3.1 Study selection
A total of 657 potentially relevant studies were identified by the Screening electronic retrieval strategy as of April 2022. Of these studies, 624 were excluded after a review of study titles and abstracts as they did not meet the original requirements. After a full-text review of 33 potentially eligible articles, 5 of them met the assessment criteria and were included in this study (Figure 1). Figure 1 shows the literature screening process, and Table 1 reveals the characteristics of the included studies (Table 1).
Table1: Characteristics have included randomized controlled trials.
Characteristic
|
R. A. Adams 2021
|
R. Geng2020
|
K. K. H. Goey2017
|
H. Y. Luo 2016
|
L. H. J. Simkens2015
|
CAP
|
AM
|
CAP
|
AM
|
CAP
|
AM
|
CAP
|
AM
|
CAP
|
AM
|
(n=127)
|
(n=127)
|
(n=25)
|
(n=22)
|
(n=278)
|
(n=279)
|
(n=136)
|
(n=138)
|
(n=278)
|
(n=279)
|
Sex, No. (%)
|
|
|
|
|
|
|
|
|
|
|
Male
|
86(68)
|
76(60)
|
15(60)
|
13(59)
|
361(65)
|
83(61)
|
86(62)
|
182(65)
|
179(64)
|
Female
|
41(32)
|
51(40)
|
10(40)
|
9(41)
|
196(35)
|
53(39)
|
52(38)
|
96(35)
|
100(36)
|
Median age, years (range)
|
64(≥18)
|
65(≥18)
|
NR
|
NR
|
64 (26–81)
|
56 (27–78)
|
54 (23–78)
|
63 (26–81)
|
64 (31–81)
|
WHO/ECOG PS, No. (%)
|
|
|
|
|
|
|
|
|
|
|
0
|
80(63)
|
76(60)
|
7(28)
|
6(27)
|
345(62)
|
28(21)
|
18(13)
|
172(62)
|
173(62)
|
1
|
45(35)
|
49(39)
|
18(72)
|
16(72)
|
212(38)
|
102(75)
|
108(78)
|
106(38)
|
106(38)
|
2
|
2(2)
|
2(2)
|
|
|
0
|
1(1)
|
5(4)
|
0
|
0
|
Primary tumor type, No. (%)
|
|
|
|
|
|
|
|
|
|
|
Right colon
|
47 (37)
|
45(35)
|
10(40)
|
8(36)
|
122(22)
|
84(62)
|
84(61)
|
194(70)
|
203(73)
|
Left colon
|
33(26)
|
32(25)
|
15(60)
|
14(64)
|
406(73)
|
|
|
|
|
Rectum
|
47(37)
|
50(39)
|
0
|
0
|
NR
|
52(38)
|
54(39)
|
84(30)
|
76(27)
|
Resected primary tumor, No.
|
(%)
|
|
|
|
|
|
|
|
|
|
Resected primary
|
54 (43)
|
62 (49)
|
16(64)
|
13(59)
|
180 (32)
|
111(82)
|
121(88)
|
155(56)
|
172(62)
|
Unresected primary
|
68 (54)
|
61 (48)
|
9(36)
|
9(41)
|
230 (41)
|
25(18)
|
17(12)
|
123(44)
|
107(38)
|
Number of metastatic sites.
|
No. (%)
|
|
|
|
|
|
|
|
|
|
1
|
40(31)
|
41(32)
|
14(56)
|
9(41)
|
229(41)
|
NR
|
NR
|
118(42)
|
111(40)
|
≥1
|
83(65)
|
84(66)
|
11(44)
|
13(59)
|
302(54)
|
NR
|
NR
|
150(54)
|
152(54)
|
Unknown
|
4(3)
|
2(2)
|
0
|
0
|
26(5)
|
NR
|
NR
|
10(4)
|
16(6)
|
Metastatic time, No. (%)
|
|
|
|
|
|
|
|
|
|
|
Metachronous
|
21 (17)
|
40 (31)
|
15 (60)
|
13 (59)
|
147(26)
|
81(60)
|
79(57)
|
59(21)
|
88(32)
|
Synchronous
|
101 (80)
|
85 (67)
|
10 (40)
|
9 (41)
|
410(74)
|
55(41)
|
59(43)
|
219(79)
|
191(68)
|
Response to induction treatment
|
|
|
|
|
|
|
|
|
|
|
CR/PR
|
76(60)
|
78(61)
|
12(48)
|
9(41)
|
366 (66)
|
58(43)
|
61(44)
|
182(65)
|
184(66)
|
SD
|
51(40)
|
49(39)
|
13(52)
|
13(59)
|
191 (34)
|
78(57)
|
77(56)
|
96(35)
|
95(34)
|
CAP, capecitabine; AM, active monitoring; WHO/ECOG PS, WHO performance status /Eastern Cooperative Oncology Group performance status; CR, Complete response; PR, Partial response; SD, Stable disease; NR, none or not reported.
3.2 Risk of bias assessment
The Cochrane tool was used to qualitatively assess the risk of bias in the included literature to assess the indicators of each study (Figure 2). Among the 5 literatures, 3 were not blind, 1 was blind and unclear, 1 was unassigned and hidden, and 2 were unclear, resulting in the risk of bias (Figure 2) [3, 12, 17, 18]. In general, there are 5 literatures with low bias risk and high quality, one of which is 6 points, and the remaining 4 literatures with moderate bias risk. In Figure. 2, "+" meets the standard, and "-" fails to meet the standard. Figure. A. 1 shows the proportion of each item in the methodological evaluation of the literature in this study (Figure A. 1 in the appendix).
3.3 Study Characteristics
The meta-analysis included five trials[2, 3, 12, 17, 18], published between April 2015 and August 2021, of which three were conducted in European countries and two in China. Five trials involved 1672 patients, of which 832 patients received capecitabine maintenance treatment, and 840 patients did not receive any maintenance treatment (all active monitoring). The median age of patients in these trials was 64 years (range: 26-81 years), of which 1071 (64%) were men and 601 (36%) were women. The time of first-line treatment varied between trials, ranging from 16 weeks to 24 weeks (Table 1). Disease evaluation (%) at the end of first-line treatment, 61% of patients were in complete (CR) or partial remission (PR), and 39% of patients were stable. The characteristics of these studies are shown in Table 1.
3.4 Efficacy
3.4 .1 Maintenance Therapy vs Active Monitoring
Five trials compared capecitabine maintenance therapy with active monitoring[2, 3, 12, 17, 18] (Table A.1 in the appendix). The median PFS was 3.88 to 11.7 months in the capecitabine maintenance group and 1.87 to 8.6 months in the active monitoring group. Capecitabine maintenance therapy had a significant benefit in PFS compared with active monitoring (HR 0.59; 95%CI: 0.52-0.66; P < 0.00001). Significant heterogeneity was found (Chi2=17.55, P =0.002; I2=77%) (Figure 3a, Table 2). On the other hand, capecitabine maintenance therapy had a median OS of 14.8 to 25.63 months compared with 15.2 to 23.3 months in the active monitoring group, and capecitabine maintenance therapy also had a benefit in OS compared with active surveillance (HR 0.85; 95%CI: 0.76-0.95; P=0.003). No heterogeneity was found (Chi2=2.22, P =0.70; I2=0%) (Figure 3b, Table 2).
Table 2. Median survival time.
Study (Cap/AM)
|
|
Median OS (Months)
|
|
Median PFS (Months)
|
|
Cap
|
AM
|
|
Cap
|
AM
|
Focus4-N
|
2021
|
|
14.8
|
15.2
|
|
3.88
|
1.87
|
R. Geng
|
2020
|
|
23.82
|
21.81
|
|
5.66
|
3.98
|
CAIR3
|
2017
|
|
21.6
|
18.2
|
|
11.6
|
8.6
|
H.Y. Luo
|
2016
|
|
25.63
|
23.3
|
|
10.43
|
7.82
|
CAIR03
|
2015
|
|
21.6
|
18.1
|
|
11.7
|
8.5
|
CAP, capecitabine; AM, active monitoring; OS: overall survival; PFS: progression-free survival.
3.4.2 Subgroup Analyses
BRAF mutants, RAS mutants and BRAF/RAS wild-type data were reported in 2 trials[3, 18] (Table A.1 in the appendix). A total of 711 patients were included in the meta-analysis. Direct comparison of fixed effect models showed that capecitabine maintenance therapy was significantly more effective than active monitoring in patients with BRAF/RAS wild-type (OR 1.65; 95%CI: 1.10-2.47, P=0.02) (Chi2=0.02, P heterogeneity =0.89; I2=0%) (Figure 4). However, the efficacy was poor in patients with BRAF mutants (OR 1.22; 95%CI: 0.66-2.26, P=0.52) (Chi2=0.24, P heterogeneity =0.62; I2=0%) (Figure 4) and RAS mutants (OR 0.83; 95%CI, 0.62-1.11, P=0.21) (Chi2=0.58, P heterogeneity =0.42; I2=0%) (Figure 4).
Figure 4: BRAF and RAS status subgroup analysis.
3.4.3 Quality of life
Two studies reported quality of life data in patients receiving capecitabine maintenance therapy [3, 17]. Richard A. Adams et al. After randomization, the trial patients were asked questions with EQ-5D questionnaire every 8 weeks. 93% of patients (AM group) and 90% of patients (capecitabine) completed the EQ-5D questionnaire. The data of 63%, 45% and 33% of patients were available at 8 weeks, 16 weeks and 24 weeks respectively, and then gradually decreased. The author investigated the data for 48 weeks. The authors reported that there were no significant differences between the two groups in terms of activity ability, self-care, daily activities, anxiety and depression. However, there are indications that capecitabine maintenance treatment patients may have less pain and discomfort (x2 AUC difference 52.49, p5.11) [3].
Like H J Simkens et al. Used QLQ-C30 questionnaire to evaluate the quality of life every 9 weeks after randomization. A total of 492 patients were analyzed for quality of life, of which 249 were in the active monitoring group and 243 in the capecitabine maintenance group. Except for insomnia, the baseline quality of life of the two groups was similar. Capecitabine maintained the overall quality of life during treatment (mean change 0.03; 95% CI: 0.35 - 0.41), and the functional and symptom scale scores of the quality of life did not deteriorate. During the active monitoring period, it was found that there was a small significant improvement in the overall quality of life (the average change was 1.4; 95% CI: 0.8-2.1). During active monitoring or capecitabine maintenance, the authors said that they observed a significant difference in the overall quality of life within the group of 4.2 points (95% CI: 1.5-6.8), well below the clinically relevant threshold of 10 points[17].
3.5 Safety
3.5.1 Grade 3–4 Hand-foot skin reaction
Grade 3-4 hand-foot skin reactions were reported in 4 trials[2, 3, 12, 17] (Table A.1 in the appendix); A total of 1132 patients were included in the meta-analysis. The incidence of grade 3-4 hand and foot skin reactions was 2.3%~8% in the capecitabine group and 0.7%~4.5% in the active monitoring group. Fixed effects model was used for combined estimation. Meta-analysis showed that capecitabine maintenance therapy significantly increased grade 3-4 hand-foot skin reactions compared with active monitoring (2.3% vs. 0.4%; OR 5.53, 95%CI: 1.42-21.58, I2=0%, P=0.01) (Table 3).
Table 3 Summary of grade 3–4 adverse events (AEs).
CAP, capecitabine; AM, active monitoring.
3.5.2 Grade 3–4 hematological toxicity
Grade 3–4 hematological toxicity was reported in 3 studies, of which neutropenia and anemia were reported in 3 trials [2, 3, 12]and thrombocytopenia was reported in 2 trials[2, 12] (Table A.1 in the appendix). The incidence was between 2.3% and 7.6% in the capecitabine maintenance group and between 1.7% and 4.3% in the active monitoring group. Fixed effects model was used for combined estimation. A total of 575 patients were assessed for grade 3-4 hematologic events. There was no significant difference between the two groups (5.1% vs. 3.3%; OR 1.62, 95%CI: 0.96-2.75, I2=0%, P=0.77) (Table 3).
3.5.3 Grade 3–4 diarrhea
Three trials described grade 3-4 diarrhea[2, 3, 12] (Table A.1 in the appendix). A total of 575 patients were included in the meta-analysis. Grade 3 to 4 diarrhea rates were 2.9% to 4.7% in the capecitabine maintenance group and 1.4% to 4.5% in the active monitoring group. Fixed effects model was used for combined estimation. Meta-analysis results showed no significant difference between the two groups (3.8% vs 2.1%; OR 1.85, 95%CI: 0.67-5.06, I2=0%, P=0. 23) (Table 3).
3.5.4 Grade 3–4 Mucositis
Three trials described mucositis of grade 3-4[2, 3, 12] (Table A.1 in the appendix). A total of 575 patients were included in the meta-analysis. The incidence of grade 3-4 mucositis was 0%~5.8% in capecitabine maintenance treatment group and 0%~2.9% in active monitoring group. Fixed effects model was used for combined estimation. Meta-analysis showed no significant difference between the two groups (3.1% vs. 1.4%; OR 2.17, 95%CI: 0.69-6.82, I2=0%, P=0.18) (Table 3).
3.5.5 grade 3-4 nausea and vomiting
Two studies reported grade 3-4 nausea and vomiting[3, 12] (Table A.1 in the appendix). The incidence ranged from 1.5% to 4.4% in the capecitabine maintenance group and from 1.5% to 3.6% in the active monitoring group. The fixed effect model is used for joint estimation. A total of 528 patients were assessed as grade 3-4 nausea and vomiting events. Meta analysis showed no statistically significant difference between the two groups (3% vs 2.6%; OR 1.16,95% CI: 0.41-3.26, I2 =0%, P=0.78) (Table 3).
3.5.6 mortality
Mortality was reported in five studies[2, 3, 12, 17, 18] (Table A.1 in the appendix). Mortality ranged from 48% to 95% in the capecitabine maintenance group and 54% to 98% in the active surveillance group. The fixed effect model is used for joint estimation. A total of 1,420 patients died. Meta-analysis showed no statistically significant difference between the two groups (83% vs.85%; OR 0.88,95% CI: 0.67-1.16, I2 =22%, P=0.36) (Figure A. 2 in the appendix).
3.6 GRADE of the outcomes
The GRADE system was used to synthesize and grade evidence for the results. In PFS, OS, neutropenia, anemia, thrombocytopenia, diarrhea, mucositis, mortality, nausea, vomiting, and hand foot skin reactions have moderate levels of evidence (Table 4). However, the evidence level of BRAF mutant, RAS mutant and BRAF/RAS wild type is low (Table 4).
Table 4 Strength of evidence for capecitabine maintenance versus active monitoring after first-line mCRC treatment.
Outcomes
|
Illustrative comparative risks* (95% CI)
|
Relative effect (95% CI)
|
No of Participants (studies)
|
Quality of the evidence (GRADE)
|
Study population
|
Assumed risk
|
Corresponding risk
|
PFS
|
0 per 1000
|
-2147483648 per 1000
|
HR 0.59(0.52 to 0.66)
|
(5 studies)
|
Moderate
|
OS
|
0 per 1000
|
-2147483648 per 1000
|
HR 0.85(0.76 to 0.95)
|
(5 studies)
|
Moderate
|
BRAF mutation
|
192 per 1000
|
33 more per 1000
|
OR 1.22 (0.66 to 2.26)
|
291(2 studies)
|
Low
|
RAS mutation
|
552 per 1000
|
46 fewer per 1000
|
OR 0.83 (0.62 to 1.11)
|
711(2 studies)
|
Low
|
RAS/BRAF WT
|
621 per 1000
|
109 more per 1000
|
OR 1.65 (1.1 to 2.47)
|
511(2 studies)
|
Low
|
Mucositis
|
14 per 1000
|
30 per 1000(10 to 88)
|
OR 2.17 (0.69 to 6.82)
|
575(3 studies)
|
Moderate
|
Nausea, vomiting
|
26 per 1000
|
31 per 1000(11 to 81)
|
OR 1.16 (0.41 to 3.26)
|
528(2 studies)
|
Moderate
|
Hand-foot skin reaction
|
4 per 1000
|
19 per 1000(5 to 71)
|
OR 5.53 (1.42 to 21.58)
|
1132(4 studies)
|
Moderate
|
Neutropenia
|
42 per 1000
|
78 per 1000(39 to 149)
|
OR 1.93 (0.93 to 4.01)
|
575(3 studies)
|
Moderate
|
Anemia
|
17 per 1000
|
20 per 1000(6 to 65)
|
OR 1.18 (0.36 to 3.93)
|
575(3 studies)
|
Moderate
|
Diarrhea
|
21 per 1000
|
38 per 1000(14 to 98)
|
OR 1.85 (0.67 to 5.06)
|
575(3 studies)
|
Moderate
|
Mortality rate
|
862 per 1000
|
836 per 1000(795 to 840)
|
OR 0.88(0.67 to 1.16)
|
1682(5 studies)
|
Moderate
|
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
PFS progression-free survival, OS overall survival, PR partial response, RR complete response, SD Stable disease.