Predictive factors for early distant metastasis after neoadjuvant chemoradiotherapy in locally advanced rectal cancer

Table 1 Baseline patients’ characteristics, n (%)

Characteristics	Total (n = 127)
Age (yr)
Median (range)	65 (27-92)
Gender
Male	93 (73.2)
Female	34 (26.8)
Performance status
0	99 (78.0)
1	25 (19.7)
2	3 (2.4)
Grade
Well differentiated	46 (36.2)
Moderately differentiated	78 (61.4)
Poorly differentiated	3 (2.4)
Tumor location
Distal (10-15 cm from AV)	44 (34.6)
Mid (5-10 cm from AV)	48 (37.8)
Proximal (0-5 cm from AV)	35 (27.6)
Mesorectal fascia involvement
No	118 (92.9)
Yes	9 (7.1)
Extramural venous invasion
No	50 (39.4)
Yes	41 (32.3)
Unknown1	36 (28.3)
AJCC 8th T stage
cT1	0
cT2	17 (13.4)
cT3	94 (74.0)
cT4	16 (12.6)
AJCC 8th N stage
cN0	7 (5.5)
cN+	120 (94.5)
AJCC 8th M stage
cM0	120 (94.5)
cM1	7 (5.5)
AJCC 8th stage
cI	0
cII	7 (5.5)
cIII	113 (89.0)
cIV	7 (5.5)
Surgery
No	34 (26.8)
Local excision	3 (2.4)
Low anterior resection	77 (60.6)
Abdominoperineal resection	13 (10.2)
Adjuvant chemotherapy
No	58 (45.7)
Yes	69 (54.3)

¹Patients who did not take magnetic resonance image of the rectum.

AV: Anal verge; AJCC: American Joint Committee on Cancer.

Table 2 Summary of treatment response

Clinical T stage	Pathologic T stage
	ypT0	ypTis	ypT1		ypT2	ypT3	ypT4
Scheduled surgery
cT2	2	0	1		6	4	0
cT3	0	1	2		16	35	4
cT4	0	0	0		1	10	0
Unscheduled surgery
cT2	0	0		0	0	1	0
cT3	1	0		0	3	3	1
cT4	0	0		0	0	0	2

cT: Clinical T.

Table 3 Pretreatment prognostic factors by univariate analysis

Characteristics	n	LRC		DMFS		DFS		OS
		Hazard ratio (95%CI)	P value	Hazard ratio (95%CI)	P value	Hazard ratio (95%CI)	P value	Hazard ratio (95%CI)	P value
Grade
Well differentiated	46	1 (ref)		1 (ref)		1 (ref)		1 (ref)
Moderately differentiated	78	1.202 (0.300-4.810)	0.795	2.175 (0.606-7.806)	0.233	1.799(0.653-4.956)	0.256	4.066 (0.499-33.148)	0.190
Poorly differentiated	3	10.312 (1.070-99.393)	0.044	37.827 (5.655-243.040)	< 0.001	22.809 (4.130-125.954)	< 0.001	67.489 (3.594-1267.323)	0.005
Tumor location
Distal	44	1 (ref)		1 (ref)		1 (ref)		1 (ref)
Mid	48	1.785 (0.327-9.746)	0.527	1.439 (0.344-6.023)	0.618	1.817 (0.547-6.039)	0.330	3.244 (0.362-29.048)	0.293
Proximal	35	1.781 (0.297-10.659)	0.504	3.539 (0.936-13.380)	0.063	3.223 (1.009-10.290)	0.048	6.479 (0.755-55.611)	0.088
Tumor size
≤ 5 cm	105	1 (ref)		1 (ref)		1 (ref)		1 (ref)
> 5 cm	22	4.173 (1.120-15.551)	0.033	4.224 (1.569-11.372)	0.004	5.909 (2.555-13.670)	< 0.001	4.224 (1.569-11.372)	0.004
MRF involvement
No	118	1 (ref)		1 (ref)		1 (ref)		1 (ref)
Yes	9	2.860 (0.355-23.016)	0.323	19.532 (4.787-79.695)	< 0.001	16.082 (5.022-51.503)	< 0.001	19.532 (4.787-79.695)	< 0.001
T3 substage
T3a or b	46	1 (ref)		1 (ref)		1 (ref)		1 (ref)
T3c or d	48	70.381 (0.053-94343.482)	0.247	5.272 (1.073-25.898)	0.041	7.852 (1.710-36.052)	0.008	5.272 (1.073-25.898)	0.041
EMVI1
No	50	1 (ref)		1 (ref)		1 (ref)		1 (ref)
Yes	41	11.428 (1.402-93.177)	0.023	4.408 (1.488-13.056)	0.007	4.387 (1.843-12.692)	0.001	4.408 (1.488-13.056)	0.007
Superior rectal lymph node		1.253 (0.973-1.614)	0.081	1.102 (0.870-1.395)	0.420	1.208 (1.005-1.451)	0.044	1.102 (0.870-1.395)	0.420

¹Patients who did not take magnetic resonance image of the rectum were excluded.

MRF: Mesorectal fascia; EMVI: Extramural venous invasion; LRC: Locoregional contro; DMFS: Distant metastasis-free survival; DFS: Disease-free survival; OS: Overall survival.

Table 4 Predictive factors for early distant metastasis, n (%)

Characteristics	Early metastasis		P value
	Yes (n = 5)	No (n = 122)
Grade			0.025
Well differentiated	3 (60.0)	43 (35.2)
Moderately differentiated	1 (20.0)	77 (63.1)
Poorly differentiated	1 (20.0)	2 (1.6)
Tumor location			0.031
Distal	0	44 (36.1)
Mid	1 (20.0)	47 (38.5)
Proximal	4 (80.0)	31 (25.4)
MRF involvement			0.002
No	2 (40.0)	116 (95.1)
Yes	3 (60.0)	6 (4.9)
EMVI1			0.012
No	0	50 (58.1)
Yes	5 (100)	36 (41.9)

¹Patients who did not take magnetic resonance image of the rectum were excluded.

MRF: Mesorectal fascia; EMVI: Extramural venous invasion.

Table 5 Summaries of studies on neoadjuvant chemotherapy followed by chemoradiotherapy

Study	Design	n	Eligibility	NAC regimen	CRT regimen	AC regimen	Response	Compliance	Recurrence	Survival
Chau et al[3]	Prospective single-arm	36	cT3N0-2; cT4N0-2	MMC (× 2); PVI 5-FU	RT 54Gy/30Fx’s; PVI 5-FU	MMC; PVI 5-FU	27.8%1 after NAC; 80.6%1 after CRT	NAC 100%; CRT 100%	LR 2 pts; DM 9 pts	1Y-OS 93.5%; 2Y-OS 70.3%
EXPERT[4,5]	Phase II single-arm	105	MR defined disease: MRF involved or threatened, cT3 tumor at or below the levators, cT4, cN2, extramural extension ≥ 5 mm	CAPOX (× 4)	RT 54Gy/30Fx’s; capecitabine	capecitabine	74%1 after NAC; 89%1 after CRT	NAC 89%; CRT 91%	LR 6 pts; DM 21 pts	5Y-OS 75.0%
GCR-3[6,7]	Phase II; RCT	54	MR defined disease: Distal edge within 12 cm from AV, lower third cT3, resectable cT4, cT3-4N+, MRF involved or threatened	CAPOX (× 4)	RT 54Gy/27Fx’s; CAPOX	-	Downstaging 43.0%; pCR 14.0%	NAC 94.0%; CRT 85.0%	LR 5%; DM 23%	5Y-OS 75.0%
		49		-	RT 54Gy/27Fx’s; CAPOX	CAPOX (× 4)	Downstaging 58.0%; pCR 13.0%	CRT 80.0%; AC 57.0%	LR 2%; DM 21%	5Y-OS 78.0%
COPERNICUS[8]	Phase II single-arm	60	Inferior margin ≥ 4 cm from AV, superior margin < S1/2 interspace, tumor > 1 mm from MRF, cT3d, cT4, mrT3a-b with either EMV invasion or mesorectal lymph nodes	Oxaliplatin/5-FU (× 4)	RT 25Gy/5Fx’s	Oxaliplatin 5-FU (× 8)	T down staging: 73.0%1 after NAC; 74.0% after surgery	NAC 75.0%; AC 37.0%	LR 2 pts; DM 6 pts	2Y-PFS 86.2%
CONTRE[9]	Prospective single-arm	39	cT3-4N0, cT1-4N+	mFOLFOX6 (× 8)	RT 50.4Gy/28Fx’s capecitabine	-	pCR 33.0%	NAC 92.0%	LR 2 pts; DM 6 pts	-
Schou et al[10]	Prospective single-arm	84	MR defined disease: MRF involved or threatened, cT3-4 N+	CAPOX (× 2)	RT 54Gy/27Fx’scapecitabine	-	T down staging 69% after surgerypCR 23.0%	NAC 88.0%	LR 1%DM 25%	5Y-OS 67.0%
Dueland et al[11]	Prospective single-arm	97	cT3 with < 3 mm from MRF, cT4, N+, resectable synchronous metastasis	Nordic FLOX (× 2)	RT 50Gy/25Fx’s; CAPOX	-	pCR 17.3%	NAC 91.0%	LR 4 pts; DM 27 pts	5Y-OS 83.0%
Koeberle et al[12]	Phase II single-arm	60	cT3-4 with N- or N+	CAPOX (× 1)	RT 45Gy/25Fx’s; CAPOX	-	pCR 23.0%	Oxaliplatin 87.0%	-	-
Maréchal et al[13]	Phase II RCT	29	cT2-4, cN+	-	RT 45Gy/25Fx’s; 5-FU	-	pCR 28%	NAC 96.0%; CRT 98.0%	-	-
		28		mFOLFOX6 (× 2)	RT 45Gy/25Fx’s; 5-FU	-	pCR 25%
EXPERT-C[14]	Phase II RCT	81	MR defined disease: Tumor within 1mm of MRF, cT3 tumor at or below the levators, cT4, presence of EMV invasion, extramural extension5mm	CAPOX (× 4) cetuximab	RT 54Gy/30Fx’s; capecitabine/ cetuximab	CAPOX (× 4); cetuximab	64.0%1 after NAC; 84.0%1 after CRT	NAC 95.0%; CRT 91.0%	LR 1 pt	-
		83		CAPOX (× 4)	RT 54Gy/30Fx’s; capecitabine	CAPOX (x4)	54.0%1 after NAC; 76.0%1 after CRT	NAC 93.0%; CRT 90.0%	LR 2 pts	-
AVACROSS[15]	Phase II single-arm	47	Distal edge ≤ 1 cm from AV, cT3N+, resectable cT4, cT3 tumor in lower third, tumor in middle third with ≤ 2 mm from MRF, N+ with ≤ 2 mm from MRF	CAPOX/bevacizumab (× 4)	RT 50Gy/25Fx’s; capecitabine/ bevacizumab	CAPOX (x4)	pCR 34.0%	NAC 85.0%; CRT 83.0%	DM 5 pts	-
Eisterer et al[16]	Phase II single-arm	25	MR defined disease: cT3 (< 5 mm from MRF), cT4	CAPOX/bevacizumab (× 3)	RT 45Gy/25Fx’s capecitabine	-	pCR 25.0%	NAC 79.2%CRT 94.7%	-	-
PRODIGE23[31]	Phase III	231	cT3-4	mFOLFIRINOX (× 6)	RT 50Gy25Fx’s; capecitabine	mFOLFOX6 or capecitabine	pCR 27.8%	-	-	3Y-DFS 75.7%
		230		-			pCR 12%	-	-	3Y-DFS 68.5%

¹Tumor response evaluation by imaging.

NAC: Neoadjuvant chemotherapy; CRT: Chemoradiotherapy; RT: Radiotherapy; AC: Adjuvant chemotherapy; OS: Overall survival; PFS: Progression-free survival; LR: Local recurrence; DM: Distant metastasis; MR: Magnetic resonse; AV: Anal verge; MRF: Mesorectal fascia; EMV: Extramural venous; MMC: Mitomycin C; PVI: Protracted venous infusion; CAPOX: Capecitabine/oxaliplatin; FLOX: Oxaliplatin/5-FU; FOLFIRINOX: Oxaliplatin/5-FU/Irinotecan; pCR: Pathological complete response; RCT: Randomized controlled trial.

Table 6 Summaries of studies on neoadjuvant chemotherapy without radiotherapy

Study	Design	n	Eligibility	NAC regimen	CRT regimen	AC regimen	Response	Compliance	Recurrence	Survival
Koizumi et al[17]	Phase II single-arm	30	Lower edge under S2, cT3-4	FOLFOX (× 6)	-	-	pCR 6.7%	NAC 93.3%	LR 2 pts; DM 5 pts	3Y-OS 95.7%
FORTUNE[18]	Phase II single-arm	106	cT3-4, cN1-2, distal edge < 12 cm from AV	mFOLFOXIRI (× 4-6)	RT 50.4Gy/28Fx’s; mFOLFOX61 or RT 25Gy/5Fx’s	mFOLFOX6(× 6)	pCR 20.4%; pCR 17.4% after NAC	NAC 100%	-	-
Ishii et al[19]	Prospectivesingle-arm	26	cT3-4 with cN0-2	IFL (× 2)	-	-	Downstaging 57.0%; pCR 3.8%	NAC 100%	-	5Y-OS 84.0%
FOWARC[20,21]	Phase III RCT	165	cT3-4, N1-2	-	RT 45Gy/25Fx’s 5-FU	5-FU (× 7)	pCR 14.0%	CRT 88.4%	LR 8.0%	3Y-OS 91.3%
		165		-	RT 45Gy/25Fx’s mFOLFOX6	mFOLFOX (× 7)	pCR 27.5%	CRT 94.9%	LR 7.0%	3Y-OS 89.1%
		165		mFOLFOX6 (× 4-6)	-	mFOLFOX6(× 6-8)	pCR 6.5%	NAC 94.5%	LR 8.3%	3Y-OS 90.7%
Schrag et al[22]	Phase II single-arm	32	Distal edge within 5-12cm from AV, cT3N-, cT3N+	mFOLFOX6/bevacizumab (× 6)	RT 50.4Gy/28Fx’s 5-FU1	FOLFOX	pCR 25.0%	NAC 93.8%	LR 0; DM 12.5%	4Y-OS 91.0%
N-SOG 03[23]	Phase II single-arm	32	MR defined disease: Inferior margin below the S2 lower margin, MRF involved or threatened, cT3b-d, cT4, cN2	CAPOX/bevacizumab (× 4)	-	-	T down staging 54.0% after surgery pCR 25.0%	NAC 79.2%; CRT 94.7%	-	-
GEMCAD 0801[24,32]	Phase II single-arm	46	MR defined disease: Distal edge > 5 cm from AV, cT3 (≥ 2 mm from MRF)	CAPOX/bevacizumab (× 4)	-	-	pCR 19.5%	NAC 95.6%	LR 2 pts; DM 8 pts; Both 1 pt	-

¹Chemoradiotherapy if any progression after neoadjuvant chemotherapy.

NAC: Neoadjuvant chemotherapy; CRT: Chemoradiotherapy; RT: Radiotherapy; AC: Adjuvant chemotherapy; OS: Overall survival; LR: Local recurrence; DM: Distant metastasis; MR: Magnetic resonse; AV: Anal verge; MRF: Mesorectal fascia; CAPOX: Capecitabine/oxaliplatin; IFL: Irinotecal/fluorouracil/leukovorin; pCR: Pathological complete response; RCT: Randomized controlled trial.