Effects of radiotherapy on lymphocytes in patients with middle and lower esophageal cancer and its relationship with prognosis

Table 1 Clinical baseline characteristics of 112 patients with esophageal squamous cell carcinoma, n (%)

Characteristics	All patients, n = 112	G1-G3 ALC nadir, n = 80	G4 ALC nadir, n = 32	P value
Gender				0.041
Male	83 (74.1)	55 (68.8)	28 (87.5)
Female	29 (25.9)	25 (31.3)	4 (12.5)
Age, years				0.064
≤ 67	58 (51.8)	37 (46.3)	21 (65.6)
> 67	54 (48.2)	43 (53.8)	11 (34.4)
BMI				0.501
< 24 kg/m2	68 (60.7)	47 (58.8)	21 (65.6)
≥ 24	44 (39.3)	33 (41.3)	11 (34.4)
Tumor length (cm)				0.509
≤ 5	51 (45.5)	38 (47.5)	13 (40.6)
> 5	61 (54.5)	42 (52.5)	19 (59.4)
T stage				0.509
T1 + T2	51 (45.5)	38 (47.5)	12 (37.5)
T3 + T4	61 (54.5)	42 (52.5)	20 (62.5)
N stage				0.017
N0	17 (15.2)	14 (17.5)	3 (9.4)
N1	67 (59.8)	52 (65.0)	15 (46.9)
N2	28 (25.0)	14 (17.5)	14 (43.8)
Clinical stage				0.003
I + II	73 (65.2)	59 (73.8)	14 (43.8)
III	39 (34.8)	21 (26.3)	18 (56.3)
RT dose				0.336
≤ 60 Gy	62 (55.4)	42 (52.5)	20 (62.5)
> 60 Gy	50 (44.6)	38 (47.5)	12 (37.5)
Treatment regimen				0.244
RT alone	41 (36.6)	33 (41.3)	8 (25.0)
Sequential CRT	27 (24.1)	17 (21.3)	10 (31.3)
Concurrent CRT	44 (39.3)	30 (37.5)	14 (43.8)
RT technique				0.321
ENI	41 (36.6)	27 (33.8)	14 (43.8)
IFI	71 (63.4)	53 (66.3)	18 (56.3)

ALC: Absolute lymphocyte count; BMI: Body mass index; RT: Radiotherapy; CRT: Chemoradiotherapy; ENI: Elective nodal irradiation; IFI: Involved-field irradiation.

Table 2 Univariate and multivariate regression analyses of factors affecting clinical outcomes

Characteristics	OS				PFS
	Univariate analysis		Multivariate analysis		Univariate analysis		Multivariate analysis
	m-OS (95%CI)	P value	HR (95%CI)	P value	m-PFS (95%CI)	P value	HR (95%CI)	P value
Gender		0.810				0.907
Male	23.2 (14.8-31.7)				18.2 (10.4-26.0)
Female	23.4 (20.0-26.8)				16.8 (11.9-21.7)
Age		0.947				0.764
≤ 67 years	23.2 (12.1-34.4)				13.4 (6.4-20.4)
> 67 years	23.1 (16.1-30.2)				18.6 (12.8-24.5)
BMI		0.649				0.742
< 24 kg/m2	23.1 (17.0-29.2)				15.8 (9.4-22.2)
≥ 24	23.2 (15.7-30.7)				17.3 (11.0-23.6)
Tumor length		0.002	1.88 (1.14-3.12)	0.014		0.012	1.08 (0.13-8.76)	0.942
≤ 5 cm	42.1 (27.3-56.8)				25.0 (1.0-49.1)
> 5 cm	17.0 (7.7-26.2)				11.9 (9.0-14.8)
T stage		0.002	1.88 (1.14-3.12)	0.014		0.012	1.62 (0.19-13.84)	0.66
T1-T2	42.1 (27.3-56.8)				25.0 (1.0-49.1)
T3-T4	17.0 (7.7-26.2)				11.9 (9.0-14.8)
N stage		0.000	0.55 (0.34-1.00)	0.051		0.000	0.38 (0.15-1.01)	0.053
N0	-				-
N1	24.4 (19.1-29.7)				17.3 (10.9-23.7)
N2	12.3 (10.4-14.3)				6.6 (4.6-8.7)
TNM stage		0.000	0.44 (0.19-1.03)	0.058		0.000	2.24 (1.35-3.71)	0.002
I + II	32.4 (18.7-46.0)				25.0 (1.2-48.9)
III	11.8 (7.5-16.0)				6.6 (5.6-7.6)
RT dose		0.110				0.540
≤ 60 Gy	22.8 (15.8-29.8)				13.4 (8.4-18.4)
> 60 Gy	29.3 (12.5-46.0)				18.6 (14.1-23.1)
Treatment regimen		0.042	1.59 (0.88-2.86)	0.093		0.033	1.83 (0.19-1.03)	0.058
RT alone	22.4 (17.5-27.3)				14.2 (7.3-21.0)
Sequential CRT	14.0 (9.7-18.2)				9.9 (0.8-19.0)
Concurrent CRT	38.4 (16.5-60.4)				-
RT technique		0.028	0.77 (0.44-1.36)	0.364		0.001	2.34 (1.32-4.14)	0.004
ENI	42.1 (25.1-59.0)				-
IFI	22.4 (16.5-28.3)				12.7 (9.7-15.7)
ALC nadir		0.013	1.98 (1.20-3.28)	0.008		0.006	1.87 (1.09-3.20)	0.023
G1-G3	26.3 (19.8-32.7)				20.2 (13.3-27.0)
G4	11.5 (6.5-16.6)				6.8 (5.5-8.1)
ALC nadir time		0.041	1.23 (0.73-2.06)	0.443		0.360
1-4 week	16.7 (6.8-26.5)				14.2 (6.8-21.5)
5-6 week	29.9 (14.5-45.2)				17.3 (8.3-26.3)

m-OS: Median overall survival; m-PFS: Median progression-free survival; BMI: Body mass index; RT: Radiotherapy; CRT: Chemoradiotherapy; ALC: Absolute lymphocyte count; ENI: Elective nodal irradiation; IFI: Involved-field irradiation; PFS: Progression-free survival; OS: Overall survival.

Table 3 Univariate and multivariate analyses of variables associated with grade 4 lymphocytopenia

Characteristics	Univariate		Multivariate
	OR	P value	OR	P value
Gender (male vs female)	3.182	0.048	4.928	0.045
Age (≤ 67 years vs > 67 years)	0.451	0.067
BMI (< 24 vs ≥ 24 kg/m2)	0.746	0.502
Tumor length (≤ 5 cm vs > 5 cm)	1.322	0.510
T stage (1+2 vs 3+4)	1.322	0.510
N stage (0 vs 1 vs 2)	2.549	0.011	0.683	0.176
TNM stage (I+II vs III)	3.612	0.003	6.754	0.003
Treatment regimen RT alone vs SCRT vs CCRT	1.351	0.219
RT technique ENI vs IFI	0.655	0.322
Dosimetric parameters of OARs
Heart V5 (≤ 93% vs > 93%)	3.458	0.006	0.518	0.228
Heart V10 (≤ 86% vs > 86%)	3.833	0.003	12.808	0.046
Aorta V5 (≤ 85% vs > 85%)	2.829	0.019	1.054	0.955
Aorta V30 (≤ 78% vs > 78%)	2.374	0.044	1.288	0.713
Thoracic vertebrae Dmean (≤ 32 Gy vs > 32 Gy)	4.259	0.001	0.470	0.339
Thoracic vertebrae V5 (≤ 69% vs > 69%)	3.300	0.007	0.803	0.822
Thoracic vertebrae V10 (≤ 67% vs > 67%)	3.133	0.010	1.938	0.462
Lung Dmean (≤ 13 Gy vs >13 Gy)	2.719	0.022	0.873	0.092
Lung V5 (≤ 58% vs > 58%)	3.300	0.007	5.324	0.048
Lung V10 (≤ 42% vs > 42%)	3.640	0.004	0.646	0.187
Lung V20 (≤ 25% vs > 25%)	2.864	0.016	7.631	0.031

BMI: Body mass index; RT: Radiotherapy; SCRT: Sequential chemoradiotherapy; CCRT: Concurrent chemoradiotherapy; ENI: Elective nodal irradiation; IFI: Involved-field irradiation; OARs: Organs at risk.

Table 4 Univariate and multivariate analyses of subgroups associated with grade 4 lymphocytopenia

Characteristics	RT alone		Sequential CRT		Concurrent CRT
	Univariate P	Multivariate P	Univariate P	Multivariate P	Univariate P	Multivariate P
Gender (male vs female)	0.952		0.097		0.092
Age (≤ 67 years vs > 67 years)	0.816		0.590		0.226
BMI (< 24 vs ≥ 24 kg/m2)	0.292		0.384		0.541
Tumor length (≤ 5 cm vs > 5 cm)	0.800		0.081		0.679
T stage (1+2 vs 3+4)	0.800		0.081		0.976
N stage (0 vs 1 vs 2)	0.358		0.146		0.355
TNM stage (I+II vs III)	0.099		0.212		0.050
RT technique ENI vs IFI	0.964		0.656		0.533
Dosimetric parameters of OARs
Heart V5 (≤ 93% vs > 93%)	0.037	0.051	0.013	0.039	0.015	0.048
Heart V10 (≤ 86% vs > 86%)	0.058	0.037	0.001	0.509	0.026	0.033
Aorta V5 (≤ 85% vs > 85%)	0.817		0.160		0.032	0.926
Aorta V30 (≤ 78% vs > 78%)	0.380		0.384		0.195
Thoracic vertebrae Dmean (≤ 32 Gy vs > 32 Gy)	0.129		0.093		0.032	0.612
Thoracic vertebrae V5 (≤ 69% vs > 69%)	0.380		0.401		0.018	0.485
Thoracic vertebrae V10 (≤ 67% vs > 67%)	0.380		0.401		0.018	0.895
Lung Dmean (≤ 13 Gy vs > 13 Gy)	0.022	0.483	0.160		0.276
Lung V5 (≤ 58% vs > 58%)	0.019	0.039	0. 016	0.045	0.013	0.043
Lung V10 (≤ 42% vs > 42%)	0.012	0.053	0.026	0.084	0.016	0.135
Lung V20 (≤ 25% vs > 25%)	0.029	0.064	0.039	0.054	0.033	0.012

BMI: Body mass index; RT: Radiotherapy; CRT: Chemoradiotherapy; ENI: Elective nodal irradiation; IFI: Involved-field irradiation; OAR: Organs at risk.

Table 5 Comparison of different grades of lymphocytopenia with different CoTNM-Heart V₁₀, CoTNM-Lung V₅, and CoTNM- Lung V₂₀ score values

	No.	G1-G3 80 (%)	G4 32 (%)	χ2	P value
CoTNM-heartV10				16.697	0.000
0 score	40	37 (46.3)	3 (9.4)
1 score	50	33 (41.3)	17 (53.1)
2 score	22	10 (12.5)	12 (27.5)
CoTNM-lungV5				10.997	0.004
0 score	40	35 (43.8)	5 (15.6)
1 score	33	24 (30.0)	9 (28.1)
2 score	39	21 (26.3)	18 (56.3)
CoTNM-lungV20				16.923	0.000
0 score	42	35 (43.8)	7 (21.9)
1 score	48	37 (46.3)	11 (34.4)
2 score	22	8 (10.0)	14 (43.8)

Table 6 Effect of CoTNM-heart V₁₀, CoTNM-Lung V₅, and CoTNM-lung V₂₀ on overall survival and progression-free survival

Characteristics	N	Median OS	OS (%)			χ2	P value	Median PFS	PFS (%)			χ2	P value
			1 year	2 years	3 years				1 year	2 years	3 years
CoTNM- heartV10						5.446	0.066					5.418	0.067
0 score	40	26.3	87.5	52.5	44.4			20.2	70.0	46.6	43.7
1 score	50	24.8	68.0	54.0	42.5			17.3	61.7	40.5	37.8
2 score	22	11.8	50.0	31.8	26.5			6.6	36.4	31.2	20.8
CoTNM-lungV5						17.499	0.000					17.440	0.000
0 score	40	-	82.5	62.5	54.6			20.2	75.0	48.5	45.9
1 score	33	29.9	84.8	57.6	44.9			-	72.5	53.2	49.1
2 score	39	11.8	48.7	28.2	21.2			6.6	33.3	22.2	15.2
CoTNM-lungV20						14.068	0.001					11.122	0.004
0 score	42	28.5	85.7	57.1	49.0			17.6	69.0	47.6	45.0
1 score	48	24.4	72.9	52.1	40.8			20.2	64.3	43.9	39.1
2 score	22	7.7	40.9	27.3	21.8			5.8	31.8	21.2	14.1

OS: Overall survival; PFS: Progression-free survival.