Revisiting oral fluoropyrimidine with cetuximab in metastatic colorectal cancer: Real-world data in Chinese population

Table 1 The schedules of chemotherapy regimens

Oral fluoropyrimidine-based regimen1,3

Cetuximab + CAPOX every 3 wk

Cetuximab: 500 mg/m2 on day 1 and 250 mg/m2 on day 15

Oxaliplatin: 130 mg/m2 on day 1

Capecitabine: 1000 mg/m2 from day 1 to day 14

Cetuximab + CAPIRI every 3 wk

Cetuximab: 500 mg/m2 on day 1 and 250 mg/m2 on day 15

Irinotecan: 200 mg/m2 on day 1

Capecitabine: 800 mg/m2 from day 1 to day 14

Infusional fluoropyrimidine-based regimen2,3

Cetuximab + FOLFOX every 2 wk

Cetuximab: 500 mg/m2 on day 1

Oxaliplatin: 85 mg/ m2 on day 1

Leucovorin: 200 mg/m2 over 2 h on day 1 and 2

5-Fluorouracil: 400 mg/m2 bolus on day 1 and 2

5-Fluorouracil: 600 mg/m2 over 20 h on day 1 and 22 h on day 2

Cetuximab + FOLFIRI every 2 wk

Cetuximab: 500 mg/m2 on day 1

Irinotecan: 180 mg/ m2 on day 1

Leucovorin: 200 mg/m2 over 2 h on day 1 and 2

5-Fluorouracil: 400 mg/m2 bolus on day 1 and 2

5-Fluorouracil: 600 mg/m2 over 20 h on day 1 and 22 h on day 2

In brief, treatment has to be withheld for grade 2 or above toxicities and to be resumed once recovered to grade 1. Dose reduction was considered for recurrent grade 2, or grade 3 or above toxicities.

¹75% dose of the regimen would be used if patients were older than 70 years old and 75% dose of capecitabine if creatinine clearance was less than 50 mL/min;

²75% dose of the regimen would be used if patients were older than 70 years old;

³Dose modification of chemotherapy due to toxicities was performed according to standard practice.

Table 2 Baseline characteristics of eligible patients

	Total (n = 95)	Oral (n = 57)	Infusional (n = 38)	P value
Gender (%)
Male	52 (54.7)	32 (56.1)	20 (52.6)	0.900
Age (yr)
Median	61.0	61.0	61.0	0.622
Age ≥ 70 (%)	21 (22.1)	12 (21.1)	9 (23.7)	0.960
ECOG performance status
0	7 (7.4)	4 (7.0)	3 (7.9)	0.383
1	80 (84.2)	50 (87.7)	30 (78.9)
2	8 (8.4)	3 (5.3)	5 (13.2)
3	0 (0)	0 (0)	0 (0)
4	0 (0)	0 (0)	0 (0)
Site of primary tumor (%)
Right-sided colon	20 (21.1)	15 (26.3)	5 (13.2)	0.114
Left-sided colon	49 (51.6)	25 (43.9)	24 (63.2)
Rectum	22 (23.2)	13 (22.8)	9 (23.7)
Multiple	4 (4.2)	4 (7.0)	0 (0.0)
Timing of metastasis (%)
Synchronous	72 (75.8)	40 (70.2)	32 (84.2)	0.187
Metachronous	23 (24.2)	17 (29.8)	6 (15.8)
Extent of the disease (%)
Primary resected1	68 (71.6)	42 (73.7)	26 (68.4)	0.745
Liver-only metastatsis	44 (46.3)	26 (45.6)	18 (47.4)	1.000
> 1 site of metastasis	40 (42.1)	24 (42.1)	16 (42.1)	1.000
Site of metastasis (%)
Liver	67 (70.5)	39 (68.4)	28 (73.7)
Lymph Nodes	28 (29.5)	17 (29.8)	11 (28.9)
Peritoneum	21 (22.1)	11 (19.3)	10 (26.3)
Lung	17 (17.9)	11 (19.3)	6 (15.8)
Bone	3 (3.2)	2 (3.5)	1 (2.6)
Others	8 (8.4)	6 (10.5)	2 (5.3)

No significant differences were recognized in the distribution of the baseline patient characteristics between the oral and infusional fluoropyrimidine groups. With regard to the clinical characteristics of the disease and extent of disease, the two groups of patients were comparable in terms of site of primary tumour, resection of primary tumour, timing of the metastasis, and proportion of liver-only disease.

¹Include both palliative surgery of primary and previous surgery of nonmetastatic patients.

Table 3 Treatment characteristics of eligible patients

	Total (n = 95)	Oral (n = 57)	Infusional (n = 38)	P value
Chemotherapy backbone (%)1
FOLFOX	26 (27.4)	0 (0)	26 (68.4)
CAPOX	43 (45.3)	43 (75.4)	0 (0)
FOLFIRI	12 (12.6)	0 (0)	12 (31.6)
CAPIRI	9 (9.5)	9 (15.8)	0 (0)
Capecitabine	5 (5.3)	5 (8.8)	0 (0)
Type of fluoropyrimidine (%)
Oral	57 (60.0)	57 (100)	0 (0)
Infusional	38 (40.0)	0 (0)	38 (100)
Chemotherapy partner (%)
Oxaliplatin	69 (76.7)	43 (75.4)	26 (68.4)	0.184
Irinotecan	21 (23.3)	9 (15.8)	12 (31.6)
Mean treatment duration
Oral/Infusional FP (wk)2	18.5	19.4	17.2	0.147
Any treatment modification (%)
Yes	75 (78.9)	43 (75.4)	32 (84.2)	0.441
Due to age	21 (22.1)	12 (21.1)	9 (23.7)
Due to adverse effects	54 (56.8)	31 (54.4)	23 (60.5)
Subsequent systemic therapy (%)
Yes	65 (68.4)	40 (70.2)	25 (65.8)	0.822
Metastasectomy of curative intent (%)
Yes	16 (16.8)	6 (10.5)	10 (26.3)	0.083

There was no statistically significant difference in the proportions of patients receiving treatment modification of the first-line treatment, metastasectomy of curative intent, subsequent systemic therapy, and the mean treatment durations in the two treatment groups.

¹The details of the regimen are shown in Table 1;

²FP refers to fluoropyrimidine.

Table 4 Cox regression analysis for the effects of different predictors on progression-free survival

Factor	Crude HR (95%CI)	Adjusted HR (95%CI)	P value1
Age	1.00 (0.98-1.02)	1.00 (0.98-1.02)	0.909
Male	0.91 (0.60-1.38)	1.00 (0.64-1.54)	0.985
Right sided primary	1.63 (0.97-2.74)	1.87 (1.08-3.25)	a0.026
Primary resected	0.39 (0.24-0.63)	0.35 (0.21-0.59)	b<0.001
Liver only disease	0.56 (0.37-0.86)	0.57 (0.36-0.91)	c0.019
Infusional FP2	0.92 (0.60-1.42)	1.00 (0.63-1.57)	0.992

¹It refers to the P-values for multivariable Cox regression analysis (i.e., adjusted HR);

²FP refers to fluoropyrimidine.

^aP: Right sided primary;

^bP: Primary resected;

^cP: Liver-only disease.

Table 5 Cox regression analysis for the effects of different predictors on overall survival

Factor	Crude HR (95%CI)	Adjusted HR (95%CI)	P value1
Age	1.01 (0.99-1.03)	1.01 (0.99-1.03)	0.394
Male	0.86 (0.56-1.31)	1.04 (0.67-1.63)	0.848
Right sided primary	1.96 (1.16-3.31)	1.92 (1.10-3.36)	a0.023
Primary resected	0.34 (0.21-0.55)	0.37 (0.22-0.62)	b<0.001
Liver only disease	0.54 (0.35-0.83)	0.58 (0.36-0.95)	c0.029
Infusional FP2	0.90 (0.58-1.39)	0.87 (0.56-1.37)	0.558

¹It refers to the P-values for multivariable Cox regression analysis (i.e., adjusted HR);

²FP refers to fluoropyrimidine.

^aP: Right sided primary;

^bP: Primary resected;

^cP: Liver-only disease.

Table 6 Grade 3 or above adverse events experienced by our patients

	Total (n = 95)	Oral (n = 57)	Infusional (n = 38)	P value
Any adverse events (%)	95 (100)	57 (100)	38 (100)	1.000
G3 or above adverse events (%)1	27 (28.4)	19 (33.3)	8 (21.1)	0.286
Hematologic (%)
Anaemia	64 (67.4)	36 (63.2)	28 (73.7)	0.396
G3 or above	4 (4.2)	4 (7.0)	0 (0)	0.147
Leucopenia	44 (46.3)	25 (43.9)	19 (50.0)	0.705
G3 or above	3 (3.2)	1 (1.8)	2 (5.3)	0.562
Neutropenia	49 (51.6)	26 (45.6)	23 (60.5)	0.224
G3 or above	10 (10.5)	5 (8.8)	5 (13.2)	0.514
Thrombocytopenia	53 (55.8)	37 (64.9)	16 (42.1)	0.047 a
G3 or above	5 (5.3)	5 (8.8)	0 (0)	0.081
Biochemistry (%)
Raised AST	68 (71.6)	47 (82.5)	21 (55.3)	0.008 b
G3 or above	2 (2.1)	1 (1.8)	1 (2.6)	1.000
Raised bilirubin	21 (22.1)	14 (24.6)	7 (18.4)	0.650
G3 or above	2 (2.1)	1 (1.8)	1 (2.6)	1.000
Non-hematologic (%)
Acneiform rash	58 (61.1)	36 (63.2)	22 (57.9)	0.764
G3 or above	3 (3.2)	1 (1.8)	2 (5.3)	0.562
Diarrhoea	25 (26.3)	17 (29.8)	8 (21.1)	0.476
G3 or above	2 (2.1)	2 (3.5)	0 (0)	0.515
Hand-foot syndrome	2 (2.1)	2 (3.5)	0 (0)	0.515
G3 or above	2 (2.1)	2 (3.5)	0 (0)	0.515

The incidence of thrombocytopenia^a and raised AST^b was significantly higher in the oral FU group. No significant difference was noted in the grade 3 or above adverse effects between the two treatment groups.

¹ G3 refers to grade 3.