Real-World Results of Raltitrexed Combined with S-1 and Bevacizumab in Heavily Pretreated Metastatic Colorectal Cancer

Figures & data

Table 1 Patient Demographics

Characteristics	N (%)
Sex
Male	25 (56.8)
Female	19 (43.2)
Age
Median (range)	54 (44−72)
<60 years	26 (59.1)
≥60 years	18 (40.9)
ECOG
0−1	41 (93.2)
2	3 (6.8)
Primary tumor site^†
Left	32 (72.7)
Right	11 (25)
Left and right	1 (2.3)
Primary tumor resection
Yes	31 (70.5)
No	13 (29.5)
Disease stage at first diagnosis
II	2 (4.5)
III	6 (13.6)
IV	34 (77.3)
NA	2 (4.5)
Time to metastasis
Simultaneous	34 (77.3)
Metachronous	8 (18.2)
NA	2 (4.5)
Metastasis organ
Liver	37 (84.1)
Lung	29 (65.9)
Peritoneum	6 (13.6)
Lymph nodes	21 (47.7)
Other metastases	17 (38.6)
Numbers of metastatic organs
1	3 (6.8)
2	20 (45.5)
3	15 (34.1)
4	5 (11.4)
5	1 (2.3)
KRAS/NRAS mutational status
Wildtype	15 (34.1)
Mutant	26 (59.1)
Unknown	3 (6.8)
BRAF^V600E mutational status
Wild type	39 (88.6)
Mutant	2 (4.5)
Unknown	3 (6.8)
MMR/MSI status
pMMR/MSS/MSI-L	25 (56.8)
dMMR/MSI-H	0
Unknown	19 (43.2)
Prior systemic antitumor treatment
VEGF inhibitors	32 (72.7)
Anti-EGFR antibodies	13 (29.5)
S-1	10 (22.7)
Raltitrexed	10 (22.7)
VEGF inhibitors and S-1^‡	7 (15.9)
Number of prior systemic regimens for metastatic disease
1	5^‡ (11.4)
2	16 (36.4)
3	11 (25)
4	7 (15.9)
5	4 (9.1)
6	1 (2.3)
Time from first-line chemotherapy
≥18 months	21 (47.7)
<18 months	23 (52.3)
Time from prior VEGF inhibitors
≤1 month	27 (61.4)
>1 month	17 (38.6)
Time from prior fluoropyrimidine
≤1 month	21 (47.7)
>1 month	23 (52.3)
LMR
Median (range)	2.27(1.23–9.05)
LMR≤2.27	12 (27.3)
LMR>2.27	30 (68.2)
Unknown	2 (4.5)

Notes: ^†Left-sided tumors were defined as those in the colon splenic flexure, descending colon, sigmoid colon, rectosigmoid junction colon, or rectum. Right-sided tumors were defined as those in the cecum, ascending colon, transverse colon, or hepatic flexure of the colon. VEGF inhibitors included bevacizumab, regorafenib, fruiquintinib, apatinib, and anlotinib. ^‡VEGF inhibitors and S-1 were used separately early or late in previous treatments or as a combination regimen.

Abbreviations: EGFR, epidermal growth factor receptor; ECOG, Eastern Cooperative Oncology Group; MSS, microsatellite stability; MSI-H, high microsatellite instability; MSI-L, low microsatellite instability; dMMR, deficient mismatch repair; pMMR, proficient mismatch repair; NA, not available; LMR, lymphocyte/monocyte ratio.

Figure 1 Kaplan–Meier survival curves of overall survival (OS).

Table 2 Multivariate Analysis of the Effect of the Chosen Parameters on OS

Parameters		HR	95% CI	p-value
CEA	≤42.8 ng/mL	0.382	0.153−0.952	0.039
	>42.8 ng/mL (ref)
Peritoneum metastases	No	0.160	0.048−0.531	0.003
	Yes (ref)
History of VEGF inhibitors and S-1	No	0.215	0.059−0.785	0.020
	Yes (ref)
Primary location	Left	0.385	0.166−0.897	0.089
	Right (ref)
BRAF^V600E	Wild	0.059	0.010−0.358	0.609
	Mutation (ref)

Abbreviations: CEA, carcinoembryonic antigen; VEGF, vascular endothelial growth factor; OS, overall survival; HR, hazard ratio; CI, confidence interval; REF, reference.

Figure 2 Kaplan–Meier survival curves of overall survival (OS) by treatment history (A: previously treated with both VEGF inhibitors and S-1; B: not previously treated with both VEGF inhibitors and S-1).

Table 3 Response of Patients with Measurable Disease (N = 43)

RECIST Response	Patients, n (%)
CR	0
PR	3 (7.0)
SD	25 (58.1)
PD	15 (34.9)
NE	1 (2.3)
ORR	3 (7.0)
DCR	25 (65.1)
DCR ≥ 6 months	15 (34.9)

Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE; not evaluable; ORR, objective response rate; DCR, disease control rate.

Figure 3 Kaplan–Meier survival curves of progression-free survival (PFS).

Table 4 Adverse Events

Adverse Event	Grade, n (%)
	Any Grade	Grade 1	Grade 2	Grade 3	Grade 4
Any AEs	39 (88.6)	13 (29.5)	22 (50)	3 (6.8)	1 (2.3)
Decreased appetite	1 (2.3)	0	1 (2.3)	0	0
Nausea	7 (15.9)	6 (13.6)	1 (2.3)	0	0
Vomiting	2 (4.5)	1 (2.3)	1 (2.3)	0	0
Diarrhea	1 (2.3)	0	0	1 (2.3)	0
Abdominal distension	1 (2.3)	1 (2.3)	0	0	0
Abdominal pain	2 (4.5)	0	2 (4.5)	0	0
Oral mucositis	1 (2.3)	1 (2.3)	0	0	0
Skin pigmentation	1 (2.3)	1 (2.3)	0	0	0
Fatigue	3 (6.8)	1 (2.3)	2 (4.5)	0	0
Rash	1 (2.3)	0	1 (2.3)	0	0
Leukopenia	7 (15.9)	1 (2.3)	5 (11.4)	0	1 (2.3)
Neutropenia	5 (11.4)	0	5 (11.4)	0	0
Thrombocytopenia	5 (11.4)	1 (2.3)	2 (4.5)	2 (4.5)	0
Elevated ALT/AST	1 (2.3)	0	1 (2.3)	0	0
Incomplete intestinal obstruction	1 (2.3)	0	1 (2.3)	0	0

Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase; AE, adverse event.