable, and metastatic breast cancer that has HER2 (also known as ERBB2) overexpression or amplification. We aimed to assess event-free survival in patients with HER2-positive locally advanced or inflammatory breast cancer receiving neoadjuvant chemotherapy with or without 1 year of trastuzumab.
                We compared 1 year of treatment with trastuzumab (given as neoadjuvant and adjuvant treatment; n=117) with no trastuzumab (118), in women with HER2-positive locally advanced or inflammatory breast cancer treated with a neoadjuvant chemotherapy regimen consisting of doxorubicin, paclitaxel, cyclophosphamide, methotrexate, and fluorouracil. Randomisation was done with a computer program and minimisation technique, taking account of geographical area, disease stage, and hormone receptor status. Investigators were informed of treatment allocation. A parallel cohort of 99 patients with HER2-negative disease was included and treated with the same chemotherapy regimen. Primary endpoint was event-free survival. Analysis was by intention to treat. This study is registered, number ISRCTN86043495.
                Trastuzumab significantly improved event-free survival in patients with HER2-positive breast cancer (3-year event-free survival, 71% [95% CI 61-78; n=36 events] with trastuzumab, vs 56% [46-65; n=51 events] without; hazard ratio 0.59 [95% CI 0.38-0.90]; p=0.013). Trastuzumab was well tolerated and, despite concurrent administration with doxorubicin, only two patients (2%) developed symptomatic cardiac failure. Both responded to cardiac drugs.
                The addition of neoadjuvant and adjuvant trastuzumab to neoadjuvant chemotherapy should be considered for women with HER2-positive locally advanced or inflammatory breast cancer to improve event-free survival, survival, and clinical and pathological tumour responses.
                F Hoffmann-La Roche.
                Copyright 2010 Elsevier Ltd. All rights reserved. To evaluate whether preoperative neoadjuvant chemotherapy in patients with primary operable breast cancer results in better overall survival (OS) and relapse-free survival rates and whether preoperative chemotherapy permits more breast-conserving surgery procedures than postoperative chemotherapy.
                Six hundred ninety-eight breast cancer patients (T1c, T2, T3, T4b, N0 to 1, and M0) were enrolled onto a randomized phase III trial that compared four cycles of fluorouracil, epirubicin, and cyclophosphamide administered preoperatively versus the same regimen administered postoperatively (the first cycle administered within 36 hours after surgery). Patients were followed up for OS, progression-free survival (PFS), and locoregional recurrence (LRR).
                At a median follow-up of 56 months, there was no significant difference in terms of OS (hazards ratio, 1.16; P =.38), PFS (hazards ratio, 1.15; P =.27), and time to LRR (hazards ratio, 1.13; P =.61). Fifty-seven patients (23%) were downstaged by the preoperative chemotherapy, whereas 14 patients (18%) underwent mastectomy and not the planned breast-conserving therapy.
                The use of preoperative chemotherapy yields similar results in terms of PFS, OS, and locoregional control compared with conventional postoperative chemotherapy. In addition, preoperative chemotherapy enables more patients to be treated with breast-conserving surgery. Because preoperative chemotherapy does not improve disease outcome compared with postoperative chemotherapy, future trials should involve quality-of-life studies to investigate whether patients will benefit from this treatment modality. The prognosis for women with primary breast cancer and 10 or more involved axillary lymph nodes is poor. High-dose chemotherapy with autologous hematopoietic stem-cell transplantation has been reported to be effective in the adjuvant setting for patients at high risk for relapse.
                We randomly assigned 540 female patients with primary breast cancer and at least 10 involved ipsilateral axillary lymph nodes to receive either six cycles of adjuvant chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) or the same adjuvant chemotherapy followed by high-dose chemotherapy with cyclophosphamide and thiotepa and autologous hematopoietic stem-cell transplantation.
                Among the 511 eligible patients, there was no significant difference in disease-free survival, overall survival, or the time to recurrence between those who received CAF alone and those who received CAF plus high-dose chemotherapy and stem-cell transplantation. Among 417 patients fulfilling strict eligibility criteria, the time to recurrence was longer for patients who underwent stem-cell transplantation than for those who received CAF alone. In the transplantation group, nine patients died of transplantation-related complications and a myelodysplastic syndrome or acute myeloid leukemia developed in nine.
                The addition of high-dose chemotherapy and autologous hematopoietic stem-cell transplantation to six cycles of adjuvant chemotherapy with CAF may reduce the risk of relapse but does not improve the outcome among patients with primary breast cancer and at least 10 involved axillary lymph nodes. Conventional-dose adjuvant chemotherapy remains the standard of care for such patients.
                Copyright 2003 Massachusetts Medical Society
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.