Who benefited most from higher cumulative dose of cisplatin among patients with locally advanced nasopharyngeal carcinoma treated by intensity-modulated radiation therapy? A retrospective study of 527 cases

Abstract

Purpose: Our previous study demonstrated the benefit of cumulative dose of cisplatin during the whole treatment on locally advanced nasopharyngeal carcinoma (NPC) treated with various chemotherapy strategies. The purpose of this study is to identify the subgroup of locally advanced NPC who benefits from higher dose of cisplatin, and to clarify whether cumulative dose of cisplatin during the whole treatment brings survival benefit to those treated with concurrent chemoradiotherapy (CCRT).

Materials and methods: This retrospective study enrolled 527 patients with locally advanced NPC treated with intensity-modulated radiation therapy (IMRT) and chemotherapy in our institution from 2009 to 2010. The median cumulative dose of cisplatin of 300mg/m² was chose to be the cutoff value of low and high dose subgroups. Survival curves were estimated using the Kaplan-Meier method. Univariate analysis was conducted using the log-rank test. Multivariate analyses (MVA) were performed using Cox proportional hazards regression model.

Results: With a median follow-up of 54.5 (1-76.7) months, high-dose subgroup had a significant higher distant metastasis-free survival (DMFS) (82.0% vs. 76.5%, p=0.029) and overall survival (OS) (84.1% vs. 74.0%, p=0.028). Cumulative dose of cisplatin were demonstrated an independent prognostic factors for DMFS (HR=0.524, 95% CI 0.340-0.806) and OS (HR=0.577, 95% CI 0.373-0.893) for the entire cohort upon MVA. As for T1-2N2-3, high-dose subgroup had a trend of better DMFS (85.7% vs. 76.3%, p=0.069) and a significant improvement in OS (87.8% vs. 76.3%, p=0.041). Similarly, in the subgroup of T3-4N2-3, higher dose of cisplatin was associated with higher OS (80.3% vs. 52.3%, p=0.032). Cumulative dose of cisplatin was an independent prognostic factor for DMFS (HR=0.483, 95%CI 0.292-0.798) and OS (HR=0.429, 95%CI 0.258-0.715) for patients with T1-4N2-3 disease upon MVA. However, the benefit of higher dose of cisplatin was not observed in the subgroup of T3-4N0-1. For patients receiving CCRT (n=278), those treated with higher dose of cisplatin had a significantly higher DMFS (87.7% vs. 75.4%, p=0.004). The benefit mainly derived from T3-4N2-3 patients treated with CCRT (5y DMFS: 87.9% vs. 58.2%, p=0.034). Cumulative dose of cisplatin was associated with a lower risk of distant metastasis (HR=0.427, 95% CI 0.228-0.801) for patients treated with CCRT upon MVA.

Conclusions: Our study identified that patients with N2-3 disease were those benefited from higher cumulative dose. The benefit of higher cumulative dose maintained in those treated with CCRT. The intensity of chemotherapy may be tailored based on various stage subgroups in locally advanced NPC.

Keywords: Nasopharyngeal carcinoma; chemotherapy; concurrent chemoradiation; cumulative dose of cisplatin; intensity-modulated radiation therapy.; prognosis.

Figure 1

Kaplan-Meier distant metastasis-free survivals (DMFS) by various stage subgroups and cisplatin dose subgroups. For the whole cohort of patients, significant benefit of DMFS was observed in the high-dose subgroup (figure 1A, 82.0% vs. 76.5%, p=0.029). Of T1-2N2-3, high-dose subgroup was prone to have a better DMFS (85.7% vs. 76.3%, p=0.069, figure 1C). Of T3-4N0-1 and T3-4N2-3, no significant benefit of higher dose of cisplatin was observed (figure 1B and figure 1D).

Figure 2

Kaplan-Meier overall survivals (OS) by various stage subgroups and cisplatin dose subgroups. For the whole cohort of patients, significant benefit of OS was observed in the high-dose subgroup (figure 2A, 84.1% vs. 74.0%, p=0.028). Of T1-2N2-3, high-dose subgroup was associated with a better OS (87.8% vs. 76.3%, p=0.041, figure 2C). Of T3-4N2-3, high-dose subgroup was associated with a better OS as well (80.3% vs. 52.3%, p=0.032, figure 2D). Of T3-4N0-1, no significant benefit of higher dose of cisplatin was observed (figure 2B).

Figure 3

Kaplan-Meier distant metastasis-free survivals (DMFS) of those treated with concurrent chemoradiation by various cisplatin dose subgroups. For the whole cohort treated with concurrent chemoradiation, significant benefit of DMFS was noted in the high-dose subgroup (87.7% vs. 75.4%, p=0.004, figure 3A). Similarly, high-dose subgroup tended to have a longer DMFS in patients with T3-4N2-3 disease treated with concurrent chemoradiation (87.9% vs. 58.2%, p=0.034, figure 3B).