Hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy for patients with locally advanced recurrent nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial

Summary

Background

Reirradiation in standard fractionation for locally advanced recurrent nasopharyngeal carcinoma after a previous course of high-dose radiotherapy is often associated with substantial late toxicity, negating its overall benefit. We therefore aimed to investigate the efficacy and safety of hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy.

Methods

This multicentre, randomised, open-label, phase 3 trial was done in three centres in Guangzhou, China. Eligible patients were aged 18–65 years with histopathologically confirmed undifferentiated or differentiated, non-keratinising, advanced locally recurrent nasopharyngeal carcinoma. Participants were randomly assigned (1:1) to either receive hyperfractionation (65 Gy in 54 fractions, given twice daily with an interfractional time interval of at least 6 h) or standard fractionation (60 Gy in 27 fractions, given once a day). Intensity-modulated radiotherapy was used in both groups. A computer program generated the assignment sequence and randomisation was stratified by treatment centre, recurrent tumour stage (T2–T3 vs T4), and recurrent nodal stage (N0 vs N1–N2), determined at the time of randomisation. The two primary endpoints were the incidence of severe late complications defined as the incidence of grade 3 or worse late radiation-induced complications occurring 3 months after the completion of radiotherapy until the latest follow-up in the safety population, and overall survival defined as the time interval from randomisation to death due to any cause in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02456506.

Findings

Between July 10, 2015, and Dec 23, 2019, 178 patients were screened for eligibility, 144 of whom were enrolled and randomly assigned to hyperfractionation or standard fractionation (n=72 in each group). 35 (24%) participants were women and 109 (76%) were men. After a median follow-up of 45·0 months (IQR 37·3–53·3), there was a significantly lower incidence of grade 3 or worse late radiation-induced toxicity in the hyperfractionation group (23 [34%] of 68 patients) versus the standard fractionation group (39 [57%] of 68 patients; between-group difference –23% [95% CI –39 to –7]; p=0·023). Patients in the hyperfractionation group had better 3-year overall survival than those in the standard fractionation group (74·6% [95% CI 64·4 to 84·8] vs 55·0% [43·4 to 66·6]; hazard ratio for death 0·54 [95% CI 0·33 to 0·88]; p=0·014). There were fewer grade 5 late complications in the hyperfractionation group (five [7%] nasal haemorrhage) than in the standard fractionation group (16 [24%], including two [3%] nasopharyngeal necrosis, 11 [16%] nasal haemorrhage, and three [4%] temporal lobe necrosis).

Interpretation

Hyperfractionated intensity-modulated radiotherapy could significantly decrease the rate of severe late complications and improve overall survival among patients with locally advanced recurrent nasopharyngeal carcinoma. Our findings suggest that hyperfractionated intensity-modulated radiotherapy could be used as the standard of care for these patients.

Funding

Key-Area Research and Development of Guangdong Province, the National Natural Science Foundation of China, the Special Support Program for High-level Talents in Sun Yat-sen University Cancer Center, the Guangzhou Science and Technology Plan Project, and the National Ten Thousand Talents Program Science and Technology Innovation Leading Talents, Sun Yat-Sen University Clinical Research 5010 Program.

Introduction

Southeast Asia has the highest prevalence of nasopharyngeal carcinoma worldwide, with age-standardised rates ranging from 22·2 to 27·2 per 100 000 among men and 9·8 to 11·3 per 100 000 among women.¹ The incidence of local recurrence after previous radical radiotherapy in patients with endemic nasopharyngeal carcinoma ranges from 10% to 20%.2, 3, 4 Previous studies have shown that in patients with resectable tumours, endoscopic surgery was associated with better survival outcomes compared with reirradiation, and endoscopic surgery has become the standard of care.5, 6 However, reirradiation is the only possible salvage option with a curative intent in patients with unresectable, locally advanced lesions.⁷ Previous studies recommended a dose of at least 60 Gy (in equivalent dose at 2 Gy fractions [EQD2]) for gross tumour volume as the optimal dose for the second course of radiotherapy in an attempt to balance tumour control and risk of complications.8, 9, 10, 11 Unfortunately, the rate of severe, late radiation-induced toxicity remained unacceptably high, with studies reporting up to 59·0–73·7% toxicity rate using standard fractionation in intensity-modulated radiotherapy of around 60 Gy.5, 12, 13 Late complications can prove lethal in approximately 31·3–40·0% of patients, substantially reducing overall survival.12, 14 Therefore, there is an unmet need to explore safer means of radiotherapy delivery that can reduce radiation-induced toxicity and improve the survival benefit without compromising the total radiation dose.

Research in context

Evidence before this study

We identified relevant studies through searches of PubMed and the WHO International Clinical Trial Registry Platform for open or closed trials from database inception to Dec 31, 2022. Search terms were “nasopharyngeal carcinoma or cancer or neoplasm”, “head and neck cancer”, “recurrence or relapse”, and “radiotherapy or reirradiation”, “hyperfractionation”, “intensity-modulated radiation therapy”, and “standard fractionation”, with no language restrictions. We found no randomised controlled trials offering a head-to-head comparison of hyperfractionation versus standard fractionation in intensity-modulated radiotherapy for patients with locally advanced recurrent nasopharyngeal carcinoma. Several retrospective studies showed that hyperfractionation was equivalent in tumour control compared with standard fractionation while causing less treatment-related toxicity. There were few prospective randomised trials of reirradiation in patients with head and neck cancer.

Added value of this study

To our knowledge, this is the first randomised phase 3 clinical trial to evaluate the safety and efficacy of a hyperfractionated schedule compared with a standard fractionated schedule in patients with locally advanced recurrent nasopharyngeal carcinoma. By keeping the same tumouricidal radiation dose to the gross tumour volume, we show that hyperfractionated intensity-modulated radiotherapy could significantly reduce the incidence of late radiation-induced toxicities, which ultimately translates into overall survival benefits compared with standard fractionated intensity-modulated radiotherapy. This study also provides a reference for the reirradiation schedule in other recurrent tumours such as recurrent head and neck cancer.

Implications of all the available evidence

This study suggests that hyperfractionated intensity-modulated radiotherapy could significantly decrease the rate of severe late complications and improve overall survival, as compared with standard fractionation, among patients with locally advanced recurrent nasopharyngeal carcinoma. On the basis of our findings, we recommend hyperfractionated intensity-modulated radiotherapy as the standard of care for these patients.

Based on the radiobiological principle, hyperfractionation with a reduced dose per fraction (1·1–1·5 Gy), given twice daily, could enhance the repair of sublethal damage in late-reacting tissues, and therefore reduce late radiation-induced toxicity.⁹ Indeed, a hyperfractionation schedule has been shown to be able to deliver higher total doses in EQD2 for gross tumour volume to improve tumour control without substantially increasing late toxicity at various anatomical sites affected by malignant diseases, including head and neck cancer.15, 16, 17, 18 Additionally, it is possible to use hyperfractionation to reduce the risk of late toxicity without changing the total dose for gross tumour volume in patients with recurrent cancer. Despite its theoretical benefit in reducing late toxicity for patients with recurrent disease, clinical data for such fractionation schedules are sparse in patients with recurrent nasopharyngeal carcinoma. A small retrospective study in 20 patients reported by Lee and colleagues¹⁹ showed that hyperfractionation to a total dose of 64·8 Gy (at 1·2 Gy per fraction, twice daily) achieved similar overall survival as 60 Gy in 30 fractions, while practically eliminating the risk of haemorrhage (30% vs 0%). Similarly, a study by Karam and colleagues²⁰ showed that hyperfractionation (1·1–1·2 Gy per fraction, twice daily) was equivalent in tumour control while causing less treatment-related toxicity.

We therefore aimed to investigate the efficacy and safety of hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy with an equivalent total dose of EQD2 per gross tumour volume in patients with locally advanced, recurrent nasopharyngeal carcinoma. The objective of this clinical trial was to determine if the hyperfractionation schedule could decrease the incidence of radiation-induced toxicity and further increase overall survival without compromising tumour control in these patients.