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Cetuximab and Radiotherapy in Laryngeal Preservation for Cancers of the Larynx and Hypopharynx: A Secondary Analysis of a Randomized Clinical Trial.

ABSTRACT: IMPORTANCE:The 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. OBJECTIVE:To 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 PARTICIPANTS:Patients 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 MEASURES:Laryngeal preservation and laryngectomy-free survival. RESULTS:Of 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 RELEVANCE:The 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 REGISTRATION:clinicaltrials.gov Identifier: NCT00004227.

SUBMITTER: Bonner J

PROVIDER: S-EPMC5025385 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Cetuximab and Radiotherapy in Laryngeal Preservation for Cancers of the Larynx and Hypopharynx: A Secondary Analysis of a Randomized Clinical Trial.

Bonner James J Giralt Jordi J Harari Paul P Spencer Sharon S Schulten Jeltje J Hossain Anwar A Chang Shao-Chun SC Chin Steve S Baselga José J

JAMA otolaryngology-- head & neck surgery 20160901 9

<h4>Importance</h4>The 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.<h4>Objective</h4>To assess the rates of laryngeal preservation and laryngectomy-free survival in patients receiving cetuximab and radiotherapy (CRT) and patients receiving radiotherapy alone.<h4>Design, setting, and participa ...[more]

PMID: 27389475

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Project description:BackgroundBoth 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.MethodsPatients 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.ResultsThe 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.ConclusionsLarynx preservation, progression-free interval, and overall survival were similar in both arms, as were acute and late toxic effects.

Project description:BackgroundFew reports from China provide confirmed evidence of the effectiveness of the larynx preservation strategy compared with surgery on the treatment of laryngeal and hypopharyngeal cancers. This study assessed the clinical outcomes of patients with locally advanced laryngeal and hypopharyngeal cancers treated with larynx preservation and determined the optimal larynx preservation procedure.MethodsData of 1,494 patients treated with total laryngectomy or larynx preservation between 2006 and 2014 were retrieved from the database of Sun-Yat Sen University Cancer Center in Guangzhou, China, and 366 eligible patients were selected for final analysis. The clinical outcomes of 228 patients received total laryngectomy and 138 patients received larynx preservation treatments, which comprises induction followed by radiotherapy and concurrent radio-chemotherapy, were compared.ResultsThere was no statistical difference in the 3-, 5-, and 10-year PFS and OS in patients received larynx preservation compared with patients treated with laryngectomy. With respect to T stage, a better overall OS in T2-stage disease (P = 0.036) but poorer PFS (P = 0.005) in T3-stage disease was observed in the larynx preservation group compared with the surgery group in Univariate analysis. T3-stage disease had poorer PFS in multivariable analysis (P = 0.022). With larynx preservation intent, induction chemotherapy followed by radiotherapy showed no advantage in the control of disease progression and survival compared with concurrent chemoradiotherapy. The patient subpopulations who received efficacy assessment after induction chemotherapy exhibited significantly longer PFS and OS compared with those without efficacy assessment.ConclusionsThis is the largest sample size study on larynx preservation treatment for laryngeal and hypopharyngeal cancers in China. Our results indicated that larynx preservation treatments did not jeopardize the survival of patients with advanced resectable laryngeal or hypopharyngeal cancers. Efficacy assessment should be emphasized in induction chemotherapy.

Project description:For long, the treatment of locoregionally advanced laryngeal and hypopharyngeal squamous cell cancers (SCC) consisted of either total laryngectomy (TL) or definitive radiotherapy (RT). The development of induction cisplatin plus 5-fluorouracil (PF) and the correlation between chemosensitivity and radiosensitivity in previously untreated patients opened a new era of treatment aiming at laryngeal preservation (LP). The fundamental concept was to employ induction PF in order to select patients for subsequent treatment with either TL or RT according to tumor response to PF. The first two trials (VALGSG for laryngeal SCC and EORTC 24891 for hypopharyngeal SCC) concluded that such an approach could preserve nearly 60% of larynx without deleterious impact on survival. The EORTC 24954 trial compared 4 cycles of induction PF followed by RT in good responders vs. alternating PF-RT in laryngeal and hypopharyngeal SCC. There was no significant difference in 5-year overall survival with a functional larynx between the two arms (31 vs. 35%). The GORTEC 2000-01 trial compared induction PF to induction PF plus docetaxel (TPF) both followed by RT in good responders in larynx and hypopharynx SCC. The 5-year LP was significantly higher in the TPF arm (60 vs. 39%) but without a difference in survival. The RTOG 91-11 trial compared induction PF followed by RT in good responders vs. concurrent chemoradiotherapy (chemo-RT) vs. RT alone in laryngeal SCC. There was no significant difference in 5-year laryngectomy-free survival between the patients treated with induction chemotherapy (44%) vs. those treated with chemo-RT (47%), both being superior to RT alone (34%). At 5 years, LP was superior with chemo-RT: 84 vs. 71% with induction PF. Two phase II trials explored the role of cetuximab (E) in LP in laryngeal and hypopharyngeal SCC. The TREMPLIN trial compared RT+E or chemo-RT (RT + P) after TPF. The DeLOS-II trial compared TPE followed by RT+E vs. TP followed by RT. However, these trials failed to indicate an advantage for the incorporation of E in the treatment paradigm. To date, two approaches for LP have been validated: induction TPF followed by RT for laryngeal and hypopharyngeal SCC and concurrent chemo-RT for laryngeal SCC. An ongoing trial (SALTORL) is comparing these two approaches, induction TPF and chemo-RT, in laryngeal/ hypopharyngeal SCC.

Project description:AimTo compare the efficacy of two altered fractionation radiotherapy treatment protocols (hyperfractionation and accelerated fractionation with concomitant boost) with conventional fractionation in improvement of locoregional disease control and survival of patients with squamous cell carcinoma of the larynx, oropharynx, or hypopharynx.MethodsFrom March 1999 to December 2000, 51 patients with previously untreated squamous cell carcinoma of the larynx, oropharynx or hypopharynx underwent conventionally fractionated radiotherapy and received 66-70 Gy in 6(1/2)-7 weeks (2 Gy per fraction a day, 5 fractions a week). From January 2001 to June 2004, 101 patients with the same diagnoses underwent either hyperfractionated radiotherapy, with 74.4-79.2 Gy delivered in 6.2-7 weeks (1.2 Gy per fraction twice a day), or accelerated fractionation with concomitant boost, which delivered 68.7-72 Gy in 6 weeks (1.8 Gy per fraction a day and 1.5 Gy per fraction a day to a boost filed as a second daily treatment for the last 11-12 treatment days). Locoregional relapse and overall survival were recorded.ResultsComplete response to treatment was obtained in 31 of 51 patients treated with conventional fractionation, 33 of 50 patients treated with hyperfractionation, and 36 of 51 patients treated with accelerated fractionation. No significant differences were observed among the patients treated with conventional, hyperfractionated, or accelerated radiotherapy modalities either in locoregional control rate (41% vs 35% vs 49%, respectively; P=0.690) or overall survival rate (50% vs 40% vs 51%, respectively; P=0.760). The grade of acute reactions of the larynx significantly differed among the treatment groups (Fisher exact test; P=0.039). The difference in the grade of acute side effects in the skin among the treatment groups was of borderline significance (chi2(2) test; P=0.054). There was also a borderline difference among the groups in the grade of late side effects in the mucous membrane (chi2(2) test; P=0.055).ConclusionAltered fractionation regimens were not more efficacious than conventional fractionation in the treatment of previously untreated head and neck carcinoma.Clinical trial registrationClinicalTrials.gov Identifier: NCT00291434.

Project description:BackgroundThe menopause transition is marked by hormonal shifts leading to body composition changes, such as fat mass gain and lean mass loss. Weight-bearing and resistance exercise can help maintain lean mass during the menopause transition; however, uptake is low. Pre-clinical research points to bisphosphonates as also being effective in preventing loss of lean mass. Thus, we sought to investigate whether bisphosphonate therapy can mitigate loss of lean mass and outperform weight-bearing exercise in the years immediately following menopause.MethodsData come from the Heartland Osteoporosis Prevention Study (NCT02186600), where osteopenic, postmenopausal women were randomized to bisphosphonate (n=91), weight-bearing/resistance exercise (n=92), or control (n=93) conditions over a one-year period. Dual energy X-ray absorptiometry (DXA)-derived body composition measures (including total lean mass, total fat mass, lean mass index, and lean mass-to-fat mass ratio) were ascertained at baseline, six, and 12-months. Adherence to risedronate and weight-bearing exercise was defined as the percentage of dosages taken and exercise sessions attended. Intent-to-treat analysis using linear modeling was used to generate treatment effects on body composition. Secondary analysis utilized per-protocol analysis and included adjustment for weight change.Results276 women (age: 54.5 years; 83.3% Caucasian; BMI: 25.7 kg/m2) were included in the analyses. 12-month adherence to the risedronate and exercise interventions was 89% and 64%, respectively. Group-by-time interactions were observed for lean mass, revealing exercise (0.43±1.49kg) and risedronate groups (0.31±1.68 kg) gained significantly more lean mass than control (-0.15±1.27 kg) over 12-months. However, after controlling for weight change in secondary analysis, the difference in lean mass change between control and risedronate became non-significant (p=0.059).ConclusionsResults suggest both 12 months of oral risedronate and 12 months of weight-bearing exercise may diminish lean mass loss experienced during the menopause transition as compared to control. The lean mass sparing effect for risedronate may be driven by overall weight change.

Dataset Information

Cetuximab and Radiotherapy in Laryngeal Preservation for Cancers of the Larynx and Hypopharynx: A Secondary Analysis of a Randomized Clinical Trial.

Publications

Cetuximab and Radiotherapy in Laryngeal Preservation for Cancers of the Larynx and Hypopharynx: A Secondary Analysis of a Randomized Clinical Trial.

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