Prognostic Model for Stratification of Radioresistant Nasopharynx Carcinoma to Curative Salvage Radiotherapy

Abstract

Purpose To investigate for a prognostic index (PI) to personalize recommendations for salvage intensity-modulated radiotherapy (IMRT) in patients with locally recurrent nasopharyngeal carcinoma (lrNPC). Methods Patients with lrNPC from two academic institutions (Sun Yat-Sen University Cancer Center [SYSUCC-A; n = 251 (training cohort)] and National Cancer Centre Singapore [NCCS; n = 114] and SYSUCC-B [n = 193 (validation cohorts)]) underwent salvage treatment with IMRT from 2001 to 2015. Primary and secondary clinical end points were overall survival (OS) and grade 5 toxicity-free rate (G5-TFR), respectively. Covariate inclusion to the PIs was qualified by a multivariable two-sided P < .05. Discrimination and calibration of the PIs were assessed. Results The primary PI comprised covariates that were adversely associated with OS in the training cohort (gross tumor volume hazard ratio [HR], 1.01/mL increase [ P < .001], age HR, 1.02/year increase [ P = .008]; repeat IMRT equivalent dose in 2-Gy fractions [EQD2] ≥ 68 Gy HR, 1.42 [ P = .03]; prior radiotherapy-induced grade ≥ 3 toxicities HR, 1.90 [ P = .001]; recurrent tumor [rT]-category 3 to 4 HR, 1.96 [ P = .005]), in ascending order of weight. Discrimination of the PI for OS was comparable between training and both validation cohorts (Harrell's C = 0.71 [SYSUCC-A], 0.72 [NCCS], and 0.69 [SYSUCC-B]); discretization by using a fixed PI score cutoff of 252 determined from the training data set yielded low- and high-risk subgroups with disparate OS in the validation cohorts (NCCS HR, 3.09 [95% CI, 1.95 to 4.89]; SYSUCC-B HR, 3.80 [95% CI, 2.55 to 5.66]). Our five-factor PI predicted OS and G5-TFR (predicted v observed 36-month OS and G5-TFR, 22% v 15% and 38% v 44% for high-risk NCCS and 26% v 31% and 45% v 46% for high-risk SYSUCC-B). Conclusion We present a validated PI for robust clinical stratification of radioresistant NPC. Low-risk patients represent ideal candidates for curative repeat IMRT, whereas novel clinical trials are needed in the unfavorable high-risk subgroup.

Dose volume effects of re‐irradiation for locally recurrent nasopharyngeal carcinoma

“…While small volume disease might benefit with slightly higher dose than 60 Gy 10 (EQD2) as shown in the multi‐dimensional logistic model, the local control rate is estimated to be less than 50% if the GTV exceeds 20 cc, and it falls rapidly to less 10% irrespective of radiation dose if the GTV exceeds 80 cc. This detrimental effect of increasing GTV volume has been consistently reported in other series . Specifically, GTV volume exceeding 30 cc and 38 cc were found to be the negative prognostic factor in the study by Tian et al and Han et al, respectively.…”

“…Higher rates of treatment related fatal complications were observed in studies that reported treatments with planned RT doses larger than 60 Gy. High re‐irradiation dose (above 68‐70 Gy) and large recurrent gross tumor volume were shown to associate with poor treatment outcomes . It is evident that local control benefited from dose escalation could be potentially offset by the detrimental effect of life‐threatening late toxicities.…”

Patterns of care and treatment outcomes for local recurrence of NPC after definite IMRT—A study by the HKNPCSG

“…Various prognostic models have been proposed aiming to identify patients who might best benefit from the use of re-RT. [10][11][12] Our analysis suggests that age and rGTV volume were the most important parameters for OS. However, in a case-matched retrospective study, similar survival outcomes were observed for patients who received re-RT vs chemotherapy alone, 22 and the latter was inevitably associated with fewer RT-related toxicities.…”

“…Analyses of survival outcome and prognostic factors were performed by using the Kaplan-Meier method, log-rank test, and Cox proportional hazard model. Prognostic factors based on prior literature findings [9][10][11][12] including age, gender, time from primary diagnosis to recurrence, rT status, presence of concomitant nodal metastasis, and treatment modalities were considered, with backward elimination used to determine the significant factors. Among the re-RT group, other prognostic factors such as recurrent tumor volume, radiation dose, and concomitant chemotherapy were also analyzed.…”

Clinical characteristics and prognostic value of pre‐retreatment plasma epstein‐barr virus DNA in locoregional recurrent nasopharyngeal carcinoma

“…Moreover, in our study, the outcomes of univariate analysis may be less convincing on account of the unbalanced distribution of recurrent tumor stage and treatment protocols, while there are no exactly standard therapeutic modalities in patients with lrNPC. With the developed surgical technology, nasopharyngectomy is recommended for early stage resectable disease . Comparing the efficacy of surgery with re‐irradiation is difficult as patients eligible for surgery generally have earlier stage disease (usually rT1‐2), smaller tumor volume and fewer comorbidities.…”