Improved OS With Hyperfractionated RT in Recurrent Nasopharyngeal Carcinoma

Compared with standard fractionation, hyperfractionated intensity-modulated radiotherapy (IMRT) could significantly increase overall survival (OS), as well as reduce the rate of severe late complications in patients with locally advanced recurrent nasopharyngeal carcinoma, according to Chinese investigators.

Their phase III trial showed that patients randomized to hyperfractionated IMRT had better rates of 3-year OS than those in the standard fractionation group (74.6% vs 55.0%; HR 0.54, 95% CI 0.33-0.88, P=0.014), reported Ming-Yuan Chen, MD, PhD, of the Sun Yat-sen University Cancer Center in Guangzhou, China, and colleagues.

Over a median follow-up of 45 months, patients treated with hyperfractionated IMRT also had a significantly lower incidence of grade 3 or worse late radiation-induced toxic effects (34% vs 57%, respectively; P=0.023).

"On the basis of our findings, we recommend hyperfractionated intensity-modulated radiotherapy as the standard of care for these patients," Chen and colleagues wrote in The Lancet.

A commentary accompanying the study called these "landmark results."

The findings "should encourage a switch to hyperfractionation to minimize the irreversible problem of late treatment-related adverse events with re-irradiation," wrote Anna W.M. Lee, MD, of the University of Hong Kong-Shenzhen Hospital in China, and colleagues. "However, widespread adoption might not be easy, given the inconvenience to patients and resource constraints, especially in low-income and middle-income countries where nasopharyngeal carcinoma is endemic."

In explaining the rationale behind the trial, the authors observed that re-irradiation in standard fractionation for locally advanced recurrent nasopharyngeal carcinoma after a previous course of high-dose radiotherapy is associated with a high rate of severe, late radiation-induced toxic events.

"Late complications can prove lethal in approximately 31.3-40.0% of patients, substantially reducing overall survival," Chen and colleagues pointed out. "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."

The trial included 144 patients (mean age 47 years, 76% male) with histopathologically confirmed undifferentiated or differentiated, non-keratinizing, advanced locally recurrent nasopharyngeal carcinoma who were treated at three centers in Guangzhou from 2015 to 2019. These patients were randomly assigned 1:1 to hyperfractionation (65 Gy in 54 fractions, given twice daily with an interfractional time interval of at least 6 hours) or standard fractionation (60 Gy in 27 fractions, given once a day).

Regarding late radiation-induced toxic effects, compared with standard fractionation there were fewer grade 3-4 adverse events in the hyperfractionation group (26% vs 34%), as well as fewer grade 5 late complications (7% vs 24%). Six of the 28 deaths (21%) in the hyperfractionation group and 17 of the 39 deaths (44%) in the standard fractionation group were from late complications. The authors suggested this difference explained the improvement in 3-year OS with hyperfractionation described above, adding that the "importance of minimizing radiation toxicity cannot be overstated."

Regarding quality of life, Chen and colleagues found significant differences favoring hyperfractionated IMRT in the general quality-of-life domains of global health status, role functioning, and social functioning, as well as in the symptom burden domains of pain, financial difficulties, and loss of appetite.

"Given the high rate of late complications with re-irradiation, any strategy that could minimize treatment-related quality-of-life impairment is important to patients," wrote Chen and colleagues. "As evidenced in this study, albeit with modest benefit, hyperfractionation leads to a generally better quality-of-life in most domains and is particularly clinically meaningful in role functioning compared with standard fractionation."

However, Lee and colleagues' commentary noted limitations to the study.

For example, they pointed out that the investigators used a standard fractionation schedule of 2.22 Gy per fraction in the control group, "meaning that late treatment-related adverse event rates in this group could have been lower had the investigators used a conventional standard fractionation regimen of 1.82 Gy per fraction." They also observed that radiotherapy quality assurance processes were not detailed in this study, and that longer follow-up is needed to better assess the results of late toxic effects.

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