Clinical treatment considerations in the intensity-modulated radiotherapy era for parotid lymph node metastasis in patients with nasopharyngeal carcinoma.

PURPOSE: No specific irradiation guidelines have been proposed for parotid lymph node (PLN) metastasis in patients with nasopharyngeal carcinoma (NPC). This study aimed to explore the dose prescription and target delineation for PLN metastasis in patients with NPC. METHODS: With the NPC database from a big-data platform, 10,685 patients with primarily diagnosed, non-distant metastatic, histologically proven NPC and treated with intensity modulated radiotherapy (IMRT) at our center from 2008 to 2019 were reviewed and those with PLN metastasis were enrolled in this study. Dosimetry parameters were collected from the dose-volume histograms (DVH). The primary endpoint was overall survival (OS). Least absolute shrinkage and selection operator regression (LASSO) was operated for variable selection. Multivariate Cox regression analysis was applied to identify the independent prognostic factors. RESULTS: PLN metastases were identified in 275/10685 (2.5%) patients. Of 367 positive PLN, 199 were in superficial intra-parotid, followed by 70 in deep intra-parotid, 54 in subparotid and 44 in subcutaneous pre-auricular. Better survival outcome was observed in PLN-radical IMRT group, compared with PLN-sparing group. In 190 patients received PLN-radical IMRT, multivariate analysis revealed that D95% of level VIII > 55 Gy was an independent beneficial prognostic factor for overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and parotid relapse-free survival (PRFS). CONCLUSION: Based on the distribution pattern of PLN metastasis in NPC and the result of dose-finding study, involving the ipsilateral level VIII into low-risk clinical target volume (CTV2) is recommended for NPC with PLN metastasis.

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.

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.