Dataset Information

Concurrent vs sequential adjuvant chemotherapy and hormone therapy in breast cancer: a multicenter randomized phase III trial.

ABSTRACT:

Background

The most appropriate timing of chemotherapy and hormone therapy administration is a critical issue in early breast cancer patients. The purpose of our study was to compare the efficacy of concurrent vs sequential administration of adjuvant chemotherapy and tamoxifen.

Methods

Women with node-positive primary breast cancer were randomly assigned to receive tamoxifen (20 mg/d for 5 years) during (concurrent arm) or after (sequential arm) adjuvant chemotherapy. Chemotherapy consisted of alternating regimens of cyclophosphamide, epidoxorubicin, and 5-fluorouracil and cyclophosphamide, methotrexate, and 5-fluorouracil every 21 days for a total of 12 cycles. The primary endpoint was overall survival (OS), and secondary endpoints were toxic effects and disease-free survival (DFS). No provision for interim analyses was made in the original study protocol. Survival curves were estimated by the Kaplan-Meier method. Multivariable Cox regression models, adjusted for age, menopausal status, tumor stage, and lymph node and hormone receptor status, were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided.

Results

From 1985 to 1992, 431 patients were randomly assigned and studied according to the intention-to-treat principle. After a maximum of 15.4 years of follow-up (median 12.3 years), the estimated actuarial 10-year OS was equivalent for the two study arms (concurrent arm: 111 patients, 66%, 95% CI = 59% to 72%; sequential arm: 114 patients, 65%, 95% CI = 59% to 72%, P = .86). No differences in DFS and toxic effects were evident. Four interim analyses were performed, but no alpha error adjustment was necessary because of the largely negative results of this final analysis (sequential vs concurrent arm: HR of death = 1.06, 95% CI = 0.78 to 1.44, P = .76; HR of relapse = 1.16, 95% CI = 0.88 to 1.52, P = .36).

Conclusions

No statistically significant differences in OS, DFS, and toxic effects between concurrent and sequential adjuvant chemo- and hormone therapies were observed. Our study does not support the superiority of one schedule of chemo- and hormone-therapy administration over the other. However, because of the limited statistical power of the study, these results must be considered with caution.

SUBMITTER: Bedognetti D

PROVIDER: S-EPMC3202939 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:ImportanceThere is no current consensus on the role of chemotherapy in addition to radiation for postoperative adjuvant treatment of patients with early-stage cervical cancer with adverse pathological factors.ObjectiveTo evaluate the clinical benefits of sequential chemoradiation (SCRT) and concurrent chemoradiation (CCRT) compared with radiation alone (RT) as a postoperative adjuvant treatment in early-stage cervical cancer.Design, setting, and participantsAfter radical hysterectomy at 1 of 8 participating hospitals in China, patients with FIGO (International Federation of Gynecology and Obstetrics) stage IB to IIA cervical cancer with adverse pathological factors were randomized 1:1:1 to receive adjuvant RT, CCRT, or SCRT. Data were collected from February 2008 to December 2018.InterventionsPatients received adjuvant RT (total dose, 45-50 Gy), CCRT (weekly cisplatin, 30-40 mg/m2), or SCRT (cisplatin, 60-75 mg/m2, plus paclitaxel, 135-175 mg/m2) in a 21-day cycle, given 2 cycles before and 2 cycles after radiotherapy, respectively.Main outcomes and measuresThe primary end point was the rate of disease-free survival (DFS) at 3 years.ResultsA total of 1048 women (median [range] age, 48 [23-65] years) were included in the analysis (350 in the RT group, 345 in the CCRT group, and 353 in the SCRT group). Baseline demographic and disease characteristics were balanced among the treatment groups except that the rate of lymph node involvement was lowest in the RT group (18.3%). In the intention-to-treat population, SCRT was associated with a higher rate of DFS than RT (3-year rate, 90.0% vs 82.0%; hazard ratio [HR], 0.52; 95% CI, 0.35-0.76) and CCRT (90.0% vs 85.0%; HR, 0.65; 95% CI, 0.44-0.96). Treatment with SCRT also decreased cancer death risk compared with RT (5-year rate, 92.0% vs 88.0%; HR, 0.58; 95% CI, 0.35-0.95) after adjustment for lymph node involvement. However, neither DFS nor cancer death risk was different among patients treated with CCRT or RT.Conclusions and relevanceIn this randomized clinical trial, conducted in a postoperative adjuvant treatment setting, SCRT, rather than CCRT, resulted in a higher DFS and lower risk of cancer death than RT among women with early-stage cervical cancer.Trial registrationClinicalTrials.gov Identifier: NCT00806117.

Project description:Importance:Locoregional failure for patients with locally advanced bladder cancer (LABC) after radical cystectomy (RC) is common even with chemotherapy and is associated with high morbidity and mortality. Adjuvant radiotherapy (RT) can decrease locoregional failure but has not been studied in the chemotherapy era. Objective:To investigate if adjuvant sequential RT plus chemotherapy can improve locoregional recurrence-free survival (LRFS) compared with adjuvant chemotherapy alone. Design, Setting, and Participants:A randomized phase 3 trial was opened to compare adjuvant RT vs sequential chemotherapy plus RT after RC for LABC, but a third arm was added later as a randomized phase 2 trial to compare chemotherapy plus RT vs adjuvant chemotherapy alone, an emerging standard. The intent-to-treat phase 2 trial reported herein enrolled patients from December 2002 to July 2008. Data were analyzed from August 3, 2015, to January 6, 2016. Routine follow-up and surveillance pelvic computed tomographic (CT) scans every 6 months during the first 2 years were performed. The setting was an academic center. Patients with bladder cancer 70 years or younger having 1 or more risk factors (≥pT3b, grade 3, or positive nodes) with negative margins after radical cystectomy plus pelvic lymph node dissection were eligible. Patients had Eastern Cooperative Oncology Group performance status of 0 to 2, no evidence of distant metastases on CT scan of the abdomen and pelvis or on chest imaging, and adequate renal, hepatic, and hematologic function. Ninety-one percent (109 of 120) had ≥ pT3 disease. Interventions:Chemotherapy plus RT included 2 cycles of gemcitabine (1000 mg/m2 intravenously on days 1, 8, and 15) and cisplatin (70 mg/m2 intravenously on day 2) before and after RT to 4500 cGy in 150 cGy twice-daily fractions over 3 weeks using 3-dimensional conformal techniques. Chemotherapy alone included 4 cycles of gemcitabine and cisplatin. Main Outcome and Measure:Locoregional recurrence-free survival. Results:The chemotherapy plus RT arm accrued 75 patients, and the chemotherapy-alone arm accrued 45 patients, with a weighted randomization to speed accrual. Fifty-three percent (64 of 120) had urothelial carcinoma, and 46.7% (56 of 120) had squamous cell carcinoma or other. The arms were balanced except for age (median, 52 vs 55 years; P = .04) and tumor size (mean, 4.9 vs 5.8 cm; P < .01), both favoring chemotherapy plus RT. Two-year outcomes and overall adjusted hazard ratios (HRs) for chemotherapy plus RT vs chemotherapy alone were 96% vs 69% (HR, 0.08; 95% CI, 0.02-0.39; P < .01) for LRFS, 68% vs 56% (HR, 0.53; 95% CI, 0.27-1.06; P = .07) for disease-free survival, and 71% vs 60% (HR, 0.61; 95% CI, 0.33-1.11; P = .11) for overall survival (OS). Five patients (7%) had RT-associated late grade 3 gastrointestinal tract adverse effects in the chemotherapy plus RT arm. Conclusions and Relevance:Adjuvant chemotherapy plus RT was reasonably well tolerated and was associated with significant improvements in LRFS and marginal improvements in disease-free survival vs chemotherapy alone in LABC. The addition of adjuvant RT should be considered for LABC. This regimen warrants further study in phase 3 trials. Trial Registration:clinicaltrials.gov Identifier: NCT01734798.

Project description:BackgroundThe addition of oxaliplatin to adjuvant 5-fluorouracil (5-FU) improves survival of patients with stage III colon cancer in randomized clinical trials (RCTs). However, RCT participants are younger, healthier, and less racially diverse than the general cancer population. Thus, the benefit of oxaliplatin outside RCTs is uncertain.Subjects and methodsPatients younger than 75 years with stage III colon cancer who received chemotherapy within 120 days of surgical resection were identified from five observational data sources-the Surveillance, Epidemiology, and End Results registry linked to Medicare claims (SEER-Medicare), the New York State Cancer Registry (NYSCR) linked to Medicaid and Medicare claims, the National Comprehensive Cancer Network (NCCN) Outcomes Database, and the Cancer Care Outcomes Research & Surveillance Consortium (CanCORS). Overall survival (OS) was compared among patients treated with oxaliplatin vs non-oxaliplatin-containing adjuvant chemotherapy. Overall survival for 4060 patients diagnosed during 2004-2009 was compared with pooled data from five RCTs (the Adjuvant Colon Cancer ENdpoinTs [ACCENT] group, n = 8292). Datasets were juxtaposed but not combined using Kaplan-Meier curves. Covariate and propensity score adjusted proportional hazards models were used to calculate adjusted survival hazard ratios (HR). Stratified analyses examined effect modifiers. All statistical tests were two-sided.ResultsThe survival advantage associated with the addition of oxaliplatin to adjuvant 5-FU was evident across diverse practice settings (3-year OS: RCTs, 86% [n = 1273]; SEER-Medicare, 80% [n = 1152]; CanCORS, 88% [n = 129]; NYSCR-Medicaid, 82% [n = 54]; NYSCR-Medicare, 79% [n = 180]; and NCCN, 86% [n = 438]). A statistically significant improvement in 3-year overall survival was seen in the largest cohort, SEER-Medicare, and in the NYSCR-Medicare cohort (non-oxaliplatin-containing vs oxaliplatin-containing adjuvant therapy, adjusted HR of death: pooled RCTs: HR = 0.80, 95% CI = 0.70 to 0.92, P = .002; SEER-Medicare: HR = 0.70, 95% CI = 0.60 to 0.82, P < .001; NYSCR-Medicare patients aged ?65 years: HR = 0.58, 95% CI = 0.38 to 0.90, P = .02). The association between oxaliplatin treatment and better survival was maintained in older and minority group patients, as well as those with higher comorbidity.ConclusionThe addition of oxaliplatin to 5-FU appears to be associated with better survival among patients receiving adjuvant colon cancer treatment in the community.

Project description:Both induction chemotherapy followed by irradiation and concurrent chemotherapy and radiotherapy have been reported as valuable alternatives to total laryngectomy in patients with advanced larynx or hypopharynx cancer. We report results of the randomized phase 3 trial 24954 from the European Organization for Research and Treatment of Cancer.Patients with resectable advanced squamous cell carcinoma of the larynx (tumor stage T3-T4) or hypopharynx (T2-T4), with regional lymph nodes in the neck staged as N0-N2 and with no metastasis, were randomly assigned to treatment in the sequential (or control) or the alternating (or experimental) arm. In the sequential arm, patients with a 50% or more reduction in primary tumor size after two cycles of cisplatin and 5-fluorouracil received another two cycles, followed by radiotherapy (70 Gy total). In the alternating arm, a total of four cycles of cisplatin and 5-fluorouracil (in weeks 1, 4, 7, and 10) were alternated with radiotherapy with 20 Gy during the three 2-week intervals between chemotherapy cycles (60 Gy total). All nonresponders underwent salvage surgery and postoperative radiotherapy. The Kaplan-Meier method was used to obtain time-to-event data.The 450 patients were randomly assigned to treatment (224 to the sequential arm and 226 to the alternating arm). Median follow-up was 6.5 years. Survival with a functional larynx was similar in sequential and alternating arms (hazard ratio of death and/or event = 0.85, 95% confidence interval = 0.68 to 1.06), as were median overall survival (4.4 and 5.1 years, respectively) and median progression-free interval (3.0 and 3.1 years, respectively). Grade 3 or 4 mucositis occurred in 64 (32%) of the 200 patients in the sequential arm who received radiotherapy and in 47 (21%) of the 220 patients in the alternating arm. Late severe edema and/or fibrosis was observed in 32 (16%) patients in the sequential arm and in 25 (11%) in the alternating arm.Larynx preservation, progression-free interval, and overall survival were similar in both arms, as were acute and late toxic effects.

Project description:BackgroundDe-escalating anthracycline is gaining popularity for breast cancer patients. We aim to evaluate the non-inferiority of an anthracycline-free or short-term regimen to the standard anthracycline-based regimen for operable patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer.MethodsIt is a prospective, open-label, phase 3, randomized non-inferiority trial from June 1, 2010 to June 1, 2017. Follow-up had been kept until July 2019. This trial was conducted at Fudan University Shanghai Cancer Center. Patients with pT1-3N+ or pT2-3N0 but high-risk (grade II/III, lymphovascular invasion, ≤35 years of age or hormone-receptor negative) HER2-negative operable breast cancer were eligible and stratified by age, pathological tumour stage, pathological node status and hormone-receptor status. Patients were randomized to 6 cycles of docetaxel and cyclophosphamide (TC, n = 524), 3 cycles of cyclophosphamide/epirubicin/fluorouracil followed by 3 cycles of docetaxel (CEF-T, n = 523) or epirubicin and cyclophosphamide for 4 cycles followed by paclitaxel for 12 weeks (EC-P, n = 524) as the intention-to-treat population. Of these patients, 94% completed allocated therapy. Difference in disease-free survival (DFS) compared to EC-P. The prespecified non-inferiority margin was 4.5%, corresponding to the hazard ratio (HR) of 1.44 (one-sided α = 0.05), with an assumed 5-year DFS of 89% for EC-P.FindingsIncluded in the intention-to-treat population were 1571 patients (median [IQR] age, 50 [45-57] years; 92% estrogen receptor [ER]-positive; 59% pN+). Through a median follow-up of 5.5 years, HR for TC versus EC-P was 1.05 (5-year DFS: 85.0% vs. 85.9%; 90% confidence interval [CI]: 0.79-1.39, non-inferior P = 0.048) and for CEF-T versus EC-P, 0.99 (5-year DFS: 85.1% vs. 85.9%; 90% CI: 0.75-1.30, non-inferior P = 0.045). Grade 3 or 4 adverse events for TC included rash (3.9%) and peripheral neuropathy (2.8%) and for CEF-T and EC-P diarrhea and nausea/vomiting were predominant. Results of per-protocol analyses were similar.InterpretationBoth TC and CEF-T are non-inferior adjuvant regimen to EC-P mainly in patients with ER+HER2- breast cancer. TC is a safe regimen that avoids anthracycline-related side effects.FundingThis work was supported by grants from the National Natural Science Foundation of China (Grants 81672600, 81722032, 82072916, and 91959207), the 2018 Shanghai Youth Excellent Academic Leader, the Fudan ZHUOSHI Project, the Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals (grant SHDC12010116), the Cooperation Project of Conquering Major Diseases in the Shanghai Municipality Health System (grant 2013ZYJB0302), the Innovation Team of the Ministry of Education (grant IRT1223), and the Shanghai Key Laboratory of Breast Cancer (grant 12DZ2260100) and the National Cancer Institute (grant P30 CA16058).