Baseline characteristics
A total of 272 patients meeting the inclusion criteria were included in the study (Table 1). Of the entire cohort, the median age was 43 years old (range, 15–78 years old). The distribution of patients between IMRT alone group and CCRT group was well balanced except for gender (P = 0.020). Of the 272 patients, 190 patients received additional CCT. 132/190 (69.5%) patients received cisplatin alone regimen, 32/190 (16.8%) patients received PF regimen, and 26/190 (13.7%) patients received taxol alone regimen.
Table 1
Baseline characteristics of patients with stage III NPC (N = 272)
Variables
|
IMRT alone (N = 82)
|
CCRT (N = 190)
|
P
|
Sex
|
|
|
0.020
|
Male
|
72 (87.8%)
|
143 (75.3%)
|
|
Female
|
10 (12.2%)
|
47 (24.7%)
|
|
Age (year)
|
|
|
0.303
|
≤43
|
38 (46.3%)
|
101 (53.2%)
|
|
>43
|
44 (53.7%)
|
89 (46.8%)
|
|
Smoking
|
|
|
0.070
|
Yes
|
43 (52.4%)
|
113 (59.5%)
|
|
No
|
39 (47.6%)
|
77 (40.5%)
|
|
Alcohol
|
|
|
0.368
|
Yes
|
19 (23.2%)
|
155 (81.6%)
|
|
No
|
63 (76.8%)
|
35 (18.4%)
|
|
T classification
|
|
|
0.146
|
T1-2
|
12 (26.8%)
|
36 (18.9%)
|
|
T3
|
60 (73.2%)
|
154 (81.1%)
|
|
N classification
|
|
|
0.970
|
N0-1
|
49 (59.8%)
|
114 (60.0%)
|
|
N2
|
33 (40.2%)
|
76 (40.0%)
|
|
EBV DNA
|
|
|
0.398
|
<2000
|
25 (30.5%)
|
68 (35.8%)
|
|
≥2000
|
57 (69.5%)
|
122 (64.2%)
|
|
Abbreviations: NPC, nasopharyngeal carcinoma; IMRT, intensity-modulated radiation therapy; CCRT, concurrent chemoradiotherapy; EBV, Epstein–Barr virus.
Prognostic factors
In univariate and multivariate analyses (Tables 2 and 3), the results demonstrated that the N classification was significantly associated with DFS (hazard ratio [HR] 1.722, 95% confidence interval [CI] 1.115–2.657, P = 0.014). Besides, CCT was significantly associated with DFS (HR 1.661, 95% CI 1.064–2.594, P = 0.026) and OS (HR 1.876, 95% CI 1.141–3.083, P = 0.013). In addition, age (HR 1.946, 95% CI 1.161–3.264, P = 0.012) and smoking (HR 0.578, 95% CI 0.336–0.996, P = 0.048) were independent prognostic factors in OS.
Table 2
Univariate analysis of prognostic factors for 272 patients with stage III NPC.
Variables
|
LRFS
|
DMFS
|
DFS
|
OS
|
HR (95% CI)
|
P
|
HR (95% CI)
|
P
|
HR (95% CI)
|
P
|
HR (95% CI)
|
P
|
Sex (male vs. female)
|
0.978 (0.400-2.392)
|
0.961
|
0.922 (0.462–1.840)
|
0.818
|
0.874 (0.499–1.530)
|
0.637
|
0.779 (0.407–1.491)
|
0.451
|
Age (≤ 43 vs. >43, year)
|
1.254 (0.612–2.570)
|
0.537
|
1.224 (0.706–2.122)
|
0.471
|
1.450 (0.936–2.247)
|
0.096
|
2.087 (1.252–3.480)
|
0.005
|
Smoking (yes vs. no)
|
0.662 (0.323–1.357)
|
0.260
|
0.618 (0.356–1.073)
|
0.087
|
0.617 (0.399–0.953)
|
0.030
|
0.472 (0.286–0.781)
|
0.003
|
Alcohol (yes vs. no)
|
0.749 (0.321–1.746)
|
0.503
|
0.748 (0.392–1.430)
|
0.380
|
0.707 (0.427–1.170)
|
0.177
|
0.594 (0.341–1.035)
|
0.066
|
T classification (T1-2 vs. T3)
|
1.486 (0.371–2.014)
|
0.735
|
1.580 (0.445–1.623)
|
0.622
|
1.268 (0.520–1.451)
|
0.590
|
1.069 (0.581–1.966)
|
0.830
|
N classification (N0-1 vs. N2)
|
1.890 (0.923–3.873)
|
0.082
|
1.672 (0.965–2.895)
|
0.067
|
1.670 (1.083–2.575)
|
0.020
|
1.506 (0.922–2.459)
|
0.102
|
CCT (yes vs. no)
|
1.721 (0.828–3.575)
|
0.146
|
1.485 (0.842–2.620)
|
0.172
|
1.721 (1.106–2.678)
|
0.016
|
1.976 (1.205–3.239)
|
0.007
|
EBV DNA (< 2000 vs. ≥2000)
|
1.747 (0.750–4.071)
|
0.196
|
1.398 (0.756–2.585)
|
0.286
|
1.084 (0.684–1.718)
|
0.732
|
1.081 (0.649–1.802)
|
0.764
|
Abbreviations: NPC, nasopharyngeal carcinoma; HR, hazard ratio; CI, confidence interval; LRFS, locoregional-free survival; DMFS, distant metastasis-free survival; DFS, disease-free survival; OS, overall survival; CCT, concurrent chemotherapy; EBV, Epstein–Barr virus.
Table 3 Multivariate analysis of prognostic factors for 272 patients with stage III NPC.
Variables
|
LRFS
|
DMFS
|
DFS
|
OS
|
HR (95% CI)
|
P
|
HR (95% CI)
|
P
|
HR (95% CI)
|
P
|
HR (95% CI)
|
P
|
Age (≤43 vs. >43, year)
|
-
|
-
|
-
|
-
|
1.378 (0.884-2.148)
|
0.157
|
1.946 (1.161-3.264)
|
0.012
|
Smoking (yes vs. no)
|
-
|
-
|
-
|
-
|
0.728 (0.452-1.172)
|
0.192
|
0.578 (0.336-0.996)
|
0.048
|
Alcohol (yes vs. no)
|
-
|
-
|
0.643 (0.369-1.121)
|
0.120
|
0.872 (0.506-1.502)
|
0.621
|
0.839 (0.462-1.522)
|
0.563
|
N classification (N0-1 vs. N2)
|
1.910 (0.930-3.920)
|
0.078
|
1.683 (0.972-2.916)
|
0.063
|
1.722 (1.115-2.657)
|
0.014
|
1.629 (0.996-2.665)
|
0.052
|
CCT (yes vs. no)
|
1.737 (0.834-3.617)
|
0.140
|
1.431 (0.808-2.535)
|
0.219
|
1.661 (1.064-2.594)
|
0.026
|
1.876 (1.141-3.083)
|
0.013
|
EBV DNA (<2000 vs. ≥2000)
|
1.664 (0.713-3.883)
|
0.239
|
-
|
-
|
-
|
-
|
-
|
-
|
Abbreviations: NPC, nasopharyngeal carcinoma; HR, hazard ratio; CI, confidence interval; LRFS, locoregional-free survival; DMFS, distant metastasis-free survival; DFS, disease-free survival; OS, overall survival; CCT, concurrent chemotherapy; EBV, Epstein–Barr virus.
Survival outcome
The median follow-up time was 108 months (range, 7-180 months). By the last follow-up, 72 patients had treatment failures, including 20 with locoregional relapse alone (15 with local relapse, 3 with regional relapse, 2 with locoregional relapse), 42 with distant metastasis alone, and 10 with both locoregional relapse and distant metastasis. Moreover, 67 patients had died at the time of the last follow-up. Specifically, 44 died of distant metastasis alone, 7 died of locoregional relapse alone, 3 died of nasopharyngeal hemorrhage, and 13 died of other reasons (ie. accidents). Of the entire cohort, the 10-year LRFS, DMFS, DFS, and OS were 87.8%, 80.7%, 68.8%, and 74.9%, respectively. Significant differences were observed between individuals treated with IMRT alone and CCRT in 10-year OS (63.8% vs. 80.1%, P = 0.006) and DFS (58.6% vs. 73.6%, P = 0.014), while no significant differences were observed in 10-year LRFS (83.3% vs. 89.6%, P = 0.140) and DMFS (75.7% vs. 82.8%, P = 0.169) (Fig. 1).
We also evaluated survival outcomes in the low-risk group (stage T3N0-1, n = 163) and the high-risk group (stage T1-3N2, n = 109) when treated with IMRT alone or CCRT. In the low-risk group, the baseline characteristics were well balanced between IMRT alone group and CCRT group except for sex (P = 0.037) (supplementary table). No significant survival differences were observed between patients who received IMRT alone (n = 49) and CCRT (n = 114), including LRFS, DMFS, DFS and OS (P > 0.05) (Fig. 2). In the high-risk group, the baseline characteristics were well balanced between IMRT alone group and CCRT group except for alcohol consumption (P = 0.040) (supplementary table). Significant survival differences were observed between patients who received IMRT alone (n = 33) and CCRT (n = 76), including LRFS (65.4% vs. 89.6%, P = 0.005), DFS (39.4% vs. 71.9%, P = 0.001) and OS (50.5% vs. 80.0%, P = 0.002). Interestingly, no significant difference was observed in DMFS (65.4% vs. 80.0%, P = 0.091) between patients who received IMRT alone and CCRT in high-risk group (Fig. 3).
Toxicity
The incidences of grade 3–4 acute adverse events (AEs) in 272 patients were listed in Table 4. Patients treated with CCRT experienced more hematological AEs, including leukopenia (11.6% vs. 1.2%, P = 0.005), neutropenia (7.4% vs. 0.0%, P = 0.012), and thrombocytopenia (4.8% vs. 0.0%, P = 0.045), than those treated with IMRT alone except for anemia (2.1% vs. 0.0%, P = 0.186). Moreover, higher incidence of mucositis was observed in CCRT group compared with IMRT alone group (50.5% vs. 19.5%, P < 0.001), while no statistical differences were observed regarding xerostomia, dermatitis, nausea/ vomiting, and hepatoxicity between the two groups (P > 0.05).
Table 4
Grade 3–4 acute adverse events in 272 patients with stage III NPC.
Variables
|
IMRT (N = 82)
|
CCRT (N = 190)
|
P
|
Hematological
|
|
|
|
Leukopenia
|
1 (1.2%)
|
22 (11.6%)
|
0.005
|
Neutropenia
|
0 (0.0%)
|
14 (7.4%)
|
0.012
|
Anemia
|
0 (0.0%)
|
4 (2.1%)
|
0.186
|
Thrombocytopenia
|
0 (0.0%)
|
9 (4.8%)
|
0.045
|
Non-hematological
|
|
|
|
Mucositis
|
16 (19.5%)
|
96 (50.5%)
|
< 0.001
|
Xerostomia
|
0 (0.0%)
|
4 (2.1%)
|
0.186
|
Dermatitis
|
3 (3.7)
|
6 (3.2%)
|
0.833
|
Nausea/ vomiting
|
0 (0.0%)
|
5 (2.6%)
|
0.139
|
Hepatoxicity
|
1 (1.2%)
|
0 (0.0%)
|
0.128
|
Abbreviations: NPC, nasopharyngeal carcinoma; IMRT, intensity-modulated radiation therapy; CCRT, concurrent chemoradiotherapy.