Hyperfractionated Intensity-Modulated Radiotherapy Decreases the Rate of Severe Late Complications and Improves Overall Survival in Locally Advanced Recurrent Nasopharyngeal Carcinoma

Compared with standard fractionated intensity-modulated radiotherapy, hyperfractionated intensity-modulated radiotherapy delivered as 65 Gy in 54 fractions, given twice daily with inter-fractional time interval of at least 6 hours, decreased the rate of severe late complications and improved overall survival (OS) among patients with locally advanced recurrent nasopharyngeal carcinoma. By means of keeping the same tumouricidal radiation dose to the gross tumour volume, the study team showed that hyperfractionated intensity-modulated radiotherapy could significantly reduce the incidence of late radiation-induced toxicities, which might translate into OS benefits compared with standard fractionated intensity-modulated radiotherapy. The findings from a randomised, phase III study are published by Prof. Ming-Yuan Chen of the Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Centre in Guangzhou, China, and colleagues on 23 February 2023 in The Lancet.

Southeast Asia has the highest prevalence of nasopharyngeal carcinoma worldwide. The incidence of local recurrence after previous radical radiotherapy in patients with endemic nasopharyngeal carcinoma ranges from 10% to 20%. 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. However, reirradiation is the only possible salvage option with a curative intent in patients with unresectable, locally advanced lesions.

Previous studies recommended a dose of at least 60 Gy given in equivalent dose at 2 Gy fractions (EQD2) for gross tumour volume as the optimal dose for the second course of radiotherapy with an attempt to balance tumour control and risk of complications. Unfortunately, the rate of severe, late radiation-induced toxicity remained unacceptably high with standard fractionation in intensity-modulated radiotherapy. Late complications can prove lethal in approximately 31.3–40.0% of patients, substantially reducing OS. 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.

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 reduce late radiation-induced toxicity. 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. 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. The authors explained in the study background that 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.

The aim of the current study was 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. This multicentre, randomised, open-label, phase III study was done in 3 centres in Guangzhou, China.

Eligible patients were aged 18–65 years with histopathologically confirmed undifferentiated or differentiated, non-keratinising, advanced locally recurrent nasopharyngeal carcinoma. Patients were randomly assigned (1:1) to either receive hyperfractionation schedule of 65 Gy in 54 fractions, given twice daily with an interfractional time interval of at least 6 hours, or standard fractionation of 60 Gy in 27 fractions, given once a day. Intensity-modulated radiotherapy was used in both groups. A computer programme generated the assignment sequence and randomisation was stratified by treatment centre, recurrent tumour stage (T2–T3 versus T4), and recurrent nodal stage (N0 versus N1–N2), determined at the time of randomisation.

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 OS defined as the time interval from randomisation to death due to any cause in the intention-to-treat population.

Between 10 July 2015 and 23 December 2019, 178 patients were screened for eligibility, of whom 144 were enroled and randomly assigned to hyperfractionation or standard fractionation, 72 in each group. A total, 35 patients (24%) were women and 109 (76%) were men.

After a median follow-up of 45.0 months, there was a significantly lower incidence of grade 3 or worse late radiation-induced toxicity in the hyperfractionation group (34%) versus the standard fractionation group (57%) with between-group difference of 23% (95% confidence interval [CI] –39 to –7; p = 0.023). Patients in the hyperfractionation group had better 3-year OS (74.6%) than those in the standard fractionation group (55.0%) with a hazard ratio for death of 0.54 (95% CI 0.33 to 0.88; p = 0.014).

There were fewer grade 5 late complications in the hyperfractionation group (7% nasal haemorrhage) than in the standard fractionation group (24% of which 3% nasopharyngeal necrosis, 16% nasal haemorrhage, and 4% temporal lobe necrosis).

The study team concluded that their findings suggest that hyperfractionated intensity-modulated radiotherapy could be used as the standard of care for these patients.

In an accompanied editorial article, Dr. Anne W M Lee of the Clinical Oncology Centre, The University of Hong Kong-Shenzhen Hospital in Shenzhen, China, and colleagues wrote that the study team should be congratulated for providing evidence on a potential new standard for reirradiation in patients with locoregionally recurrent nasopharyngeal carcinoma. These landmark results should encourage a switch to hyperfractionation to minimise the irreversible problem of late treatment-related adverse events with reirradiation. However, widespread adoption might not be easy, given the inconvenience to patients and resource constraints, especially in low- and middle-income countries where nasopharyngeal carcinoma is endemic.

The editorialists underlined that the efforts should focus on understanding the biological mechanisms that underpin radioresistance, development of biomarkers to identify patients with hypersensitivity for normal tissue damage, and to find a way to accurately estimate the maximum tolerable doses to different organs at risk. Future therapeutic gains might come from precise clinical stratification and novel combinations with systemic treatment, including immunotherapy.

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