Meta-Analysis of Radiotherapy in Carcinomas of Head and neck (MARCH) Collaborative Group. Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis

ArticleinThe Lancet 368(9538):843-54 · September 2006with62 Reads
Impact Factor: 45.22 · DOI: 10.1016/S0140-6736(06)69121-6 · Source: PubMed

Several trials have studied the role of unconventional fractionated radiotherapy in head and neck squamous cell carcinoma, but the effect of such treatment on survival is not clear. The aim of this meta-analysis was to assess whether this type of radiotherapy could improve survival. Randomised trials comparing conventional radiotherapy with hyperfractionated or accelerated radiotherapy, or both, in patients with non-metastatic HNSCC were identified and updated individual patient data were obtained. Overall survival was the main endpoint. Trials were grouped in three pre-specified categories: hyperfractionated, accelerated, and accelerated with total dose reduction. 15 trials with 6515 patients were included. The median follow-up was 6 years. Tumours sites were mostly oropharynx and larynx; 5221 (74%) patients had stage III-IV disease (International Union Against Cancer, 1987). There was a significant survival benefit with altered fractionated radiotherapy, corresponding to an absolute benefit of 3.4% at 5 years (hazard ratio 0.92, 95% CI 0.86-0.97; p=0.003). The benefit was significantly higher with hyperfractionated radiotherapy (8% at 5 years) than with accelerated radiotherapy (2% with accelerated fractionation without total dose reduction and 1.7% with total dose reduction at 5 years, p=0.02). There was a benefit on locoregional control in favour of altered fractionation versus conventional radiotherapy (6.4% at 5 years; p<0.0001), which was particularly efficient in reducing local failure, whereas the benefit on nodal control was less pronounced. The benefit was significantly higher in the youngest patients (hazard ratio 0.78 [0.65-0.94] for under 50 year olds, 0.95 [0.83-1.09] for 51-60 year olds, 0.92 [0.81-1.06] for 61-70 year olds, and 1.08 [0.89-1.30] for over 70 year olds; test for trends p=0.007). Altered fractionated radiotherapy improves survival in patients with head and neck squamous cell carcinoma. Comparison of the different types of altered radiotherapy suggests that hyperfractionation has the greatest benefit.

    • "In parallel with the rise in life expectancy, the number of elderly patients with head and neck squamous cell carcinomas [HNSCCs] is increasing, especially in women [2,3]. Overall survival [OS] in patients with HNSCCs has been estimated at about 50% after 5 years, with large variations across tumour sites456. Two studies suggest lower 5-year OS rates in patients aged 75 or over than in younger patients [7,8]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Survival is poorer in elderly patients with head and neck squamous cell carcinomas [HNSCCs] than in younger patients. Possible explanations include a contribution of co-morbidities to mortality, frequent refusal of standard therapy, and the use of suboptimal treatments due to concern about toxicities. The Comprehensive Geriatric Assessment [CGA] is a multidimensional assessment of general health that can help to customise treatment and follow-up plans. The CGA has been proven effective in several health settings but has not been evaluated in randomised studies of patients with cancer. Our aim here was to assess the impact of the CGA on overall survival, function, and nutritional status of elderly patients with HNSCC. Methods/design: EGeSOR is an open-label, multicentre, randomised, controlled, parallel-group trial in patients aged 70 years or older and receiving standard care for HNSCC. The intervention includes four components: the CGA conducted by a geriatrician before cancer treatment, participation of the same geriatrician in cancer treatment selection, a standardised geriatric therapeutic intervention designed by the same geriatrician; and geriatric follow-up for 24 months. The primary endpoint, assessed after 6 months, is a composite criterion including death, functional impairment [Activities of Daily Living score decrease ≥ 2], and weight loss ≥ 10%. Secondary endpoints include progression-free survival, unscheduled admissions, quality of life, treatment toxicities, costs, and completion of the planned cancer treatment. A centralised online system is used to perform 1:1 randomisation with a minimisation algorithm for centre, age, T and N stages, and tumour site [oral, oropharyngeal, hypopharyngeal, or laryngeal]. The estimated sample size is 704 patients, who are being recruited by 14 centres in 9 French cities. Discussion: EGeSOR is the first randomised trial of the CGA in elderly cancer patients. We expect the CGA to have direct clinical benefits on the management of elderly patients with HNSCC. If this expectation is fulfilled, the trial may lead to modifications of the management model for elderly patients with cancer. Trial registration: Trial registration: NCT02025062.
    Full-text · Article · Jun 2014 · BMC Cancer
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    • "The most common ones in the statistical literature are the log-rank test for the cause-specific hazard [1,13] and nonparametric and semiparametric tests for the cumulative incidence function (CIF) [14,15]. However, Peto and the Early Breast Cancer Trialists’ Collaborative Group proposed the log-rank subtraction method in the context of oncology [16-19], which is quite popular in the clinical literature and especially in meta-analyses: see for instance references [20-24]. This test imputes deaths to the cancer whenever the cause is unknown or when they occur after a recurrence, whatever the recorded cause. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Chemotherapy is expected to reduce cancer deaths (CD), while possibly being harmful in terms of non-cancer deaths (NCD) because of toxicity. Peto’s log-rank test is popular in the medical literature, but its operating characteristics are barely known. We compared this test to the most common ones in the statistical literature: the cause-specific hazard test and Gray’s test on the hazard of the subdistribution. We investigated for the first time the impact of reclassifications of causes of death (CoD) after recurrences, and of misclassification of CoD. Methods We present a simulation study in which we varied the censoring rate and the correlation between CD and NCD times, we generated recurrence times to study the role of the reclassification of CoD, and we added 20% misclassified CoD. We considered four scenarios for the treatment effect: none; none for CD and negative for NCD; positive for CD and none for NCD; positive for CD and negative for NCD. We applied the three tests to a randomized clinical trial evaluating adjuvant chemotherapy in 1,867 patients with non-small-cell lung cancer. Results Most often the three tests well preserved their nominal size, Gray’s test did not when the treatment had an effect on the competing CoD. With a high rate of misclassified CoD, Gray’s and the cause-specific tests lost much of their power, whereas the Peto’s test had the highest power. The cause-specific test had inflated size for NCD when the treatment was beneficial for CD with many misclassified CoD, but had the highest power for NCD when the treatment had no effect on CD, and had similar power to Peto’s test for CD when the treatment had no effect on NCD. Gray’s test performed best when the effect on the two CoD was opposite. The higher the censoring, the lower the rejection probabilities of all the tests and the smaller their differences. Conclusions In this first head-to-head comparison of the three tests, the cause-specific test often proved to be the most reliable. Comparing results with and without misclassification of the CoD, Peto’s test was the least influenced by the presence of such misclassification.
    Full-text · Article · May 2014 · BMC Medical Research Methodology
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    • "The same results were reported in EORTC 22791 (hyperfractionation improved 5-year actuarial LRC compared with conventional RT, 59 % vs. 40 % respectively, P=0.02, with a trend toward improved survival) and in the DAHANCA 6 and 7 studies (improved 5-year LRC, and disease-specific survival , but no significant effect on overall survival) [7, 8]. A meta-analysis of randomized trials by Bourhis et al. concluded that survival was improved by using altered fractionation schedules compared with conventional RT, and hyperfractionation provided the most significant benefit [6]. Recently, image-guided intensity-modulated radiation therapy (IG-IMRT), an advanced mode of high-precision RT, was introduced for the treatment of LA-HNC to improve the therapeutic index. "
    [Show abstract] [Hide abstract] ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cause of cancer death worldwide. Its treatment is complex and evolving. In general, early-stage disease may be managed with single-modality treatment while an advanced stage (about 60% of clinical presentation) needs a multidisciplinary approach. In this setting concurrent chemoradiation has been associated with improvement in locoregional control and organ preservation, but at the cost of significant acute and chronic toxicity. Molecular target therapies specially directed to epidermal growth factor receptor (EGFR) might improve the outcomes and reduce toxicities. In recurrent-metastatic (R/M) HNSCC, cetuximab, a monoclonal antibody against EGFR, plus platinum-based chemotherapy (CT) allow an overall survival (OS) of about 10 months. However, the prognosis for R/M-HNSCC remains dismal and additional efforts are needed. At the 2013 American Society of Clinical Oncology (ASCO) Meeting, data on induction CT, anti-EGFR inhibitors, innovative molecular targets and predictor factors were reported. Further results on target therapies were presented at the European Cancer Congress (ECC) 2013, where a large study also showed that hyperfractionated radiotherapy (RT) improve OS rates compared with standard RT. The aim of this review is to discuss current standards and emerging therapies by considering recent new updates. © 2014 S. Karger AG, Basel.
    Full-text · Article · May 2014 · Oncology
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