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Phase 3 randomized trial on larynx preservation comparing sequential vs alternating chemotherapy and radiotherapy.

ABSTRACT: 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.

SUBMITTER: Lefebvre JL

PROVIDER: S-EPMC2724854 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Phase 3 randomized trial on larynx preservation comparing sequential vs alternating chemotherapy and radiotherapy.

Lefebvre J L JL Rolland F F Tesselaar M M Bardet E E Leemans C R CR Geoffrois L L Hupperets P P Barzan L L de Raucourt D D Chevalier D D Licitra L L Lunghi F F Stupp R R Lacombe D D Bogaerts J J Horiot J C JC Bernier J J Vermorken J B JB

Journal of the National Cancer Institute 20090127 3

<h4>Background</h4>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.<h4>Methods</h4>Patients with resectable advanced squamous cell carcinoma of the larynx (tumor stage T3-T4) or hypopharynx (T2-T4), with r ...[more]

PMID: 19176454

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Project description:BackgroundThe 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.MethodsWomen 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.ResultsFrom 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).ConclusionsNo 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.

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:ImportanceThe appropriate use of surgery or radiotherapy-based approaches for organ preservation has been the subject of much debate. Unfortunately, there has been a lack of improvement in overall survival for patients with laryngeal carcinoma in the last 30 years.ObjectiveTo assess the rates of laryngeal preservation and laryngectomy-free survival in patients receiving cetuximab and radiotherapy (CRT) and patients receiving radiotherapy alone.Design, setting, and participantsPatients were enrolled in a multicenter, open-label, stratified, randomized, phase 3 study from April 1, 1999, through March 31, 2002, from 73 centers in the United States and 14 other countries. A secondary subgroup analysis of patients with hypopharyngeal and laryngeal carcinoma was undertaken. Rates of laryngeal preservation and laryngectomy-free survival were estimated by the Kaplan-Meier method. The hazard ratios (HRs) were calculated using a Cox proportional hazards regression model. Quality of life was evaluated using the European Organization for Research and Treatment of Cancer core questionnaire and head and neck module.Main outcomes and measuresLaryngeal preservation and laryngectomy-free survival.ResultsOf the 424 patients included in the trial, 168 treated patients with cancer of the larynx or hypopharynx were included in this analysis (90 in the CRT group and 78 in the radiotherapy alone group). The median (range) age of the patients was 59 (40-80) years in the CRT group and 61 (35-81) years in the radiotherapy alone group. In the CRT group, 72 patients (80.0%) were male and 18 (20.0%) were female. In the radiotherapy alone group, 62 (79.5%) were male and 16 (20.5%) were female. The rates of laryngeal preservation at 2 years were 87.9% for CRT vs 85.7% for radiotherapy alone, with an HR of 0.57 (95% CI, 0.23-1.42; P = .22). Similarly, the HR for laryngectomy-free survival comparing CRT vs radiotherapy alone was 0.78 (95% CI, 0.54-1.11; P = .17). This study was not powered to assess organ preservation. Median overall survival was 27 (95% CI, 20-45) vs 21 (95% CI, 17-35) months for the CRT and radiotherapy alone groups, respectively, with an HR of 0.87 (95% CI, 0.60-1.27). No differences between treatments were reported regarding overall quality of life, need for a feeding tube, or speech.Conclusions and relevanceThe results of a possible cetuximab-related laryngeal preservation benefit for patients with hypopharyngeal or laryngeal cancer are intriguing; these results need to be interpreted in the context of a retrospective subset analysis with limited sample size.Trial registrationclinicaltrials.gov Identifier: NCT00004227.

Project description:ImportanceThe role of locoregional radiotherapy in patients with de novo metastatic nasopharyngeal carcinoma (mNPC) is unclear.ObjectiveTo investigate the efficacy and safety of locoregional radiotherapy in de novo mNPC.Design, setting, and participantsPatients with biopsy-proven mNPC, who demonstrated complete or partial response (RECIST v1.1) following 3 cycles of cisplatin and fluorouracil chemotherapy, were enrolled. Eligible patients were randomly assigned (1:1) to receive either chemotherapy plus radiotherapy or chemotherapy alone. Overall, 126 of 173 patients screened were eligible to the study, and randomized to chemotherapy plus radiotherapy (n = 63) or chemotherapy alone (n = 63). Median (IQR) follow-up duration was 26.7 (17.2-33.5) months.InterventionsThe chemotherapy regimens were fluorouracil continuous intravenous infusion at 5 g/m2 over 120 hours and 100 mg/m2 intravenous cisplatin on day 1, administered every 3 weeks for 6 cycles. Patients assigned to the chemotherapy plus radiotherapy group received intensity-modulated radiotherapy (IMRT) after chemotherapy.Main outcomes and measuresThe primary end point of the study was overall survival (OS). The secondary end point was progression-free survival (PFS) and safety.ResultsOverall, 126 patients were enrolled (105 men [83.3%] and 21 women [16.7%]; median [IQR] age, 46 [39-52] years). The 24-month OS was 76.4% (95% CI, 64.4%-88.4%) in the chemotherapy plus radiotherapy group, compared with 54.5% (95% CI, 41.0%-68.0%) in the chemotherapy-alone group. The study met its primary end point of improved OS (stratified hazard ratio [HR], 0.42; 95% CI, 0.23-0.77; P = .004) in favor of chemotherapy plus radiotherapy. Progression-free survival was also improved in the chemotherapy plus radiotherapy group compared with the chemotherapy-alone group (stratified HR, 0.36; 95% CI, 0.23-0.57). No significant differences in acute hematological or gastrointestinal toxic effects were observed between the treatment arms. The frequency of acute grade 3 or higher dermatitis, mucositis, and xerostomia was 8.1%, 33.9%, and 6.5%, respectively, in the chemotherapy plus radiotherapy group. The frequency of late severe grade 3 or higher hearing loss and trismus was 5.2% and 3.4%, respectively, in the chemotherapy plus radiotherapy group.Conclusions and relevanceIn this randomized clinical trial, radiotherapy added to chemotherapy significantly improved OS in chemotherapy-sensitive patients with mNPC.Trial registrationClinicalTrials.gov Identifier: NCT02111460.

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Phase 3 randomized trial on larynx preservation comparing sequential vs alternating chemotherapy and radiotherapy.

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Phase 3 randomized trial on larynx preservation comparing sequential vs alternating chemotherapy and radiotherapy.

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