Discussion

Our study revealed that an extension of seven days or more in the ΔRTT for patients with NPC correlates with a poorer prognosis. Furthermore, our findings suggest that the frequency of RTIs may influence survival outcomes in these patients, particularly when RT is prolonged.

In the era of IMRT, significant debate persists about the impact of interrupted RT on patients with tumor. Some evidence suggests that interruptions do not significantly affect the prognosis of patients with head and neck tumors and anorectal squamous cell carcinoma.20,21 However, Xu et al. demonstrated that interruptions in RT yield varied prognostic outcomes in NPC,12 highlighting the lack of consensus regarding the prognostic implications of different modes of RTI.

In a retrospective study conducted by Li et al., no statistically significant correlation was identified between survival outcomes and the duration of RTT within the interval of 36–63 days.22 Conversely, our research indicated that prolonged RTT is associated with diminished survival outcomes. Further analysis revealed that an RTT of 50 days or more particularly correlates with poorer prognostic outcomes. However, the variability in TNM stages among patients, implying differences in RT session frequency, challenges the accuracy of prognosis assessment for patients undergoing fewer RT fractions within this 50-day cut-off period.

Therefore, we conducted an analysis to evaluate the impact of RTT on patient survival, focusing on adherence to the RT schedule. Contrary to expectations, although OS and PFS rates were higher among patients who completed their RT on schedule compared to those with earlier or extended completion times, the higher proportion of patients with advanced TNM staging within the on-schedule group—known to be associated with poorer survival outcomes—may have influenced these results. Consequently, there was no statistical significance among the survival curves (p > 0.05). To ensure the study’s generalizability across patients at various stages and with diverse treatment options, we further investigated the impact of ΔRTT on survival outcomes.

The prognostic relevance of ΔRTT remains controversial, as evidenced by several previous retrospective studies. Kong et al. reported that a median interruption of three days was associated with a significantly poorer prognosis (p = 0.046).23 Xu et al. demonstrated that a four-day interruption threshold significantly affected both PFS and OS.24 Shyh-An Yeh et al. determined that interruptions of five days or more during IMRT, irrespective of concurrent chemotherapy, significantly compromise OS in patients with NPC.25 The observed variations in ΔRTT across these studies may be attributable to limited sample sizes, brief follow-up durations, or the analysis of ΔRTT as a categorical variable. To obtain a more precise measure, we examined a cohort of 2,059 patients with extended follow-up periods and conducted a continuous analysis of ΔRTT. Our findings corroborated those of Yao et al., emphasizing the necessity of limiting RTIs to fewer than seven days to mitigate the risk of adverse health outcomes.26

We also examined the correlation between interruptions in continuous or decentralized RT and the prognosis of patients with NPC. In our univariate and multivariate analyses, continuous interruptions in RT did not emerge as an independent adverse prognostic factor for the four survival endpoints. However, when patients were stratified based on the frequency of RTIs (one or more times), Kaplan-Meier survival analysis revealed that OS, PFS, LRFFS, and DMFFS rates were lower in patients experiencing more than one interruption compared to those with a single interruption. Nevertheless, statistical significance was only observed in the Kaplan-Meier curve for the group with a ΔRTT greater than zero. These findings suggest that patients who exceed the prescribed duration of RT should minimize the number of interruptions to optimize treatment outcomes. The adverse impact of prolonged RTT and multiple interruptions observed in our cohort is fundamentally driven by accelerated repopulation. This radiobiological phenomenon, characterized by the rapid proliferation of tumor cells during treatment gaps, serves as the biological basis for maintaining RT continuity. During these delays, surviving clonogens accelerate their growth, effectively diminishing the biologically effective dose (BED) as subsequent fractions are partially consumed to counteract new cell production. Within the framework of the “Four Rs” of radiobiology, such interruptions allow the tumor to outpace cumulative radiation damage, thereby compromising local control and survival. Therefore, minimizing treatment disruptions is critical to preventing this proliferative recovery and ensuring optimal therapeutic efficacy in NPC.

In this study, databases pertaining to RTT and ΔRTT were developed using data from 2,059 patients who experienced interruptions in their RT for various reasons. By assessing multiple survival endpoints, including OS, PFS, LRFFS, and DMFFS, it was determined that a ΔRTT of seven days or more may lead to poor prognosis in patients with NPC. This finding aligns with results from a large cohort study conducted at another center, further substantiating that a ΔRTT of seven days or more may be a critical factor influencing the efficacy of RT in these patients. Additionally, the study elucidates the differential impact of ΔRTT across various patient subgroups, categorized by overall stage and chemotherapy modalities, thereby providing insights that can inform personalized treatment strategies. Furthermore, this study demonstrates that the number of RTIs influences survival outcomes in patients with NPC who exceed the prescribed duration of treatment. This finding sheds light on a previously unexamined aspect of how continuous versus dispersed RTIs impact patient prognosis. In clinical practice, various dose-compensation protocols are employed to mitigate the effects of RTIs. Mainstream strategies typically involve increasing the dose per fraction or utilizing twice-daily treatments to maintain the BED when the overall treatment time is extended. At our institution, we follow a similar protocol where interruptions longer than 3 days require dose compensation through fraction size adjustments. However, our results demonstrate that a ΔRTT of 7 days or more still significantly correlates with a poorer prognosis despite these interventions. This underscores the limitation of current compensation methods in completely counteracting accelerated repopulation, particularly when multiple interruptions occur. For clinical oncologists, this highlights the necessity of prioritizing treatment continuity and keeping ΔRTT below the 7-day threshold even when compensation protocols are available.

Our study indicates that a ΔRTT of seven days or more constitutes a critical factor contributing to poor prognosis in patients with NPC undergoing IMRT. Additionally, recurrent interruptions in RT are associated with adverse prognostic outcomes. Consequently, it is imperative in clinical practice to enhance RT management protocols to ensure that ΔRTT remains below seven days and to minimize the frequency of RTIs.

Limitations of the study

Despite the strengths of the study, several limitations must be acknowledged. Being retrospective, the study is susceptible to inherent biases and confounding factors that could have influenced the results. Specifically, due to the retrospective nature of our database, we were unable to granularly distinguish between the etiologies of interruptions, such as treatment-related toxicities versus non-medical factors (e.g., public holidays or machine maintenance). While these different causes might theoretically reflect different aspects of patient frailty or radiobiological impact, our findings prioritize the cumulative ΔRTT as a pragmatically critical determinant of survival. Additionally, the research was conducted at a single institution, potentially limiting the generalizability of the findings. Future research should prioritize prospective, multicenter studies to validate these results and further investigate the biological mechanisms underlying the impact of RTIs on the prognosis of NPC.