The prolonged interval between induction chemotherapy and radiotherapy is associated with poor prognosis in patients with nasopharyngeal carcinoma

We retrospectively reviewed an inpatient database that included 2191 patients with newly diagnosed, biopsy-proven, non-metastatic NPC treated at Sun Yat-sen University Cancer Center between November 2009 and October 2012. Patients receiving IC before RT were included, while patients without pretreatment plasma Epstein-Barr virus (EBV) DNA data were excluded.

All patients underwent a comprehensive pretreatment evaluation, including complete history, physical examination, hematology and biochemistry profiles, magnetic resonance imaging (MRI) of the neck and nasopharynx, chest radiography, abdominal.

ultrasonography, and whole-body bone scanning using single photon emission computed tomography (SPECT). Positron emission tomography and computed tomography (PET/CT) was performed when necessary. All patients were restaged according to the 8th edition of the American Joint Committee on Cancer/International Union against Cancer (AJCC/UICC) staging system based on imaging materials and medical records.

The nasopharyngeal and neck tumor volumes of all patients were treated using radical radiotherapy based on IMRT for the entire course. Gross tumor volumes were defined based on MR, CT and PET/CT imaging before IC; target volumes were delineated slice-by-slice on treatment planning CT scans using an individualized delineation protocol [11], in accordance with the International Commission on Radiation Units and Measurements reports 50 and 62. The prescribed doses were 66–72 Gy to the planning target volume (PTV) of the primary gross tumor volume (GTVnx), 64–70 Gy to the PTV of the GTV of involved lymph nodes (GTVnd), 59.4–63 Gy to the PTV of the high-risk clinical target volume (CTV1), and 50.4–56 Gy to the PTV of the low-risk clinical target volume (CTV2) in 28–33 fractions. All targets were treated simultaneously using the simultaneous integrated boost technique.

During the study, institutional guidelines recommended IMRT alone for stage I NPC and IMRT combined with chemotherapy for stage II-IVa NPC. Three regimes of IC were frequently used: cisplatin (80 mg/m²) with 5-fluorouracil (750–1000 mg/m² per day for 5 days), cisplatin (75 mg/m²) with docetaxel (75 mg/m²), and cisplatin (60 mg/m²) plus docetaxel (60 mg/m²) with 5-fluorouracil (600–750 mg/m² per day for 5 days) every 3 weeks for 2–4 cycles. Concurrent chemotherapy consisted of cisplatin (80–100 mg/m²) every 3 weeks for 2–3 cycles or cisplatin (30–40 mg/m²) weekly for 5–7 cycles. Adjuvant chemotherapy was less often chosen because of poor compliance. When possible, salvage treatments (intracavitary brachytherapy, surgery, or chemotherapy) were provided for documented relapse or persistent disease.

The interval between IC and RT was calculated from the last day of the last cycle of IC to the initiation of RT. Analyzed covariates were as follows: tumor factors, including T category, N category, WHO pathology type and pretreatment plasma EBV DNA concentration; host factors, including age, gender and Charlson comorbidity index (CCI); treatment factors, including IC cycles and use or non-use of concurrent chemotherapy. Pretreatment plasma EBV DNA quantification was performed by real-time quantitative polymerase chain reaction assay amplifying the BamHI-W region of the EBV genome [12]. We added 1 to all EBV DNA values and then performed a natural log transformation to generate a new variable, lnDNA. Charlson comorbidity index was calculated based on medical records to assess the comorbidities [13].

The follow-up duration was measured from first day of treatment to the day of last examination or death. Patients were examined at least every 3 months during the first 2 years, then every 6 months for at least 3 years, and annually thereafter until death. The primary endpoint was OS, defined as the time from the initiation of therapy to death from any cause. The secondary endpoints included DFS, defined as the time from initiation of therapy to failure or death from any cause, whichever occurred first. Distant metastasis-free survival (DMFS) was defined as the time from initiation of therapy to first distant failure. Locoregional recurrence-free survival (LRFS) was defined as the time from initiation of therapy to first locoregional failure.

We intended to dichotomize the interval for simplification of the analysis and better interpretation of the results. Because there was no referenced cutoff point reported previously, we categorized the interval into five consecutive groups to explore the relationship between the interval and OS preliminarily, and we then determined a suitable cutoff point. The associations between the dichotomized interval and other binary or nominal variables were tested with Pearson chi-square test or Fisher’s exact test. Independent samples t-test or Wilcoxon rank-sum test were used for continuous and ordinal variables. Actuarial survival rates were estimated using the Kaplan-Meier method, and survival curves were compared using log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) for each covariate were estimated from univariate Cox regression analyses. The multivariate Cox regression model was used to adjust prognostic effects of the interval for other prognostic factors. Covariates were selected by a backward elimination method with removal criterion of 0.2. The interval and selected covariates entered the multivariate analyses. Age and lnDNA were modeled as continuous variables assuming linear correlation with the outcomes, while the interval and other covariates were modeled as binary variables. Heterogeneity of effect size in different subgroups was appraised by I² statistic, and a value > 25% indicated the existence of heterogeneity [14]. SPSS version 22.0 (IBM Corporation, Armonk, NY, USA), and Stata version 12.0 (StataCorp, College Station, TX, USA) were used for all statistical analyses. Two-tailed P-values < 0.05 were considered statistically significant.

The median interval between IC and RT was 20 days (range, 1–67 days; interquartile range, 15–27 days). Three extreme values of 61, 66 and 67 were confirmed by review of medical records. We categorized the interval into ≤10, 11–20, 21–30, 31–40 and ≥ 41 groups, and the 5-year OS rates were 86.7, 85.7, 87.5, 68.7 and 70.6%, respectively. The log rank test showed no significant differences among ≤10, 11–20 and 21–30 groups and between 31 and 40 and ≥ 41 groups (Fig. 1). Therefore, we chose 30 days as the cutoff point to categorize the interval into a ≤ 30 days group with a median of 19 (interquartile range, 14–25) and a >  30 days group with a median of 36 (interquartile range, 32–42).

Patient characteristics for the entire included cohort are displayed in Table 1. Patients with the interval >  30 days tended to receive more cycles of IC (P < 0.001) and were less likely to receive concurrent chemotherapy during RT (P = 0.028) than were patients with interval ≤ 30 days. We also observed that patients in the > 30 days group were more likely to be at advanced T categories (P = 0.034). However, after we recategorized T categories as binary variables (T1–2 and T3–4) before entering the Cox regression, the correlation between T categories and the interval became statistically insignificant (Pearson chi-square test, P = 0.154, data not shown). As for the remaining characteristics, no significant correlation between these and the interval was found, even after some of them were recategorized into binary variables (CCI, 0 and ≥ 1; N categories, N0–1 and N2–3; WHO pathology, I/II and III).

The 5-year OS rate was significantly lower for patients with interval > 30 days than for those with interval ≤ 30 days (69.2% vs. 86.6%, P < 0.001; Fig. 2a). The 5-year DFS rate (64.5% vs. 78.2%, P = 0.004; Fig. 2b) and DMFS rate (71.2% vs. 88.0%, P < 0.001; Fig. 2c) were also significantly lower for patients with interval > 30 days than for those with interval ≤ 30 days. However, the difference in 5-year LRFS rate (85.1% vs. 89.8%, P = 0.204; Fig. 2d) failed to reach significance. The unadjusted HRs and 95% CIs for the interval and other covariates estimated from univariate Cox regression are shown in Table 2.

Results of multivariable analyses are presented in Table 3. The interval > 30 days remained a significant negative prognostic factor for NPC patients in terms of OS (HR 2.44, 95% CI 1.48–4.01), DFS (HR 1.99, 95% CI 1.27–3.11) and DMFS (HR 2.62, 95% CI 1.54–4.47).

We further explored the prognostic effects of the interval in subgroups stratified by N category, IC cycles and concurrent chemotherapy. For patients with N2–3 disease, the interval remained a significant prognostic factor in terms of OS, DFS and DMFS. By contrast, the interval may not exert a significant impact on OS, DFS and DMFS for patients with N0–1 disease (Additional file 1: Figure S3). After the cohort was stratified by IC cycles (Additional file 1: Figure S4) or concurrent chemotherapy (Additional file 1: Figure S5), the interval remained a significant prognostic factor, indicating its independence.

Heterogeneity analyses of effect size of the interval in subgroups suggested the existence of a modification effect by N category and concurrent chemotherapy. The interval > 30 days may be more dangerous for patients with advanced N category or not receiving concurrent chemotherapy during RT in terms of OS and DFS. Heterogeneity was not detected in terms of DMFS, possibly due to the lower number of events in subgroups. (Additional file 1: Figure S6)

To help readers gain a general understanding of our study, we provided a study profile recommended by the Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) [15] in Table 4.