Role of adjuvant chemoradiotherapy and chemotherapy in patients with resected gallbladder carcinoma: a multi-institutional analysis (KROG 19-04)

Sung Uk Lee; Jinsil Seong; Tae Hyun Kim; Jung Ho Im; Woo Chul Kim; Kyubo Kim; Hae Jin Park; Tae Gyu Kim; Youngkyong Kim; Bae Kwon Jeong; Jin Hee Kim; Byoung Hyuck Kim; Taek-Keun Nam

doi:10.20892/j.issn.2095-3941.2020.0667

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Figure 1
Patterns of failures among adjuvant treatment groups. (A) stage II, and (B) stage III–IV. LR, locoregional recurrence; DM, distant metastasis; NED, no evidence of disease; No-AT, no adjuvant treatment; CTx, chemotherapy; CRT, chemoradiotherapy.
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Figure 2
LRFS (A and D), RFS (B and E), and OS (C and F) curves among the adjuvant treatment groups in stage II and III–IV patients, respectively. LRFS, locoregional recurrence-free survival; RFS, recurrence-free survival; OS, overall survival; LR, locoregional recurrence; DM, distant metastasis; NED, no evidence of disease; No-AT, no adjuvant treatment; CTx, chemotherapy; CRT, chemoradiotherapy. *Log-rank test.
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Figure 3
LRFS (A), RFS (B), and OS (C) curves among the adjuvant treatment groups in stage II patients with of perineural invasion and/or Nx classification. LRFS, locoregional recurrence-free survival; RFS, recurrence-free survival; OS, overall survival; LR, locoregional recurrence; DM, distant metastasis; NED, no evidence of disease; No-AT, no adjuvant treatment; CTx, chemotherapy; CRT, chemoradiotherapy. *Log-rank test.

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Table 1

Comparison of the baseline patient characteristics among the adjuvant treatment groups

Characteristics	Stage II (n = 381)				Stage III–IV (n = 352)
Characteristics	No-AT (n = 258)	CTx (n = 82)	CRT (n = 41)	P value	No-AT (n = 114)	CTx (n = 133)	CRT (n = 105)	P value
Gender, n (%)
Male	113 (44)	33 (40)	22 (54)	0.364*	44 (39)	55 (41)	43 (41)	0.897*
Female	145 (56)	49 (60)	19 (46)		70 (61)	78 (59)	62 (59)
Age (years)
Median [range]	67 [29–87]	61 [29–88]	66 [44–81]	0.000^†	71 [41–91]	62 [38–87]	63 [26–83]	0.000^†
≤60 years, n (%)	53 (21)	36 (44)	10 (24)	0.000*	22 (19)	52 (39)	39 (37)	0.002*
>60 years, n (%)	205 (79)	46 (56)	31 (76)		92 (81)	81 (61)	66 (63)
Tumor size (cm)
Median [range]	2.3 [0.1–8.8]	2.7 [0.7–9.0]	2.5 [0.5–10.5]	0.420^†	3.4 [1.0–13]	3.5 [0.9–13.0]	3.5 [1.0–9.0]	0.534^†
≤3 cm, n (%)	79 (67)	38 (63)	22 (65)	0.846*	35 (43)	34 (44)	37 (47)	0.866*
>3 cm, n (%)	38 (33)	22 (37)	12 (35)		47 (57)	43 (56)	42 (53)
T classification, n (%)
T2	258 (100)	82 (100)	41 (100)	–	44 (39)	58 (44)	48 (46)	0.554*
T3–4	–	–	–		70 (61)	75 (56)	57 (54)
N classification, n (%)
Nx	52 (20)	11 (13)	3 (7)	0.075^‡	8 (7)	2 (2)	1 (1)	0.027^‡
N0	206 (80)	71 (87)	38 (93)		27 (24)	25 (19)	17 (16)
N1					60 (53)	90 (68)	74 (71)
N2					19 (17)	16 (12)	13 (12)
Preop CA 19-9 level (U/mL)
Median [range]	10 [0.1–2,400]	9 [0.8–383]	10 [2–119]	0.347^†	21 [0.1–2,960]	21 [0.1–8,340]	19 [0.1–9,410]	0.370^†
≤37 U/mL, n (%)	168 (83)	57 (84)	29 (85)	0.926*	59 (64)	81 (68)	60 (67)
>37 U/mL, n (%)	35 (17)	11 (16)	5 (15)		34 (37)	39 (33)	29 (33)
Postop CA 19-9 level (U/mL)
Median [range]	8 [0.1–3,056]	8 [0.7–62]	9 [2.6–606]	0.639^†	13 [0.1–3,487]	15 [0.1–850]	14 [0.1–1,445]	0.064^†
≤37 U/mL, n (%)	204 (94)	72 (97)	34 (94)	0.543^‡	70 (74)	104 (83)	78 (84)	0.131*
>37 U/mL, n (%)	13 (6)	2 (3)	2 (6)		25 (26)	21 (17)	15 (16)
Histologic differentiation, n (%)
WD/MD	224 (90)	69 (86)	36 (90)	0.639*	74 (70)	97 (76)	73 (72)	0.554*
PD	25 (10)	11 (14)	4 (10)		31 (30)	30 (24)	29 (28)
Resection margin, n (%)
Negative	249 (99)	72 (95)	38 (93)	0.025^‡	97 (88)	118 (90)	96 (92)	0.599*
Positive	3 (1)	4 (5)	3 (7)		13 (12)	13 (10)	8 (8)
LVSI, n (%)
No	187 (79)	58 (82)	27 (67)	0.196*	38 (36)	51 (40)	51 (50)	0.122*
Yes	50 (21)	13 (18)	13 (33)		68 (64)	76 (60)	52 (50)
PNI, n (%)
No	193 (88)	43 (80)	31 (82)	0.199*	55 (54)	50 (43)	49 (49)	0.280*
Yes	26 (12)	11 (20)	7 (18)		47 (46)	66 (57)	52 (51)
Extent of surgical resection, n (%)
Non-radical	60 (23)	14 (17)	5 (12)	0.175*	20 (18)	7 (5)	6 (6)	0.001*
Radical	198 (77)	68 (83)	36 (88)		94 (82)	126 (95)	99 (94)

No-AT, no adjuvant therapy; CTx, chemotherapy; CRT, chemoradiotherapy; Preop, preoperative; Postop, postoperative; CA 19-9, carbohydrate antigen 19-9; WD, well differentiation; MD, moderate differentiation; PD, poor differentiation; LVSI, lymphovascular space invasion; PNI, perineural invasion; Non-radical, cholecystectomy ± lymph node dissection; Radical, radical cholecystectomy and lymph node dissection. *Pearson’s chi-square test. ^†One-way analysis of variance. ^‡Fisher’s exact test.

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Table 2

Univariate analysis of LRFS, RFS, and OS according to tumor stage

Characteristics	n	Stage II (n = 381)						n	Stage III–IV (n = 352)
		LRFS		RFS		OS			LRFS		RFS		OS
		5-year (%)	P value*	5-year (%)	P value*	5-year (%)	P value*		5-year (%)	P value*	5-year (%)	P value*	5-year (%)	P value*
Gender
Male	168	86.2	0.096	78.3	0.621	80.2	0.672	142	47.8	0.360	32.2	0.449	48.8	0.445
Female	213	80.1		76.0		78.4		210	52.0		36.1		44.2
Age
≤60 years	99	91.0	0.021	84.5	0.039	90.6	0.005	113	48.6	0.502	34.3	0.342	54.7	0.007
>60 years	282	79.3		74.0		74.8		239	52.0		34.9		41.6
T classification
T2	381	–	–	–	–	–	–	150	63.1	< 0.001	48.4	0.000	60.7	<0.001
T3–4	0	–		–		–		202	40.0		23.9		34.9
N classification
N0	315	85.3	0.003	80.8	<0.001	82.7	<0.001	69	53.5	<0.001	37.8	0.000	51.2	<0.001
N1	0	–		–		–		224	54.6		38.8		50.7
N2	0	–		–		–		48	30.8		13.4		22.2
Nx	66	68.7		56.7		62.6		11	0.0		0.0		0.00
Preop CA 19-9 level
≤37 U/mL	254	86.0	0.001	81.1	0.001	83.2	0.026	200	51.9	0.037	35.8	0.046	46.9	0.428
>37 U/mL	51	69.7		61.3		64.3		102	44.5		28.6		43.2
Postop CA 19-9 level (U/mL)
≤37	310	84.9	0.000	79.0	0.000	83.7	0.000	252	55.2	<0.001	39.7	0.000	82.4	0.000
>37	17	42.2		47.4		43.6		61	25.6		6.3		14.4
Histologic differentiation
WD/MD	329	82.8	0.740	77.2	0.608	78.9	0.964	244	53.4	0.036	38.5	0.004	51.3	0.004
PD	40	84.3		74.3		78.0		90	44.8		25.2		34.1
Resection margin
Negative	359	84.1	0.005	79.0	<0.001	81.8	<0.001	311	50.6	0.119	36.2	0.001	48.5	0.001
Positive	10	60.0		40.0		48.0		34	39.1		11.1		18.1
LVSI
No	272	87.7	0.000	83.2	<0.001	84.6	<0.001	140	64.6	<0.001	48.5	0.000	66.0	<0.001
Yes	76	63.9		55.8		65.1		196	38.6		23.9		33.3
PNI
No	267	87.0	0.000	83.1	<0.001	85.4	<0.001	154	59.6	0.001	44.2	0.000	63.8	0.000
Yes	44	57.2		45.5		49.6		165	40.4		24.2		30.9
Extent of surgical resection
Non-radical	79	78.1	0.036	71.3	0.035	64.7	0.009	33	38.7	0.036	34.5	0.335	36.4	0.028
Radical	302	83.9		78.4		83.1		319	51.3		34.6		47.1
Adjuvant treatment
No-AT	258	83.9	0.510	79.8	0.076	78.3	0.946	114	37.9	<0.001	28.8	0.006	35.4	<0.001
CTx	82	81.5		72.5		80.3		133	45.0		30.0		45.7
CRT	41	79.3		69.4		84.3		105	67.8		45.2		56.9

LRFS, locoregional recurrence-free survival; RFS, recurrence-free survival; OS, overall survival; n, number; No-AT, no adjuvant therapy; CTx, chemotherapy; CRT, chemoradiotherapy; Preop, preoperative; Postop, postoperative; CA 19-9, carbohydrate antigen 19-9; WD, well differentiation; MD, moderate differentiation; PD, poor differentiation; LVSI, lymphovascular space invasion; PNI, perineural invasion; Non-radical, cholecystectomy ± lymph node dissection; Radical, radical cholecystectomy and lymph node dissection. *Log-rank test.

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Table 3

Multivariate analysis of LRFS, RFS, and OS according to tumor stage

Factors	LRFS		RFS		OS
Factors	HR (95% CI)	P value*	HR (95% CI)	P value*	HR (95% CI)	P value*
Stage II
Age
≤ 60 years	1	0.157	1	0.142	1	0.044
> 60 years	2.07 (0.75–5.70)		1.97 (0.79–4.89)		2.78 (1.02–7.53)
N classification
N0	1	0.002	1	<0.001	1	0.024
Nx	3.53 (1.57–7.94)		3.70 (1.81–7.58)		2.55 (1.12–5.76)
Preop CA 19-9 level
≤37 U/mL	1	0.181	1	0.125	1	0.580
>37 U/mL	1.78 (0.76–4.19)		1.81 (0.84–3.86)		1.30 (0.51–3.29)
Postop CA 19-9 level
≤ 37 U/mL	1	0.048	1	0.094	1	0.038
>37 U/mL	3.60 (1.01–12.85)		2.78 (0.84–9.21)		4.27 (1.08–16.91)
Resection margin
Negative	1	0.001	1	0.001	1	0.002
Positive	11.11 (2.70–45.65)		10.82 (2.78–42.10)		9.84 (2.25–42.98)
LVSI
No	1	0.217	1	0.405	1	0.419
Yes	1.64 (0.74–3.61)		1.35 (0.66–2.78)		1.36 (0.64–2.92)
PNI
No	1	0.005	1	<0.001	1	<0.001
Yes	3.25 (1.42–7.40)		3.85 (1.86–7.98)		4.16 (1.91–9.07)
Extent of surgical resection
Non-radical	1	0.278	1	0.532	1	0.517
Radical	0.55 (0.18–1.61)		0.74 (0.29–1.87)		0.71 (0.26–1.97)
Stage III–IV
Age
≤ 60 years	1	0.895	0.702	1	0.108
> 60 years	0.97 (0.63–1.48)		1.07 (0.75–1.53)		1.37 (0.93–2.03)
T classification
T2	1	0.040	1	0.048	1	0.054
T3–4	1.64 (1.02–2.64)		1.48 (1.00–2.19)		1.51 (0.99–2.32)
N classification
N0	1		1		1
N1	2.02 (1.10–3.68)	0.022	1.77 (1.08–2.91)	0.023	1.68 (0.96–2.94)	0.066
N2	4.30 (2.22–8.29)	<0.001	3.91 (2.24–6.82)	<0.001	4.25 (2.31–7.79)	<0.001
Nx	39.95 (9.33–170.98)	<0.001	21.56 (5.73–81.05)	<0.001	7.85 (1.62–37.84)	0.010
Preop CA 19-9 level
≤ 37 U/mL	1	0.789	1	0.895	1	0.128
> 37 U/mL	1.06 (0.69–1.62)		0.97 (0.67–1.40)		0.73 (0.49–1.09)
Postop CA 19-9 level
≤37 U/mL	1	0.002	1	<0.001	1	<0.001
>37 U/mL	2.18 (1.33–3.56)		2.76 (1.80–4.24)		2.49 (1.59–3.89)
Histologic differentiation
WD/MD	1	0.402	1	0.126	1	0.229
PD	1.20 (0.78–1.83)		1.31 (0.92–2.19)		1.26 (0.86–1.85)
Resection margin
Negative	1	0.889	1	0.153	1	0.320
Positive	1.05 (0.48–2.31)		1.54 (0.85–2.80)		1.36 (0.74–2.50)
LVSI
No	1	0.055	1	0.065	1	0.019
Yes	1.65 (0.98–2.75)		1.46 (0.97–2.19)		1.74 (1.09–2.77)
PNI
No	1	0.123	1	0.241	1	0.051
Yes	1.42 (0.90–2.25)		1.25 (0.86–1.81)		1.52 (0.99–2.31)
Extent of surgical resection
Non-radical	1	0.010	1	0.169	1	0.259
Radical	0.39 (0.19–0.79)		0.62 (031–1.22)		0.65 (0.30–1.37)
Adjuvant treatment
No-AT	1		1		1
CTx	0.80 (0.50–1.29)	0.366	0.91 (0.60–1.39)	0.687	0.78 (0.51–1.21)	0.280
CRT	0.28 (0.15–0.51)	<0.001	0.52 (0.33–0.82)	0.006	0.42 (0.25–0.70)	0.001

LRFS, locoregional recurrence-free survival; RFS, recurrence-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval; Preop, preoperative; Postop, postoperative; CA 19-9, carbohydrate antigen 19-9; LVSI, lymphovascular space invasion; PNI, perineural invasion; WD, well differentiation; MD, moderate differentiation; PD, poor differentiation; No-AT, no adjuvant therapy; CTx, chemotherapy; CRT, chemoradiotherapy. *Cox proportional hazards model.