Timing matters: Early vs late recurrence in nasopharyngeal carcinoma and its impact on survival

Table 1 General characteristics of the entire, local, regional and locoregional recurrence group, n (%)

Variables	Total (n = 330)	Local (n = 167)	Regional (n = 86)	Locoregional (n = 77)	P value
Gender					0.615
Male	257 (77.88)	131 (78.44)	69 (80.23)	57 (74.03)
Female	73 (22.12)	36 (21.56)	17 (19.77)	20 (25.97)
Age					0.374
< 60	271 (82.12)	133 (79.64)	71 (82.56)	67 (87.01)
≥ 60	59 (17.88)	34 (20.36)	15 (17.44)	10 (12.99)
Smoking status					0.112
No	202 (61.21)	94 (56.29)	54 (62.79)	54 (70.13)
Yes	128 (38.79)	73 (43.71)	32 (37.21)	23 (29.87)
Drinking status					0.663
No	223 (67.58)	109 (65.27)	60 (69.77)	54 (70.13)
Yes	107 (32.42)	58 (34.73)	26 (30.23)	23 (29.87)
KPS status					0.783
60-70	11 (3.33)	7 (4.19)	2 (2.33)	2 (2.60)
80-90	319 (96.67)	160 (95.81)	84 (97.67)	75 (97.40)
Weight loss status					0.044
< 10%	308 (93.33)	154 (92.22)	85 (98.84)	69 (89.61)
≥ 10%	22 (6.67)	13 (7.78)	1 (1.16)	8 (10.39)
T					< 0.001
1 or 2	150 (45.45)	57 (34.13)	58 (67.44)	35 (45.45)
3 or 4	180 (54.55)	110 (65.87)	28 (32.56)	42 (54.55)
N					< 0.001
0 or 1	150 (45.45)	98 (58.68)	24 (27.91)	28 (36.36)
2 or 3	180 (54.55)	69 (41.32)	62 (72.09)	49 (63.64)
TNM					0.853
I-II	63 (19.09)	33 (19.76)	17 (19.77)	13 (16.88)
III-IV	267 (80.91)	134 (80.24)	69 (80.23)	64 (83.12)
Radiotherapy technique					0.863
Non-IMRT	196 (59.39)	101 (60.48)	49 (56.98)	46 (59.74)
IMRT	134 (40.61)	66 (39.52)	37 (43.02)	31 (40.26)
Time of treatment					0.632
1990-1999	113 (34.24)	57 (34.13)	25 (29.07)	31 (40.26)
2000-2009	126 (38.18)	65 (38.92)	36 (41.86)	25 (32.47)
2010-2020	91 (27.58)	45 (26.95)	25 (29.07)	21 (27.27)
Chemotherapy					0.149
No	206 (62.42)	112 (67.07)	47 (54.65)	47 (61.04)
Yes	124 (37.58)	55 (32.93)	39 (45.35)	30 (38.96)
Early or late recurrence					0.109
Early	156 (47.27)	74 (44.31)	49 (56.98)	33 (42.86)
Late	174 (52.73)	93 (55.69)	37 (43.02)	44 (57.14)
rT					< 0.001
0	86 (26.06)	0 (0.00)	86 (100.00)	0 (0.00)
1 or 2	119 (36.06)	74 (44.31)	0 (0.00)	45 (58.44)
3 or 4	125 (37.88)	93 (55.69)	0 (0.00)	32 (41.56)
rN					< 0.001
0	167 (50.61)	167 (100.00)	0 (0.00)	0 (0.00)
1 or 2	150 (45.45)	0 (0.00)	77 (89.53)	73 (94.81)
3	13 (3.94)	0 (0.00)	9 (10.47)	4 (5.19)
rTNM					< 0.001
I-II	158 (47.88)	74 (44.31)	57 (66.28)	27 (35.06)
III-IV	172 (52.12)	93 (55.69)	29 (33.72)	50 (64.94)
Post recurrence treatment					< 0.001
Chemotherapy	36 (10.91)	19 (11.38)	7 (8.14)	10 (12.99)
RT	150 (45.45)	90 (53.89)	19 (22.09)	41 (53.25)
Surgery	107 (32.42)	33 (19.76)	56 (65.12)	18 (23.38)
BST	37 (11.21)	25 (14.97)	4 (4.65)	8 (10.39)

IMRT: Intensity-modulated radiation therapy; BST: Best supportive treatment; KPS: Karnofsky Performance Status; rN: Recurrent N stage; rT: Recurrent T stage; rTNM: Recurrent TNM stage; RT: Radiotherapy.

Table 2 Comparison of general characteristics between early vs late recurrence in terms of the entire, local, regional and locoregional recurrence group, n (%)

Variables	Total (n = 330)			Local (n = 167)			Regional (n = 86)			Locoregional (n = 77)
	Early (n = 156)	Late (n = 174)	P value	ETR (n = 74)	LTR (n = 93)	P value	ENR (n = 49)	LNR (n = 37)	P value	ETNR (n = 33)	LTNR (n = 44)	P value
Gender			0.689			0.718			0.708			0.822
Male	123 (78.85)	134 (77.01)		59 (79.73)	72 (77.42)		40 (81.63)	29 (78.38)		24 (72.73)	33 (75.00)
Female	33 (21.15)	40 (22.99)		15 (20.27)	21 (22.58)		9 (18.37)	8 (21.62)		9 (27.27)	11 (25.00)
Age			0.975			0.424			0.754			0.129
< 60	128 (82.05)	143 (82.18)		61 (82.43)	72 (77.42)		41 (83.67)	30 (81.08)		26 (78.79)	41 (93.18)
≥ 60	28 (17.95)	31 (17.82)		13 (17.57)	21 (22.58)		8 (16.33)	7 (18.92)		7 (21.21)	3 (6.82)
Smoking status			0.090			0.144			0.729			0.281
No	88 (56.41)	114 (65.52)		37 (50.00)	57 (61.29)		30 (61.22)	24 (64.86)		21 (63.64)	33 (75.00)
Yes	68 (43.59)	60 (34.48)		37 (50.00)	36 (38.71)		19 (38.78)	13 (35.14)		12 (36.36)	11 (25.00)
Drinking status			0.922			0.922			0.300			0.350
No	105 (67.31)	118 (67.82)		48 (64.86)	61 (65.59)		32 (65.31)	28 (75.68)		25 (75.76)	29 (65.91)
Yes	51 (32.69)	56 (32.18)		26 (35.14)	32 (34.41)		17 (34.69)	9 (24.32)		8 (24.24)	15 (34.09)
KPS status			0.177			0.213			0.504			0.504
60-70	3 (1.92)	8 (4.60)		1 (1.35)	6 (6.45)		2 (4.08)	0 (0.00)		0 (0.00)	2 (4.55)
80-90	153 (98.08)	166 (95.40)		73 (98.65)	87 (93.55)		47 (95.92)	37 (100.00)		33 (100.00)	42 (95.45)
Weight loss status			0.250			0.471			1.000			0.419
< 10%	143 (91.67)	165 (94.83)		67 (90.54)	87 (93.55)		48 (97.96)	37 (100.00)		28 (84.85)	41 (93.18)
≥ 10%	13 (8.33)	9 (5.17)		7 (9.46)	6 (6.45)		1 (2.04)	0 (0.00)		5 (15.15)	3 (6.82)
T			0.008			0.002			0.627			0.064
1 or 2	59 (37.82)	91 (52.30)		16 (21.62)	41 (44.09)		32 (65.31)	26 (70.27)		11 (33.33)	24 (54.55)
3 or 4	97 (62.18)	83 (47.70)		58 (78.38)	52 (55.91)		17 (34.69)	11 (29.73)		22 (66.67)	20 (45.45)
N			0.028			0.162			0.416			0.338
0 or 1	61 (39.10)	89 (51.15)		39 (52.70)	59 (63.44)		12 (24.49)	12 (32.43)		10 (30.30)	18 (40.91)
2 or 3	95 (60.90)	85 (48.85)		35 (47.30)	34 (36.56)		37 (75.51)	25 (67.57)		23 (69.70)	26 (59.09)
TNM			0.002			0.003			0.708			0.114
I-II	19 (12.18)	44 (25.29)		7 (9.46)	26 (27.96)		9 (18.37)	8 (21.62)		3 (9.09)	10 (22.73)
III-IV	137 (87.82)	130 (74.71)		67 (90.54)	67 (72.04)		40 (81.63)	29 (78.38)		30 (90.91)	34 (77.27)
Radiotherapy technique			0.351			0.473			1.000			0.569
Non-IMRT	88 (56.41)	108 (62.07)		42 (56.76)	59 (63.44)		28 (57.14)	21 (56.76)		18 (54.55)	28 (63.64)
IMRT	68 (43.59)	66 (37.93)		32 (43.24)	34 (36.56)		21 (42.86)	16 (43.24)		15 (45.45)	16 (36.36)
Time of treatment			0.008			0.205			0.032			0.531
1990-1999	41 (26.28)	72 (41.38)		20 (27.03)	37 (39.78)		9 (18.37)	16 (43.24)		12 (36.36)	19 (43.18)
2000-2009	71 (45.51)	55 (31.61)		33 (44.59)	32 (34.41)		25 (51.02)	11 (29.73)		13 (39.39)	12 (27.27)
2010-2020	44 (28.21)	47 (27.01)		21 (28.38)	24 (25.81)		15 (30.61)	10 (27.03)		8 (24.24)	13 (29.55)
Chemotherapy			0.753			0.902			0.733			0.946
No	96 (61.54)	110 (63.22)		50 (67.57)	62 (66.67)		26 (53.06)	21 (56.76)		20 (60.61)	27 (61.36)
Yes	60 (38.46)	64 (36.78)		24 (32.43)	31 (33.33)		23 (46.94)	16 (43.24)		13 (39.39)	17 (38.64)
rT			0.069			0.488			-			0.423
0	49 (31.41)	37 (21.26)		0 (0.00)	0 (0.00)		49 (100.00)	37 (100.00)		0 (0.00)	0 (0.00)
1 or 2	56 (35.90)	63 (36.21)		35 (47.30)	39 (41.94)		0 (0.00)	0 (0.00)		21 (63.64)	24 (54.55)
3 or 4	51 (32.69)	74 (42.53)		39 (52.70)	54 (58.06)		0 (0.00)	0 (0.00)		12 (36.36)	20 (45.45)
rN			0.532			-			0.791			0.824
0	74 (47.44)	93 (53.45)		74 (100.00)	93 (100.00)		0 (0.00)	0 (0.00)		0 (0.00)	0 (0.00)
1 or 2	75 (48.08)	75 (43.10)		0 (0.00)	0 (0.00)		43 (87.76)	34 (91.89)		32 (96.97)	41 (93.18)
3	7 (4.49)	6 (3.45)		0 (0.00)	0 (0.00)		6 (12.24)	3 (8.11)		1 (3.03)	3 (6.82)
rTNM			0.342			0.488			0.826			0.836
I-II	79 (50.64)	79 (45.40)		35 (47.30)	39 (41.94)		32 (65.31)	25 (67.57)		12 (36.36)	15 (34.09)
III-IV	77 (49.36)	95 (54.60)		39 (52.70)	54 (58.06)		17 (34.69)	12 (32.43)		21 (63.64)	29 (65.91)
Post recurrence treatment			0.054			0.283			0.516			0.573
Chemotherapy	18 (11.54)	18 (10.34)		11 (14.86)	8 (8.60)		3 (6.12)	4 (10.81)		4 (12.12)	6 (13.64)
RT	64 (41.03)	86 (49.43)		38 (51.35)	52 (55.91)		11 (22.45)	8 (21.62)		15 (45.45)	26 (59.09)
Surgery	61 (39.10)	46 (26.44)		17 (22.97)	16 (17.20)		34 (69.39)	22 (59.46)		10 (30.30)	8 (18.18)
BST	13 (8.33)	24 (13.79)		8 (10.81)	17 (18.28)		1 (2.04)	3 (8.11)		4 (12.12)	4 (9.09)

BST: Best supportive treatment; ENR: Early regional recurrence; ETNR: Early locoregional recurrence; ETR: Early local recurrence; KPS: Karnofsky Performance Status; LNR: Late regional recurrence; LTNR: Late locoregional recurrence; LTR: Late local recurrence; rN: Recurrent N stage; rT: Recurrent T stage; rTNM: Recurrent TNM stage; RT: Radiotherapy.

Table 3 Multivariable analysis of early vs late recurrence as a post-recurrence prognostic factor in the entire, local, regional and locoregional recurrence group

Variables	Total (n = 330)		Local (n = 167)		Regional (n = 86)		Locoregional (n = 77)
	P value	HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)
Gender
Male		1.00 (reference)		1.00 (reference)		1.00 (reference)		1.00 (reference)
Female	0.135	0.76 (0.53-1.09)	0.358	0.79 (0.47-1.31)	0.012	0.29 (0.11-0.76)	0.394	1.35 (0.68-2.66)
Age
< 60		1.00 (reference)		1.00 (reference)		1.00 (reference)		1.00 (reference)
≥ 60	0.003	1.73 (1.21-2.48)	0.056	1.61 (0.99-2.61)	0.014	2.53 (1.20-5.31)	0.385	1.50 (0.60-3.78)
TNM
I-II		1.00 (reference)		1.00 (reference)		1.00 (reference)		1.00 (reference)
III-IV	0.269	1.26 (0.84-1.88)	0.053	1.77 (0.99-3.17)	0.553	0.79 (0.36-1.74)	0.422	0.65 (0.23-1.85)
Early or late recurrence
Early		1.00 (reference)		1.00 (reference)		1.00 (reference)		1.00 (reference)
Late	0.461	0.89 (0.66-1.21)	0.872	1.04 (0.67-1.59)	0.561	1.21 (0.64-2.28)	0.006	0.37 (0.19-0.76)
rTNM
I-II		1.00 (reference)		1.00 (reference)		1.00 (reference)		1.00 (reference)
III-IV	< 0.001	1.88 (1.38-2.56)	0.132	1.39 (0.91-2.13)	< 0.001	3.26 (1.68-6.34)	0.451	1.32 (0.64-2.74)

rTNM: Recurrent TNM stage; HR: Hazard ratio; CI: Confidence interval.