Elsevier

The Lancet Oncology

Volume 11, Issue 1, January 2010, Pages 21-28
The Lancet Oncology

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Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival

https://doi.org/10.1016/S1470-2045(09)70311-0Get rights and content

Summary

Background

Previous results from our phase 3 randomised trial showed that adding cetuximab to primary radiotherapy increased overall survival in patients with locoregionally advanced squamous-cell carcinoma of the head and neck (LASCCHN) at 3 years. Here we report the 5-year survival data, and investigate the relation between cetuximab-induced rash and survival.

Methods

Patients with LASCCHN of the oropharynx, hypopharynx, or larynx with measurable disease were randomly allocated in a 1:1 ratio to receive either comprehensive head and neck radiotherapy alone for 6–7 weeks or radiotherapy plus weekly doses of cetuximab: 400 mg/m2 initial dose, followed by seven weekly doses at 250 mg/m2. Randomisation was done with an adaptive minimisation technique to balance assignments across stratification factors of Karnofsky performance score, T stage, N stage, and radiation fractionation. The trial was un-blinded. The primary endpoint was locoregional control, with a secondary endpoint of survival. Following discussions with the US Food and Drug Administration, the dataset was locked, except for queries to the sites about overall survival, before our previous report in 2006, so that an independent review could be done. Analyses were done on an intention-to-treat basis. Following completion of treatment, patients underwent physical examination and radiographic imaging every 4 months for 2 years, and then every 6 months thereafter. The trial is registered at www.ClinicalTrials.gov, number NCT00004227.

Findings

Patients were randomly assigned to receive radiotherapy with (n=211) or without (n=213) cetuximab, and all patients were followed for survival. Updated median overall survival for patients treated with cetuximab and radiotherapy was 49·0 months (95% CI 32·8–69·5) versus 29·3 months (20·6–41·4) in the radiotherapy-alone group (hazard ratio [HR] 0·73, 95% CI 0·56–0·95; p=0·018). 5-year overall survival was 45·6% in the cetuximab-plus-radiotherapy group and 36·4% in the radiotherapy-alone group. Additionally, for the patients treated with cetuximab, overall survival was significantly improved in those who experienced an acneiform rash of at least grade 2 severity compared with patients with no rash or grade 1 rash (HR 0·49, 0·34–0·72; p=0·002).

Interpretation

For patients with LASCCHN, cetuximab plus radiotherapy significantly improves overall survival at 5 years compared with radiotherapy alone, confirming cetuximab plus radiotherapy as an important treatment option in this group of patients. Cetuximab-treated patients with prominent cetuximab-induced rash (grade 2 or above) have better survival than patients with no or grade 1 rash.

Funding

ImClone Systems, Merck KGaA, and Bristol-Myers Squibb.

Introduction

Squamous-cell cancers of the head and neck with advanced primary lesions, with or without regional lymph-node metastases, are challenging to treat effectively while maintaining the function of vital healthy structures. Extensive surgical resection of the primary tumour and regional cervical lymphatics used to be the standard of care in the USA.1, 2 More recently, additional organ-preserving strategies using either radiation alone3, 4 or chemoradiotherapy5 have become a treatment option for these patients, and have been the focus of much investigation.

The systematic clinical investigation of organ-preserving radiotherapy and chemoradiotherapy regimens suggested that these regimens could produce overall survival results as good as surgical resection for patients with locoregionally advanced squamous-cell cancer of the head and neck (LASCCHN),5, 6, 7, 8, 9 thus radiation had become a cornerstone of treatment for patients with LASCCHN by the 1990s.3, 4 The addition of chemotherapy to radiotherapy has also been extensively investigated. A recent meta-analysis of 87 randomised trials that compared locoregional treatment with or without chemotherapy found that the addition of chemotherapy to locoregional treatment was associated with an absolute survival advantage of 4·5% at 5 years.10 However, chemoradiotherapy is associated with increased toxicity compared with radiotherapy alone.8, 9, 10, 11, 12 Adding to the complexity of treatment decisions, altered fractionated radiotherapy has been shown to be associated with a survival advantage compared with once-daily radiotherapy,11 but can be difficult to deliver with chemotherapy.12 Therefore, a judicious approach to the optimal use of altered fractionated radiotherapy with or without chemoradiotherapy is warranted. Mitigating toxicity remains an important goal in developing new treatment approaches for patients with LASCCHN.11, 12

High levels of epidermal growth factor receptor (EGFR) expression, which have been seen in approximately 90% of squamous-cell cancers of the head and neck,13 have been shown to correlate with worse clinical outcome,14 decreased response to radiotherapy, and increased locoregional recurrence following definitive radiotherapy.15 Preclinical studies in human squamous-cell cancer of the head and neck cell lines have shown that the inhibition of EGFR results in radiosensitisation.16, 17, 18 Cetuximab is an IgG1 monoclonal antibody that exclusively targets EGFR with high affinity, and inhibits endogenous ligand binding, thereby blocking receptor dimerisation, tyrosine kinase phosphorylation, and signal transduction.19, 20, 21, 22, 23 Cetuximab has been shown to inhibit growth across various squamous-cell carcinoma cell lines, and exposure to cetuximab before or after radiation increases the radiosensitivity of such cells.13, 17, 18 Furthermore, in-vitro and in-vivo studies have shown that there is synergy between cetuximab and radiotherapy, with the combination resulting in a greater reduction in cellular proliferation than either treatment alone.13, 17, 18

In 1998, based on preclinical and phase 1b and 2a clinical studies, we designed a randomised trial to test the value of adding cetuximab to radiotherapy in the definitive treatment of patients with LASCCHN.13, 16, 17, 18, 24 Recruitment was completed in March, 2002, and, compared with radiotherapy alone, the addition of cetuximab was shown to be associated with a 13% absolute improvement in locoregional control at 3 years (34% vs 47%) and a 10% absolute improvement in survival at 3 years (45% vs 55%).25 The previously published results of all trial endpoints were reported after locking the dataset to further input. After the dataset was locked, a thorough independent review was undertaken. This decision was made based on discussions with the US Food and Drug Administration (FDA). The treating sites were asked to provide only information regarding overall survival following the initiation of the independent review. Here we report an update of survival, and aim to use this updated data for subgroup analyses of patient and tumour characteristics.

Data from several studies across multiple cancers (including recurrent/metastatic squamous-cell cancer of the head and neck, colorectal, non-small cell lung cancer, and pancreatic cancer) suggest a correlation between overall survival and the presence and/or intensity of cetuximab-induced acne-like rash.26, 27, 28, 29 Thus, we also assess the significance of cetuximab-induced rash in the context of these updated survival data.

Section snippets

Patients

As previously described in detail,25 following the approval of the protocol by the institutional review board of each participating institution, patients with stage III or IV non-metastatic, measurable cancers of the oropharynx, hypopharynx, or larynx were randomly assigned to either radiotherapy alone or radiotherapy with cetuximab. Only those patients judged to be medically suitable for definitive radiotherapy, and who had a Karnofsky performance score (KPS) of at least 60 with normal

Results

The trial recruited 424 patients between April, 1999, and March, 2002, at 73 centres in the USA and 14 other countries in Europe, North America, Africa, and Oceania. 213 patients were randomly assigned to radiotherapy alone, and 211 were assigned to receive radiotherapy and cetuximab (figure 1). The treatment groups were well balanced with respect to stratification factors, other potential prognostic factors, and additional therapies such as elective neck dissections and other treatments (table

Discussion

Previously reported results from this trial showed better survival and locoregional disease control associated with cetuximab plus radiotherapy in patients with LASCCHN, relative to radiotherapy alone, and these differences were not associated with reduced quality of life or increased radiation-induced mucositis or dysphagia.25, 34 This updated analysis was done to assess additional 5-year overall survival results. The long-term results corroborate the earlier findings that the addition of

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