A Nomogram to Identify the Optimal Candidates for Induction Chemotherapy in Advanced N-Stage Nasopharyngeal Carcinoma

Figures & data

Table 1 Baseline Characteristics of Patients Before and After Matching

Characteristics	Before Matching			After Matching
	CCRT (n = 216)	IC+CCRT (n = 408)	p-value	CCRT (n = 178)	IC+CCRT (n = 178)	p-value
Age (years)			0.002			0.745
≤ 50	124 (57.4)	286 (70.1)		105 (59.0)	109 (61.2)
> 50	92 (42.6)	122 (29.9)		73 (41.0)	69 (38.8)
Sex			1.000			0.722
Female	58 (26.9)	109 (26.7)		47 (26.4)	51 (28.7)
Male	158 (73.1)	299 (73.3)		131 (73.6)	127 (71.3)
Pathological type			0.010			0.728
WHO type I/II	29 (13.4)	28 (6.9)		20 (11.2)	17 (9.6)
WHO type III	187 (86.6)	380 (93.1)		158 (88.8)	161 (90.4)
T stage			< 0.001			0.612
T2	94 (43.5)	148 (36.3)		73 (41.0)	68 (38.2)
T3	93 (43.1)	146 (35.8)		77 (43.3)	75 (42.1)
T4	29 (13.4)	114 (27.9)		28 (15.7)	35 (19.7)
N stage			< 0.001			0.708
N2	172 (79.6)	222 (54.4)		134 (75.3)	138 (77.5)
N3	44 (20.4)	186 (45.6)		44 (24.7)	40 (22.5)
Clinical stage			< 0.001			1.000
III	150 (69.4)	145 (35.5)		113 (63.5)	113 (63.5)
IVA	66 (30.6)	263 (64.5)		65 (36.5)	65 (36.5)
BMI (Kg/m^2)			0.680			1.000
< 18.5	22 (10.2)	36 (8.8)		17 (9.6)	18 (10.1)
≥ 18.5	194 (89.8)	372 (91.2)		161 (90.4)	160 (89.9)
Smoke			0.433			0.560
Yes	62 (28.7)	158 (38.7)		55 (30.9)	49 (27.5)
No	154 (71.3)	250 (61.3)		123 (69.1)	129 (72.5)
EBV DNA (copies/mL)			0.426			1.000
≤ 6000	151 (69.9)	271 (66.4)		121 (68.0)	121 (68.0)
> 6000	65 (30.1)	137 (33.6)		57 (32.0)	57 (32.0)
NLR			0.012			1.000
≤ 2.60	151 (69.9)	242 (59.3)		118 (66.3)	117 (65.7)
> 2.60	65 (30.1)	166 (40.7)		60 (33.7)	61 (34.3)
PLR			0.407			0.915
≤ 152.5	10 (55.6)	211 (51.7)		100 (55.6)	98 (55.1)
> 152.5	96 (44.4)	197 (48.3)		78 (44.4)	80 (44.9)
LMR			0.038			0.832
≤ 3.80	99 (45.8)	224 (54.9)		84 (47.2)	87 (48.9)
> 3.80	117 (54.2)	184 (45.1)		94 (52.8)	91 (51.1)
ALB (g/L)			0.246			0.429
≤ 38.5	65 (30.1)	143 (35.0)		54 (30.3)	62 (34.8)
> 38.5	151 (69.9)	265 (65.0)		124 (69.7)	116 (65.2)
ALP (U/L)			< 0.001			1.000
≤ 51	46 (21.3)	43 (10.5)		29 (16.3)	29 (16.3)
> 51	170 (78.7)	365 (89.5)		149 (83.7)	149 (83.7)
LDH (U/L)			0.068			0.911
≤ 195	145 (67.1)	242 (59.3)		117 (65.7)	115 (64.6)
> 195	71 (32.9)	166 (40.7)		61 (34.3)	63 (35.4)
PT_ necrosis
No	205 (94.9)	376 (92.2)	0.261	168 (94.4)	164 (92.1)	0.526
Yes	11 (5.1)	32 (7.8)		10 (5.6)	14 (7.9)
RLN_laterality			0.995			0.846
None	60 (27.8)	112 (27.5)		50 (28.1)	54 (30.3)
Unilateral	91 (42.1)	172 (42.2)		76 (42.7)	71 (39.9)
Bilateral	65 (30.1)	124 (30.4)		52 (29.2)	53 (29.8)
RLN_ necrosis			0.179			0.370
No	177 (81.9)	314 (77.0)		143 (80.3)	135 (75.8)
Yes	39 (18.1)	94 (23.0)		35 (19.7)	43 (24.2)
CLN_ necrosis			0.016			0.492
No	154 (31.3)	250 (61.3)		126 (70.8)	119 (66.9)
Yes	62 (28.7)	158 (38.7)		52 (29.2)	59 (33.1)
CLN_ ENE			0.196			0.303
No	47 (21.8)	70 (17.2)		34 (19.1)	43 (24.2)
Yes	169 (78.2)	338 (82.8)		144 (80.9)	135 (75.8)
NG			< 0.001			0.133
No	180 (83.3)	257 (63.0)		143 (80.3)	178 (63.0)
Yes	36 (16.7)	151 (37.0)		35 (19.7)	48 (27.0)

Notes: Data are shown as numbers (percentage). P-values were calculated by the Chi-square test or Fisher’s exact test.

Abbreviations: IC, induction chemotherapy; CCRT, concurrent chemoradiotherapy; WHO, World Health Organization; EBV DNA, Epstein–Barr virus DNA; NLR, neutrophil to lymphocyte ratio; PLR, platelet to lymphocyte ratio; LMR, lymphocyte to monocyte ratio; ALB, albumin; ALP, alkaline phosphatase; LDH, lactate dehydrogenase; PT, primary tumor; RLN, retropharyngeal lymph node; CLN, cervical lymph node; ENE, extranodal extension; NG, nodal grouping.

Figure 1 Kaplan-Meier survival curves of OS (A), LRRFS (B), DMFS (C), and DFS (D) of patients between IC+CCRT and CCRT alone in the matched data set.

Abbreviations: IC, induction chemotherapy; CCRT, concurrent chemoradiotherapy; OS, overall survival; LRRFS, locoregional relapse-free survival; DMFS, distant metastasis-free survival; DFS, disease-free survival.

Table 2 Identification of Risk Factors of OS by Univariate and Multivariate Cox Models

Characteristics	Univariate Cox Regression	p-value	Multivariate Cox Regression	p-value
	HR (95% CI)		HR (95% CI)
Gender (Male vs Female)	1.128 (0.761–1.673)	0.548
Age (> 50 vs ≤ 50)	1.744 (1.241–2.453)	0.001	1.938 (1.371–2.738)	< 0.001
Pathological type (WHO III vs WHO I/II)	1.247 (0.673–2.313)	0.483
T stage (T3/4 vs T2)	1.440 (1.001–2.071)	0.049	1.385 (0.960–2.000)	0.082
N stage (N3 vs N2)	1.931 (1.374–2.715)	< 0.001	1.876 (1.328–2.652)	< 0.001
Clinical stage (IVA vs III)	2.461 (1.693–3.576)	< 0.001
BMI (≥ 18.5 vs < 18.5)	0.739 (0.438–1.247)	0.257
Smoke (Yes vs No)	1.237 (0.867–1.765)	0.242
EBV DNA (> 6000 vs ≤ 6000)	1.944 (1.381–2.737)	< 0.001	1.797 (1.271–2.541)	0.001
ALB (> 38.5 vs ≤ 38.5)	0.595 (0.420–0.843)	0.012	0.804 (0.561–1.153)	0.235
NLR (>2.60 vs ≤2.60)	1.522 (1.081–2.143)	0.016	0.949 (0.615–1.465)	0.814
PLR (> 152.5 vs ≤152.5)	1.636 (1.159–2.309)	0.005	1.303 (0.900–1.887)	0.160
LMR (> 3.80 vs ≤ 3.80)	0.530 (0.372–0.755)	< 0.001	0.523 (0.365–0.749)	< 0.001
ALP (> 51 vs ≤ 51)	1.411 (0.836–2.382)	0.197
LDH (> 195 vs ≤ 195)	1.596 (1.087–2.344)	0.017	1.282 (0.901–1.824)	0.167
PT_ necrosis (Yes vs No)	1.161 (0.626–2.152)	0.635
RLN_laterality (Unilateral vs None)	0.826 (0.551–1.238)	0.353
RLN_laterality (Bilateral vs None)	0.830 (0.535–1.288)	0.406
RLN_ necrosis (Yes vs No)	1.858 (1.292–2.672)	0.001	1.484 (1.001–2.201)	0.049
CLN_ necrosis (Yes vs No)	1.777 (1.264–2.497)	0.001	1.452 (1.004–2.098)	0.047
CLN_ ENE (Yes vs No)	1.630 (0.992–2.697)	0.054	1.118 (0.650–1.923)	0.687
NG (Yes vs No)	1.687 (1.193–2.385)	0.003	1.179 (0.804–1.730)	0.399

Abbreviations: IC, induction chemotherapy; CCRT, concurrent chemoradiotherapy; WHO, World Health Organization; EBV DNA, Epstein–Barr virus DNA; NLR, neutrophil to lymphocyte ratio; PLR, platelet to lymphocyte ratio; LMR, lymphocyte to monocyte ratio; ALB, albumin; ALP, alkaline phosphatase; LDH, lactate dehydrogenase; PT, primary tumor; RLN, retropharyngeal lymph node; CLN, cervical lymph node; ENE, extranodal extension; NG, nodal grouping.

Figure 2 (A) Nomogram for predicting OS; Calibration curves of the nomogram in the training (B) and validation (C) cohorts.

Abbreviations: OS, overall survival; EBV DNA, Epstein–Barr virus DNA; LMR, lymphocyte to monocyte ratio; RLN, retropharyngeal lymph node; CLN, cervical lymph node.

Figure 3 Time-dependent receiver operating characteristic (tdROC) curves of 3- and 5-year OS for respective comparison of the nomogram with the 8th TNM staging system in the training (A and C) and validation cohort (B and D).

Abbreviation: OS, overall survival.

Figure 4 Kaplan-Meier survival curves of OS (A), LRRFS (B), DMFS (C), and DFS (D) of patients between IC+CCRT and CCRT alone in the nomogram-defined high-risk group after matching.

Abbreviations: IC, induction chemotherapy; CCRT, concurrent chemoradiotherapy.

Table 3 Acute Adverse Events of Patients in the CCRT and IC+CCRT Groups

Adverse Event	CCRT	IC+CCRT	p-value
	(n = 178)	(n = 178)
Leucopenia
All	147 (82.6)	171 (96.1)	< 0.001
Grade 3–4	41 (23.0)	68 (38.2)	0.002
Neutropenia
All	109 (61.2)	150 (84.3)	< 0.001
Grade 3–4	24 (13.5)	59 (33.1)	< 0.001
Anemia
All	96 (53.9)	130 (73.0)	< 0.001
Grade 3–4	1 (0.6)	4 (2.2)	0.371
Thrombocytopenia
All	33 (18.5)	64 (36.0)	< 0.001
Grade 3–4	6 (3.4)	11 (6.2)	0.214
ALT increase
All	61 (34.3)	84 (47.2)	0.013
Grade 3–4	0 (0)	5 (2.8)	0.061
AST increase
All	49 (27.5)	71 (39.9)	0.018
Grade 3–4	0 (0)	3 (1.7)	0.248
Bilirubin increase
All	19 (10.7)	47 (26.4)	< 0.001
Grade 3–4	0 (0)	1 (0.6)	1.000
Gastrointestinal reaction
All	92 (51.7)	150 (84.3)	< 0.001
Grade 3–4	4 (2.2)	13 (7.3)	0.044

Notes: All data are presented as number of patients (%). P-values were calculated by the Chi-square test or Fisher’s exact test.

Abbreviations: ALT, alanine aminotransferase; AST, aspartate transaminase.