STAR★Methods

Key resources table

REAGENT or RESOURCE | SOURCE | IDENTIFIER
Software and algorithms

R (version 3.3.1) | The R Foundation | https://www.r-project.org/

Experimental model and study participant details

Patients

This retrospective study involved a cohort of patients treated with IMRT at Fujian Cancer Hospital between January 2017 and December 2019. All participants were newly diagnosed with non-metastatic NPC, confirmed pathologically, and had complete clinical data. The patients underwent IMRT as planned, with or without CCRT, induction chemotherapy (IC), and adjuvant chemotherapy (AC). Daily RT data were accessed through the MOSAIQ integrated platform. Ultimately, 2,059 patients were enrolled in the study.

Ethics approval and security

The study received ethical approval from the Fujian Cancer Hospital's Research Ethics Committee (Fujian, China) and adhered to the principles of the Declaration of Helsinki (K2024-517-01). Given the retrospective nature of the research, the requirement for informed consent was waived. All procedures were performed in accordance with the relevant guidelines and regulations. For the cohort of NPC patients, we compiled comprehensive clinical and demographic profiles including age, TNM stage, and other tumor-related characteristics. Complete sample distributions and detailed baseline characteristics of this study population are provided in Tables 1 and 2.

Influence of sex on the results

Among the 2,059 patients enrolled, 1,504 (73.05%) were male and 555 (26.95%) were female. Both univariate and multivariate analyses identified sex as a significant independent prognostic factor for OS, PFS, LRFFS, and DMFFS (p < 0.05, Tables 3 and 4; Tables S3 and S4). Additionally, subgroup analysis revealed that the survival benefit of maintaining a low ΔRTT was particularly pronounced and statistically significant in female patients.

Method details

Treatment and evaluation

Radical IMRT was administered using simultaneous integrated boost with 6MV photons. All patients were immobilized in a supine position utilizing a thermoplastic mask. The delineation of target volumes and identification of organs at risk were facilitated by the fusion of computed tomography (CT)/magnetic resonance imaging (MRI) images. The gross tumor volume (GTV) included all visible disease, comprising nasopharyngeal primary tumors (GTV-T) and positive lymph nodes (GTV-N), as identified through imaging, clinical examination, and endoscopic findings. The clinical target volume (CTV) was defined as the GTV along with its surrounding subclinical lesions. A planned target volume (PTV) was established as a safety margin around the GTV/CTV, incorporating an additional 3mm to account for positional uncertainties and intrinsic organ movements. Radiation doses prescribed for NPC adhered to our institution's guidelines, specifying a dose range of 6600 to 7310 cGy for PTV-GTV-T, 6000-7310 cGy for PTV-GTV-N, and 5000 to 6600 cGy for PTV-CTV across 28 to 36 fractions delivered once daily, five times per week. Dose constraints for organs at risk were determined in accordance with the RTOG 0225 protocol. For unscheduled treatment interruptions, our institutional protocol required immediate resumption of the original dose/fractionation schedule for interruptions ≤3 days, with replanning required for longer delays, while dose compensation through fraction size adjustments maintained the total prescribed dose. Chemotherapy regimens were tailored to each patient based on overall stage, physical condition, drug availability, and comorbidities. Treatment modalities were categorized into seven groups: RT alone, IC+RT, IC+RT+AC, CCRT, CCRT+AC, IC+CCRT and IC+CCRT+AC. According to guidelines, IMRT is recommended for stage I NPC, while stages II to IVa are managed with platinum-based CCRT, with the option of adding IC or AC.

Follow-up and endpoints

Patients participated in systematic follow-up evaluations, which encompassed clinical examinations, nasopharyngoscopy, and imaging modalities such as CT, MRI, and positron emission tomography-CT. These assessments were conducted quarterly during the initial two-year period, biannually over the subsequent three years, and annually thereafter. The most recent follow-up was conducted on May 20, 2024. The principal aim of this study was to assess OS, which is delineated as the interval from the initiation of radiation therapy to the occurrence of death from any cause or the most recent verified date of survival. Secondary outcomes encompassed progression-free survival (PFS), locoregional failure-free survival (LRFFS), and distant metastasis failure-free survival (DMFFS). PFS was delineated as the interval commencing from the initiation of radiation therapy to the occurrence of disease progression, mortality, or the most recent follow-up, whichever event transpired first. LRFFS and DMFFS were defined as the duration from the start of radiation therapy to the first occurrence of local/regional recurrence, distant metastasis, mortality, or the most recent follow-up assessment. For patients who did not return for follow-up, information was obtained primarily via telephone, either from the patient, their family, or the medical records department.

The definitions of RTT and ΔRTT

Radiation treatment time (RTT) refers to the interval spanning from the commencement of RT to the conclusion of the prescribed therapeutic regimen. For patients undergoing IMRT, the deviation in RTT(ΔRTT) was determined by calculating the difference between the actual time required to complete the prescribed treatment regimen and the initially planned treatment duration. For example, if the prescribed dose was 70 Gy administered over 35 fractions, with a planned treatment duration of 47 days (commencing on a Monday) or 49 days (commencing on any weekday other than Monday), the ΔRTT was determined accordingly. Treatment interruptions were defined as missed days of scheduled radiotherapy occurring on workdays (Monday through Friday). While standard weekends were not considered interruptions, gaps resulting from public holidays falling on a weekday were included in the treatment interruptions count. In cases where a holiday fell on a weekend and the facility was closed on the preceding Friday, that Friday was also recorded as a treatment interruption.

Quantification and statistical analysis

Covariates analyzed in this study included host factors (such as gender [male vs. female], age [≤45 years vs. >45 years], hemoglobin(HGB) levels, and neutrophil-to-lymphocyte ratio(NLR),27 tumor characteristics (including T stage, N stage, and overall stage), in addition to treatment-related variables (such as RTT, ΔRTT, the number of prescribed fractions, and the modality of treatment). Both HGB and NLR detections were performed respectively before treatment. Regarding NLR, it is calculated as the absolute neutrophil count divided by the absolute lymphocyte count. A normal NLR range is typically considered to be between 1 and 2. The concentration of plasma EBV-DNA was quantified using reverse transcription-quantitative PCR, with detectable vs. undetectable levels determined using a cut-off value of 0 copies/mL.28 Variables were categorized based on clinical findings, whereas continuous variables were transformed into categorical formats utilizing established cutoff points or results from previous studies. Clinicopathologic characteristics were compared across different groups using the chi-squared test or Fisher’s exact test for categorical variables. We conducted recursive partitioning analyses (RPAs) to determine the best RTT and ΔRTT thresholds. The recursive partitioning analysis (RPA) method determined optimal splitting nodes at each step to identify the most favorable RTT and ΔRTT thresholds through classification and regression tree-based analysis. Survival curves were estimated using the Kaplan-Meier method,29 with comparisons made using the log-rank test. Cox regression analysis was employed to calculate hazard ratios and 95% confidence intervals, quantifying the impact of potential confounders on survival outcomes. Additionally, a subgroup analysis was conducted to assess the impact of continuous interruptions. Statistical significance was defined as a p-value less than 0.05. R software, version 3.3.1(https://www.r-project.org/), was used for all statistical analyses.

The exact value of n, representing the total number of patients, along with comprehensive statistical details, is explicitly specified and can be found across the text of the results section, Tables 1, 2, 3, and 4, and the corresponding main and supplementary figure legends.