Patient characteristics and treatment failure
The clinical and treatment characteristics of the patients in this cohort are summarized in Table 1. The median age at diagnosis was 44 years (range, 18-76 years); 49.1% (1536/3123) of subjects were at stage III, and 50.8% (1587/3123) were at stage IVa. In total, 56.3% (17658/3123) of patients received 1-2 cycles of IC, and 43.7% (1365/3123) received more than 2 cycles. TPF was the most commonly used IC regimen (43.2%; 1350/3123). For 77.3% (2414/3123) receiving concurrent cisplatin, 2230 patients received CCD ≤200 mg/m2, and only 185 patients received CCD >200 mg/m2.
The median follow-up of the entire cohort was 67.5 months (interquartile range 59.5–81.5 months). During the follow-up period, 13.0% (407/3123) of patients experienced locoregional recurrence, 16.4% (511/3123) experienced distant metastasis, and 19.8% (619/3123) died. The 5-year OS, FFS, LRFFS and DFFS values of the whole cohort were 83.2%, 74.0%, 89.9% and 84.1%, respectively.
Early or late treatment failure
The P-values of differences in post-failure OS regarding various cut-off points to evaluate early locoregional recurrence or distant metastasis are shown in Figure 1. At a median follow-up of 26.9 months (interquartile range 15.7 – 40.0 months), the optimal length of early LRFFS (ELRFFS), based on subsequent post-recurrence survival, was 14 months (P = 1.47×10-3, Fig. 1A). In the current study cohort of 407 patients with locoregional recurrence, 88 patients (21.6%) developed early locoregional failure, with 1- and 3-year post-failure OS rates of 65.9% and 34.1%, and 319 patients (78.4%) developed late locoregional failure, with 1- and 3-year post-failure OS rates of 83.8% and 46.8% (P=0.002, Fig. 2A). At a median follow-up of 18.5 months (interquartile range 10.6 – 32.8 months), the optimal length of DFFS to distinguish between early and late distant failure was within 20 months (P = 1.95×10-4, Fig. 1B). For 511 patients with distant metastasis, 278 patients (54.4%) with early metastasis had 1- and 3-year post-failure OS rates of 60.1% and 17.6%, respectively, compared with 71.3% and 29.8% for the late metastasis group (P < 0.001, Fig. 2B).
Multivariable analyses of locoregional failure cohort suggest ELRFFS (hazard ratio (HR), 4.606; 95% confidence interval (CI), 3.391-6.257; P <0.001), post failure treatment strategy (P <0.001) and clinical stage (HR, 1.639; 95% CI, 1.283-2.170; P = 0.001), were independently risk factors for OS (Table 2). In distance failure cohort, EDFFS (HR, 4.239; 95% CI, 3.408-5.273; P <0.001) and post failure treatment strategy (P <0.001) were independently risk factors for OS (Table 3).
Table 4 illustrates the multivariate analysis results of the whole cohort. The WHO histological type and overall stage were independently associated with LRFFS, in which the WHO histological type was an independent risk factor for early LRFFS (hazard ratio (HR), 0.354; 95% confidence interval (CI), 0.144-0.874; P = 0.024), and age (HR, 1.324; 95% CI, 1.063-1.649; P = 0.012) and clinical stage (HR, 1.427; 95% CI, 1.138-1.790; P = 0.002) were independent risk factors for late LRFFS. For DFFS, nodal stage was an independent unfavourable risk factor (HR, 2.160; 95% CI, 1.646-2.833; P <0.002). Sex, nodal stage and clinical stage were independently associated with EDFFS and LDFFS (all P < 0.02). EBV DNA >4000 copies/ml was independently associated with an increased likelihood of EDFFS (HR, 2.152; 95% CI, 1.615-2.867; P < 0.001) but not LDFFS.
Cisplatin-based concurrent chemotherapy and the timing of treatment failure
Kaplan-Meier survival analysis indicated that patients with cisplatin-based concurrent chemotherapy had higher 5-year FFS and OS rates than patients without, and CCD >200 mg/m2 presented a better survival than a medium-level CCD (101–200 mg/m2) ([0 mg/m2 vs. 1-200 mg/m2 vs. >200 mg/m2]: FFS: 70.4% vs. 74.4% vs. 82.6%, all P < 0.03, Fig. 3A; OS: 79.5% vs. 83.8% vs. 90.8%, all P < 0.01, Fig. 3B).
Although there was no significant difference between patients without concurrent cisplatin who received a medium dose in terms of 5-year DFFS (82.2% vs. 84.1%, P =0.283, Fig. 3D), CCD > 200 mg/m2 significantly improved DFFS compared to the other groups ([>200 mg/m2 vs. 0 mg/m2]: 91.3% vs. 82.2%, P =0.010; [>200 mg/m2 vs. 1-200 mg/m2]: 91.3% vs. 84.1%, P =0.026, Fig. 3D). However, no significantly different survival outcomes were observed in different applications of CCD regarding LRFFS ([0 mg/m2 vs. 1-200 mg/m2 vs. >200 mg/m2]: 86.1% vs. 87.6% vs. 89.4%, all P > 0.05, Fig. 3C).
Cox regression modelling predicted that cisplatin-based concurrent chemotherapy was an independent positive factor for OS, FFS and EDFFS (all P < 0.05, Table 2). CCD >200 g/m2 was a significant factor in reducing the risk of early distant failure (HR, 0.351; 95% CI, 0.169-0.732; P = 0.005, Table 2).
Cumulative risk is summarized in the supplementary files 2. The monthly risk-adjusted event-occurring probability for the three groups is summarized in Figure 4. Generally, disease failure mainly occurred in the first 4 years (Fig. 4A), locoregional recurrence occurred in the 6th to 48th month (Fig. 4B), and distant metastasis occurred in approximately the first 3 years (Fig. 4C). The peak occurrence time for all endpoints was approximate in all groups, but the lowest probability of distant failure and disease failure was observed in the CCD>200 g/m2 group (Fig. 4A, C). It is worth noting that there was still a small rise in distant metastasis in patients who received concurrent cisplatin after 5 years of follow-up (Fig. 4C). For locoregional recurrence, the probability at peak was approximate, but locoregional recurrences slightly increased in patients without concurrent cisplatin after the 7th year of follow-up (Fig. 4B).