Optimal Courses of Chemotherapy Combined with Radiotherapy for Low-Risk Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type: A Propensity Score Matching Analysis

Figures & data

Table 1 Chemotherapy Regimens

Regimen	Drugs	Dosage
GELOX/P-GEMOX	Gemcitabine	800 mg/m2, d1 and d8
	Oxaliplatin	85 mg/m2, d1
	L-asparaginase/pegaspargase	5000 U/m2, d1-7/2500 IU/m2, d1
SMILE	Dexamethasone	15mg, d1-7
	Methotrexate	60mg/m2, d1
	Ifosfamide	1.5g/m2, d2–4
	L-asparaginase/pegaspargase	5000 U/m2, d1-7/2500 IU/m2, d1
	Etoposide	100mg/m2, d2-4
VLP	Vincristine	2mg, d1
	L-asparaginase/pegaspargase	5000 U/m2, d1-7/2500 IU/m2, d1
	Prednisone	100mg/d, d1-5

Table 2 Patient Characteristics Before and After Propensity Score Matching

Characteristics	Before Propensity Score Matching				After Propensity Score Matching
	≤4-Cycle Group (%)	≥5-Cycle Group (%)	p	N (%)	≤4-Cycle Group (%)	≥5-Cycle Group (%)	p	N (%)
Age (years)	41.0 ± 10.4	36.2 ± 11.6	0.001		36.9 ± 10.2	36.8 ± 11.4	0.976
Radiation dose (Gy)	54.8 ± 2.8	54.8 ± 2.9	0.928		54.6 ± 2.9	55.0 ± 3.0	0.435
Sex			0.347				1.000
Male	108 (65.1)	61 (70.9)		169 (67.1)	49 (68.1)	49 (68.1)		98 (68.1)
Female	58 (34.9)	25 (29.1)		83 (32.9)	23 (31.9)	23 (31.9)		46 (31.9)
ECOG			0.977				0.316
0–1	164 (98.8)	85 (98.8)		249 (98.8)	72 (100.0)	71 (98.6)		143 (99.3)
2–4	2 (1.2)	1 (1.2)		3 (1.2)	0 (0.0)	1 (1.4)		1 (0.7)
Primary tumor location			0.498				0.839
Nasal	128 (77.1)	63 (73.3)		191 (75.8)	56 (77.8)	57 (79.2)		113 (78.5)
Extranasal	38 (22.9)	23 (26.7)		61 (24.2)	16 (22.2)	15 (20.8)		31 (21.5)
Ann Arbor stage			0.031				0.732
IE	124 (74.7)	53 (61.6)		177 (70.2)	43 (59.7)	45 (62.5)		88 (61.1)
IIE	42 (25.3)	33 (38.4)		75 (29.8)	29 (40.3)	27 (37.5)		56 (38.9)
LDH			0.031				0.543
Elevated	32 (19.3)	27 (31.4)		59 (23.4)	14 (19.4)	17 (23.6)		31 (21.5)
Normal	134 (80.7)	59 (68.8)		193 (76.6)	58 (80.6)	55 (76.4)		113 (78.5)
B symptoms			0.050				1.000
Present	58 (34.9)	41 (47.7)		99 (39.3)	31 (43.1)	31 (43.1)		62 (43.1)
Absent	108 (65.1)	45 (52.3)		153 (60.7)	41 (56.9)	41 (56.9)		82 (56.9)
PTI			0.300				1.000
Present	91 (54.8)	53 (61.6)		144 (57.1)	45 (62.5)	45 (62.5)		90 (62.5)
Absent	75 (45.2)	33 (38.4)		108 (42.9)	27 (37.5)	27 (37.5)		54 (37.5)
Chemotherapy regimen			0.112				0.469
GELOX/P-GEMOX	115 (69.3)	66 (76.7)		181 (71.8)	53 (73.6)	56 (77.8)		109 (75.7)
SMILE	15 (9.0)	12 (14.0)		27 (10.7)	6 (8.3)	8 (11.1)		14 (9.7)
VLP	36 (21.7)	8 (9.3)		44 (17.5)	13 (18.1)	8 (11.1)		21 (14.6)
Chemoradiotherapy pattern			<0.001				0.412
Sequential	92 (55.4)	13 (15.1)		105 (41.7)	17 (23.6)	13 (18.1)		30 (20.8)
Sandwich	74 (44.6)	73 (84.9)		147 (58.3)	55 (76.4)	59 (81.9)		114 (79.2)

Note: The bold meant p<0.05.

Table 3 Adverse Events Before and After Propensity Score Matching

Adverse Events	Before Propensity Score Matching						After Propensity Score Matching
	Grade 1–2			Grade 3–4			Grade 1–2			Grade 3–4
	≤4-cycle (%)	≥5-cycle (%)	p	≤4-cycle (%)	≥5-cycle (%)	p	≤4-cycle (%)	≥5-cycle (%)	p	≤4-cycle (%)	≥5-cycle (%)	p
Hematologic
Neutropenia	45 (34.9)	37 (48.1)	0.062	25 (19.4)	23 (29.9)	0.085	22 (41.5)	29 (45.3)	0.680	13 (24.5)	21 (32.8)	0.326
Anemia	43 (33.3)	47 (61.0)	<0.001	2 (1.6)	1 (1.3)	0.884	16 (30.2)	38 (59.4)	0.002	1 (1.9)	1 (1.6)	0.893
Thrombocytopenia	18 (14.0)	11 (14.3)	0.947	3 (3.8)	11 (8.5)	0.194	7 (13.2)	11 (17.2)	0.553	3 (4.6)	7 (13.2)	0.096
Non-hematologic
Nausea/Vomiting	40 (31.0)	34 (44.2)	0.057	11 (8.5)	3 (3.9)	0.201	20 (37.7)	27 (42.2)	0.625	5 (9.4)	3 (4.7)	0.311
Transaminase elevation	35 (27.1)	40 (51.9)	<0.001	4 (3.1)	1 (1.3)	0.416	13 (24.5)	33 (51.6)	0.003	1 (1.9)	1 (1.6)	0.893
Radio-mucositis	45 (34.9)	31 (41.6)	0.338	15 (11.6)	7 (9.1)	0.568	19 (35.8)	24 (37.5)	0.854	6 (11.3)	7 (10.9)	0.948
Radiodermatitis	27 (20.9)	21 (27.3)	0.298	4 (3.1)	0 (0.0)	0.119	12 (22.6)	16 (25.0)	0.766	1 (1.9)	0 (0.0)	0.270

Note: The bold meant p<0.05.

Figure 1 Kaplan-Meier survival curves in patients treated with ≤4 cycles and ≥5 cycles of chemotherapy before and after matching. (A) Before matching, the 3-year OS rates between the ≤4 cycles and ≥5 cycles groups were 82.5% and 87.2% (p = 0.500). (B) Before matching, the 3-year PFS rates between the ≤4 cycles and ≥5 cycles groups were 77.1% and 79.1% (p = 0.567). (C) After matching, the 3-year OS rates between the ≤4 cycles and ≥5 cycles groups were 81.9% and 88.9% (p = 0.309). (D) After matching, the 3-year PFS rates between the ≤4 cycles and ≥5 cycles groups were 76.4% and 80.6% (p = 0.449).

Table 4 Univariate and Multivariate Analyses for Factors Affecting Survival Outcomes Before and After Propensity Score Matching

Variable	Before Propensity Score Matching								After Propensity Score Matching
	Overall Survival				Progression-Free Survival				Overall Survival				Progression-Free Survival
	Univariate		Multivariate		Univariate		Multivariate		Univariate		Multivariate		Univariate		Multivariate
	HR (95% CI)	p	HR (95% CI)	p	HR (95% CI)	p	HR (95% CI)	p	HR (95% CI)	p	HR (95% CI)	p	HR (95% CI)	p	HR (95% CI)	p
Age (years)
<18	Reference				Reference				Reference				Reference
18–40	0.545 (0.074–4.020)	0.552			0.753 (0.181–3.134)	0.697			0.620 (0.081–4.774)	0.646			0.827 (0.190–3.598)	0.800
>40	0.960 (0.540–1.707)	0.891			0.871 (0.524–1.447)	0.593			0.844 (0.379–1.878)	0.677			0.783 (0.392–1.566)	0.489
Sex (male vs female)	0.546 (0.272–1.095)	0.088			0.580 (0.320–1.051)	0.072			0.411 (0.141–1.197)	0.103			0.445 (0.184–1.076)	0.072
ECOG (2–4 vs 0–1)	0.504 (0.070–3.660)	0.499			1.484 (0.777–2.832)	0.232			2.200 (0.756–6.405)	0.148			2.001 (0.818–4.898)	0.129
Primary tumor location (nasal vs extranasal)	1.915 (1.066–3.439)	0.030	1.811 (1.008–3.252)	0.047	2.047 (1.231–3.406)	0.006	1.953 (1.174–3.250)	0.010	1.779 (0.766–4.132)	0.180			2.234 (1.102–4.529)	0.026	2.223 (1.096–4.507)	0.027
Ann Arbor stage (IE vs IIE)	2.266 (1.278–4.018)	0.005	1.879 (1.053–3.352)	0.033	2.052 (1.241–3.395)	0.005	1.723 (1.037–2.860)	0.036	2.635 (1.191–5.828)	0.017	2.132 (0.959–4.738)	0.063	2.001 (1.019–3.930)	0.044	1.737 (0.881–3.427)	0.111
LDH (elevated vs normal)	1.055 (0.538–2.069)	0.876			1.109 (0.612–2.009)	0.733			1.326 (0.455–3.868)	0.605			1.272 (0.526–3.072)	0.593
B symptoms (present vs absent)	1.028 (0.576–1.834)	0.926			0.949 (0.575–1.568)	0.839			1.177 (0.529–2.622)	0.689			1.023 (0.520–2.014)	0.947
PTI (absent vs present)	2.928 (1.520–5.639)	0.001	2.628 (1.356–5.091)	0.004	2.841 (1.609–5.018)	<0.001	2.609 (1.472–4.624)	0.001	9.328 (2.192–39.698)	0.003	8.362 (1.953–35.808)	0.004	4.554 (1.758–11.796)	0.002	4.270 (1.644–11.089)	0.003
Radiation dose (<55Gy vs ≥55Gy)	0.960 (0.507–1.818)	0.901			1.043 (0.591–1.841)	0.884			1.981 (0.679–5.778)	0.211			2.247 (0.869–5.811)	0.095
Regimen
GELOX/P-GEMOX	Reference				Reference				Reference
SMILE	0.958 (0.425–2.159)	0.918			0.777 (0.401–1.507)	0.456			0.768 (0.261–2.259)	0.631			0.626 (0.257–1.528)	0.304
VLP	0.837 (0.265–2.646)	0.762			0.790 (0.305–2.044)	0.627			0.532 (0.097–2.910)	0.467			0.534 (0.133–2.138)	0.375
Chemoradiotherapy pattern (sequential vs sandwich)	1.030 (0.768–1.380)	0.844			1.007 (0.782–1.297)	0.956			0.917 (0.561–1.499)	0.729			0.932 (0.614–1.414)	0.740
Course (≤4 cycles vs ≥5 cycles)	0.815 (0.450–1.476)	0.500			0.859 (0.511–1.444)	0.567			0.666 (0.303–1.465)	0.312			0.771 (0.393–1.514)	0.451

Note: The bold meant p<0.05.

Figure 2 Subgroup analyses of low-risk stage IE and IIE patients about chemotherapy courses with OS and PFS after matching. (A) The 3-year OS rates between the ≤4 cycles and ≥5 cycles groups were 93.0% and 91.1% (p = 0.336) in stage IE. (B) The 3-year PFS rates between the ≤4 cycles and ≥5 cycles groups were 88.4% and 80.0% (p = 0.220) in stage IE. (C) The 3-year OS rates between the ≤4 cycles and ≥5 cycles groups were 65.5% and 85.2% (p = 0.024) in stage IIE. (D) The 3-year PFS rates between the ≤4 cycles and ≥5 cycles groups were 58.6% and 81.5% (p = 0.027) in stage IIE.

Table 5 Chemoradiotherapy for Stage IE-IIE Extranodal NK/T Cell Lymphoma, Nasal Type

	Study (Reference)	Study Type	N	Chemoradiotherapy Pattern	CR	PFS	OS
≤4 cycles	Xuejun Ma et al^Citation39	Phase II	38	2-4*CEOP + RT (50Gy)	94.4%	2-year 69.4%	2-year 77.4%
	Jieun Lee et al^Citation35	Retrospective	27	CCRT (4*cisplatin, 44–54 Gy) ± 1–4*chemotherapy (VIPD, L-EID, SMILE)	70.0%	3-year 41.0%	3-year 59.0%
	Seok Jin Kim et al^Citation40	Phase II	30	CCRT (4*cisplatin, 36–44 Gy) + 2*VIDL ± ASCT	86.7%	5-year 60.0%	5-year 73.0%
	Q-H Ke et al^Citation41	Phase II	32	CCRT (4*cisplatin, 56 Gy) + 3*GDP	84.4%	3-year 84.4%	3-year 87.5%
	Dongryul Oh et al^Citation42	Phase II +retrospective	62	CCRT (4*cisplatin, 40–45 Gy) + chemotherapy (3*VIPD, 2*VIDL, 2*MIDLE)	90.3%	3-year 77.1%, 5-year 69.9%	3-year 83.1%, 5-year 80.1%
	Jean-Marie Michot et al^Citation43	Retrospective	13	CCRT (2*ESHAP, 40 Gy) + 2–3*ESHAP	92.0%	—	2-year 72.0%
	Dok Hyun Yoon et al^Citation44	Phase II	28	CCRT (cisplatin + L-Asp, 36–44 Gy) + 2*MIDLE	82.1%	3-year 74.1%	3-year 81.5%
	Li-Hua Dong et al^Citation45	Retrospective	33	4*L-DICE + RT (45 Gy)	90.9%	5-year 82.9%	5-year 89.2%
	Ming Jiang et al^Citation46	Phase II	66	2*LVDP + CCRT (2*cisplatin, 56 Gy) + 2*LVDP	83.3%	3-year 67.4%	3-year 70.1%
	Fei Qi et al^Citation47	Phase II	40	RT + 4*GDP	95.0%	2-year 84.7%, 5-year 79.4%	2-year 89.9%, 5-year 82.1%
	Fei Qi et al^Citation48	Retrospective	45	RT + 4*GDP	93.3%	5-year 81.6%	5-year 83.9%
≥5 cycles	Keun-wook Lee et al^Citation49	Prospective	16	6*IMEP + RT	79.0%	—	3-year 80.4%
	Ningjing Lin et al^Citation50	Phase II	31	6–8*L-CHOP + sequential RT (40–60 Gy)	81.6%	2-year 81.0%	2-year 80.1%
	Agustin Avile´s et al^Citation51	Retrospective	202	RT (55 Gy) + 6*CMED	91.0%	5-year 91.0%	5-year 86.0%
	Hong-qiang Guo et al^Citation9	Retrospective	45	RT+ ≥4*GELOXD	55.6%	1-year 87.0%	1-year 98.0%
	Jian Zang et al^Citation36	Retrospective	64	8–12*L-CHOP/SMILE + RT (sequential or sandwich, 26–60 Gy)	64.1%	3-year 64.7%	3-year 69.9%
	Wen Zheng et al^Citation52	Prospective	21	6*L-CHOP+RT (sequential or sandwich)	90.5%	—	1-year 100.0%, 2-year 90.6%, 3-year 80.5%

Abbreviations: RT, radiotherapy; CCRT, concurrent radiotherapy; ASCT, autologous stem cell transplantation; CEOP, cyclophosphamide, epirubicin, vincristine, and prednisone; VIPD, etoposide, ifosfamide, cisplatin, and dexamethasone; L-EID, etoposide, ifosfamide, dexamethasone, and L-asparaginase; SMILE, dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide; VIDL, etoposide, ifosfamide, dexamethasone, and L-asparaginase; GDP, gemcitabine, dexamethasone, cisplatin; MIDLE, methotrexate, etoposide, ifosfamide, mesna and L-asparaginase; ESHAP, etoposide, steroid, high-dose Ara-C and platinum; L-DICE, dexamethasone, cisplatin, etoposide, ifosfamide, and L-asparaginase; LVDP, L-asparaginase, etoposide, cisplatin, and dexamethasone; IMEP, ifosfamide, methotrexate, etoposide and prednisolone; L-CHOP, L-asparaginase, cyclophosphamide, vincristine, doxorubicin and dexamethasone; CMED, cyclophosphamide, methotrexate, etoposide and dexamethasone; GELOXD, gemcitabine, oxaliplatin, L‑asparaginase and dexamethasone.

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