Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial

Summary

Background

Concomitant chemoradiotherapy and accelerated radiotherapy independently improve outcomes for patients with locally advanced head and neck squamous-cell carcinoma (HNSCC). We aimed to assess the efficacy and safety of a combination of these approaches.

Methods

In our open-label phase 3 randomised trial, we enrolled patients with locally advanced, stage III and IV (non-metastatic) HNSCC and an Eastern Cooperative Oncology Group performance status of 0–2. We randomly allocated patients centrally with a computer program (with centre, T stage, N stage, and localisation as minimisation factors) in a 1:1:1 ratio to receive conventional chemoradiotherapy (70 Gy in 7 weeks plus three cycles of 4 days' concomitant carboplatin-fluorouracil), accelerated radiotherapy-chemotherapy (70 Gy in 6 weeks plus two cycles of 5 days' concomitant carboplatin-fluorouracil), or very accelerated radiotherapy alone (64·8 Gy [1·8 Gy twice daily] in 3·5 weeks). The primary endpoint, progression-free survival (PFS), was assessed in all enrolled patients. This trial is completed. The trial is registered with ClinicalTrials.gov, number NCT00828386.

Findings

Between Feb 29, 2000, and May 9, 2007, we randomly allocated 279 patients to receive conventional chemoradiotherapy, 280 to accelerated radiotherapy-chemotherapy, and 281 to very accelerated radiotherapy. Median follow-up was 5·2 years (IQR 4·9–6·2); rates of chemotherapy and radiotherapy compliance were good in all groups. Accelerated radiotherapy-chemotherapy offered no PFS benefit compared with conventional chemoradiotherapy (HR 1·02, 95% CI 0·84–1·23; p=0·88) or very accelerated radiotherapy (0·83, 0·69–1·01; p=0·060); conventional chemoradiotherapy improved PFS compared with very accelerated radiotherapy (0·82, 0·67–0·99; p=0·041). 3-year PFS was 37·6% (95% CI 32·1–43·4) after conventional chemoradiotherapy, 34·1% (28·7–39·8) after accelerated radiotherapy-chemotherapy, and 32·2% (27·0–37·9) after very accelerated radiotherapy. More patients in the very accelerated radiotherapy group had RTOG grade 3–4 acute mucosal toxicity (226 [84%] of 268 patients) compared with accelerated radiotherapy-chemotherapy (205 [76%] of 271 patients) or conventional chemoradiotherapy (180 [69%] of 262; p=0·0001). 158 (60%) of 265 patients in the conventional chemoradiotherapy group, 176 (64%) of 276 patients in the accelerated radiotherapy-chemotherapy group, and 190 (70%) of 272 patients in the very accelerated radiotherapy group were intubated with feeding tubes during treatment (p=0·045).

Interpretation

Chemotherapy has a substantial treatment effect given concomitantly with radiotherapy and acceleration of radiotherapy cannot compensate for the absence of chemotherapy. We noted the most favourable outcomes for conventional chemoradiotherapy, suggesting that acceleration of radiotherapy is probably not beneficial in concomitant chemoradiotherapy schedules.

Funding

French Ministry of Health.

Introduction

Chemotherapy has been used widely in locally advanced head and neck squamous-cell carcinoma (HNSCC) as induction treatment,1, 2, 3, 4, 5, 6 concomitantly with radiotherapy,1, 2, 7, 8, 9, 10, 11, 12, 13, 14 or as adjuvant treatment after radiotherapy or surgery.1, 2, 15 The updated meta-analysis of chemotherapy in head and neck cancer (MACH-NC)1, 2 used individual patient data from 93 randomised trials (level 1A evidence) and showed that concomitant chemoradiotherapy is the standard of care in locally advanced HNSCC. By 5 years, addition of concomitant chemotherapy to radiotherapy was associated with an increase in survival of 6·5%, a 12–13% improvement in locoregional control, and about a 3% decrease in distant metastases relative to radiotherapy alone.² However, the addition of concomitant chemotherapy was also associated with a substantial increase in acute and late toxic effects,¹² emphasising the need to improve these therapeutic combinations.

Previously, we showed that a regimen of fluorouracil plus carboplatin combined concomitantly with conventional radiotherapy was better than conventional radiotherapy alone, although the addition of this chemotherapy increased rates of acute and late side-effects significantly.10, 12 However, this increase in toxicity was regarded as acceptable because of the magnitude of benefit noted for locoregional control (25% at 3 years) and overall survival (8% at 5 years). The benefit associated with this carboplatin-fluorouracil regimen was much the same as was that noted for concomitant cisplatin alone in the recent update of the MACH-NC meta-analysis.² We used this regimen as the first reference group in our present study.

Non-conventional fractionated radiotherapy for locally advanced HNSCC is an attractive possible treatment, either through use of hyperfractionated radiotherapy16, 17, 18, 19 or accelerated radiotherapy.19, 20, 21 The aim of such modified fractionated radiotherapies is to increase the dose intensity of treatment, either by increasing the total dose (hyperfractionation) or by reduction of the overall treatment time (acceleration). In most cases, a benefit in tumour control probability has been reported by comparison with conventional radiotherapy, and the MARCH meta-analysis¹⁹ (which was based on the collection of updated individual patient data from 15 randomised trials) concluded a small but significant improvement in local control and overall survival after altered fractionated radiotherapy. In this context, we previously showed that a very accelerated regimen was substantially better than was conventional radiotherapy alone in terms of locoregional control (gain of 24% at 3 years), although rates of the acute mucosal toxicity were greatly increased (but late side-effects of radiation were not).²⁰ We used this regimen as a second reference group in our present study.

On the basis of the MARCH¹⁹ and MACH-NC² meta-analyses and the previous experience of the Groupe d'Oncologie Radiothérapie Tête et Cou (GORTEC),10, 12, 20 we aimed to assess the value of combining accelerated radiotherapy with concomitant chemotherapy in patients with locally advanced HNSCC. Our accelerated radiotherapy-chemotherapy groups combined two notable advances in oncology: concomitant chemotherapy and accelerated radiotherapy, which have both been shown to improve the probability of tumour control outcome independently. Before the start of this trial, there were no data for this type of comparison and our hypothesis was that the increase in the dose intensity attributable to the combination of accelerated radiotherapy-chemotherapy would lead to an improvement in progression-free survival (PFS) and disease control, as compared with either very accelerated radiotherapy alone or compared with conventional concomitant chemoradiotherapy.