The detrimental effects of radiotherapy interruption on local control after concurrent chemoradiotherapy for advanced T-stage nasopharyngeal carcinoma: an observational, prospective analysis

In Southern China, nasopharyngeal carcinoma (NPC) is a common malignancy [1, 2]. Radiotherapy is the mainstay of treatment of NPC given the anatomical restrictions and its radio-sensitivity [3]. The tumor often present with bulky disease and located near multiple critical structures, leading to difficulties in achieving satisfactory local control using two dimensional radiotherapy. Several studies have reported a 5-year local relapse-free survival (LRFS) of 61–79% and overall survival (OS) of 59–69% using two dimensional radiotherapy [4, 5].

With advances in radiation technology, intensity-modulated radiotherapy (IMRT) has become the primary means of radiotherapy due to better treatment outcome. The phase II trial of RTOG 0225 conducted by Memorial Sloan-Kettering Cancer Center reported the excellent local control (2-year rate, 92.6%) for NPC in the era of IMRT [6]. Additionally, Peng et al. [7] conducted a randomised study and found that IMRT had a significant improvement in local control of 7.7% (5-year rate) compared with two dimensional radiotherapy. However, approximately 8–10% patients still experience local relapse in the era of IMRT, which has become a major cause of treatment failure in NPC [8, 9].

Many prognostic factors may directly and/or indirectly affect the local control, including radiotherapy interruption (RTI), which is a significant independent factor in the local control of lung cancer [10], laryngeal cancer [11] and NPC [12, 13] using two dimensional radiotherapy. However, it remains unknown whether RTI still affects local control in the era of IMRT. Based on this knowledge, we, therefore, did an observational prospective study to identify the relationship between RTI and local control in patients with stage T3–4 stage NPC treated by definitive IMRT.

Local failure is one of the major treatment failures in NPC, especially for patients with T3–4 stage [18, 19]. Several important prognostic factors for local control have been identified, including radiation technique [7, 18], dose per fraction [20], the volume of tumor [21], T stage [22], daily fraction size [22], presence of Epstein–Barr virus (EBV) DNA [23], RTI [13] and chemotherapy schedule [24]. Of all these factors, the volume of tumor was excluded in the current study due to the difficulty of measuring before treatment. Another potentially valuable prognostic factor is plasma EBV DNA, but the the large interlaboratory variability of EBV DNA enables the difficulty to apply in routine clinical practice. For this reason, we did not include.

In this study, all patients were treated with concurrent radiochemotherapy. Daily fraction size was 2.12 Gy or 2.27 Gy for patients with conventional fractionation. Given the relatively homogeneous in radiation technique, daily fraction size, beam energy, and chemotherapy in the current study, we take more attention to the effect of RTI on local control. Based on the ROC analysis, RTI was analyzed as a categorical variable (RTI either ≤5 or > 5 days) in the present study. The 5-year LRFS rate was 97% if radiotherapy was completed within 5 days of schedule, whereas it was only 83% for RTI > 5 days. Further analysis revealed that RTI was a significant prognostic factor for local control in the current study. However, some studies suggest that RTI may be less relevant for IMRT or chemotherapy in head and neck carcinoma [25]. A recent retrospective analysis was conducted for 321 patients with various stages of localized NPC treated with doses ranging from 64 to 74 Gy over a time period of 5 to 9 weeks [26]. The median RTI was 3 days and no relationship was found between survival outcomes and radiation treatment duration. However, this was likely due to a relatively narrow RTI window and analysis of radiotherapy time as a continuous variable.

Although we found that the 5-year OS rate was higher in the RTI ≤ 5 days group than in the RTI > 5 days group, we did not find a significant correlation between RTI and OS (P > 0.05). This could be due to a number reasons. First, OS is not only associated with RTI but also associated with age, sex, N stage, and overall stage, as well as the addition of chemotherapy and supportive care [27]. In the present study, all patients received concurrent chemotherapy that may reduce the effect of RTI on OS. Moreover, salvage treatment after initial treatment failure may be influential. Recently, Chen et al. [28] reported a 2-year OS rate of 84.2% in locally relapse NPC using endoscopic nasopharyngectomy. Moreover, re-irradiation and chemotherapy were associated with satisfactory OS for patients with local recurrent disease [29]. This might partially explain the significant difference in LRFS, but not OS for patients with RTI > or ≤ 5 days.

T stage is known to be a prognostic factor of local relapse of NPC patients [30]. However, we did not find any difference between T3 and T4 disease in terms of local control. This is consistent with a previous study [31], which indicates that the current T-stage does not fully reflect local control in NPC patients after IMRT treatment in combination with chemotherapy. It is well recognized that serious acute side effects that could cause radiotherapy interruption, which have been confirmed to be highly detrimental in radiobiologic efficacy [32, 33]. In this study, we included patients with advanced T-stage, who were more likely to receive a higher radiation dose (> 69 Gy) in combination with a higher intensity of chemotherapy, and the incidence of serious acute side effects could be increased for this group of patients. Moreover, we found patients older than 50 years of age were generally more associated with prolonging RTI. Considering that older patients were more likely to have poor performance status, multiple comorbidities, and inadequate social support, our findings seem reasonable due to patients of older age might have a lower tolerance to intense treatment (RT and/or chemotherapy) [34].

An interesting finding of this study was that patients have a significant difference in distribution of RTI (RTI > or ≤ 5 days) when treated with different fraction size (70 Gy/33 F vs. 68 Gy/30 F). Although we did not observe a significant effect of fraction schedule on survival outcomes, patients treated with 70 Gy/33 F tended to have a longer RTI than patients treated with 68 Gy/30 F. One possible reason might be that patients with 70 Gy/33 F had a longer radiotherapy time in comparison with those treated with 68 Gy/30 F, and they were more likely to experience interruption due to severe acute toxicity, holidays, equipment failure, and other causes.

There are some limitations must be noted. First, the 5-year OS curves were not well defined in the groups of RTI ≤ 5 days and RTI > 5 days. The differences in OS between the two groups may be greater with larger sample size. Second, we failed to include data regarding other prognostic factors, such as the alcohol and/or smoking consumption status. However, no studies to date have demonstrated the effect of alcohol consumption or cigarette smoking on local control for NPC.

In this study, we described the long-term outcomes for patients with T3–4 stage NPC treated with definitive chemoradiotherapy in the IMRT era. Our results suggest that prolonged RTI > 5 days is an independent adverse prognostic factor on local control for this group of patients. We consider that attention to RTI seems to be warranted for patients with advanced T3–4 stage NPC.