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. 2020 Nov;9(11):6963–6987. doi: 10.21037/tcr-20-2303

Is there an efficacy-effectiveness gap between randomized controlled trials and real-world studies in colorectal cancer: a systematic review and meta-analysis

Xiao Zhang 1, Shihui Fu 1, Rui Meng 1, Yu Ren 1, Ye Shang 1, Lei Tian 1,✉
PMCID: PMC8799209  PMID: 35117304

Abstract

Background

To investigate whether patients with colorectal cancer (CRC) enrolled in randomized controlled trials (RCTs) and real-world studies (RWS) differ in terms of baseline characteristics, leading to an efficacy-effectiveness gap.

Methods

A systematic literature reviews was conducted to identify RCTs and RWS with CRC, treated with bevacizumab (BEV), cetuximab (CET) or oxaliplatin combined with capecitabine (XELOX). Using random-effects meta-analyses compared the baseline characteristics and treatment effects of RCTs and RWS, overall and by drug. Correlation between treatment effects and baseline characteristics and study types were estimated using meta-regression analyses.

Results

Two hundred and fifty-three studies were included. Compared with patients enrolled in RWS, the proportion of male patients in RCTs was 0.032 higher (P=0.004), the proportion of patients with Eastern Cooperative Oncology Group (ECOG) performance ≥2 was 0.085 less (P<0.001). No significant differences in treatment effects [progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR)] were found by overall analysis. But the OS of patients in RCTs was 4.184 higher (P=0.023) in the CET group. Meta-regression results showed that OS difference in the CET group was related to the difference in treatment lines, not related to other baseline characteristics and study types.

Conclusions

No efficacy-effectiveness gap was found in CRC between RCTs and RWS. CRC treatment effects Between RCTs and RWS had high consistency.

Keywords: Efficacy-effectiveness gap, randomized controlled trials (RCTs), real-world studies (RWS), colorectal cancer (CRC)

Introduction

In the process of developing clinical diagnosis and treatment guidelines and healthcare policy, it is essential to obtain valid clinical trial evidence, in which randomized controlled trials (RCTs) are recognized as the gold standard for evaluating interventions (1). In most countries, such as the United Kingdom, Canada, and South Korea, the development of health decision-making and clinical practice guidelines are based on research-based RCTs (2). With the increasingly complicated situation and high cost of cancer treatment, the conducting clinical trials in cancer are facing more challenges. People have begun to realize that RCTs do not match the real-world environment and lack external validity, due to moderately and highly standardized trial designs, strict patient inclusion and exclusion criteria, and short follow-up time (3). Unlike RCTs, real-world studies (RWS) are a type of research that reflects the actual clinical diagnosis and treatment process, based on the real-world data. Principles of its research design are mainly non-randomization, non-intervention, and openness, which are closer to the actual clinical treatment environment and have higher external validity. RWS have received an increasing amount of attention, since the United States Congress passed the 21st Century Cures Act in 2016, which made it clear that the FDA could use real-world data as evidence of approval for post-marketing research and new indications for medical devices and drugs, where appropriate. In 2018, the FDA announced Real-World Evidence Program, which presents a detailed standard for evaluating the quality of real-world evidence. Recently, the FDA approved a new indication for Pfizer’s Ibrance based on the real-world data, which is the first drug indication approved by the FDA based on real-world data. RWS immediately ignited the hot topic (4,5).

There has been much controversy about the application and differences in results between RCTs and RWS. A study by Jaksa et al. (6) showed that RWS may amplify the positive effects of interventions and allow health policymakers to make favorable decisions. A study by Naudet et al. (7) showed that RCTs are more efficient than RWS in the study of treatment for major depression. Some studies (8-12) have compared the baseline characteristics and treatment effects of patients in RCTs and RWS and showed that RCTs tend to include patients with better prognostic factors and high treatment effects. They also proposed the concept of the efficiency-effectiveness gap to describe the gap between treatment effects observed in RCTs and those observed in RWS. However, other studies (13-18) have shown that most RCTs in the same disease and treatment methods have very similar results to RWS. As the design and reporting quality of RWS improve, respectively, the consistency with the results of RCTs becomes higher.

Although there is much debate about the differences between RCTs and RWS, comparative studies for colorectal cancer (CRC) are still lacking. no valid evidence is available to indicate the difference between RCTs and RWS in CRC. Based on previous studies, we performed a meta-analysis to investigate whether patients with CRC enrolled in RCTs and RWS differ in terms of baseline characteristics, leading efficacy-effectiveness gap. Oxaliplatin combined with capecitabine (XELOX), and targeted drugs [e.g., cetuximab (CET), bevacizumab (BEV)] combined with chemotherapy should be used as effective first- and second-line treatments for chemotherapy-resistant patients with metastatic CRC according to NCCN Clinical practice guidelines in oncology (version 1.2017) (19) and The Chinese Diagnosis and Treatment Specification of Colorectal Cancer (2017 edition) (20). Therefore, this study selected XELOX, CET monotherapy or combined chemotherapy, BEV monotherapy or combined chemotherapy as the therapeutic regimens.

We present the following article in accordance with the PRISMA reporting checklist (available at http://dx.doi.org/10.21037/tcr-20-2303).

Methods

Literature search strategy

We searched Medline and Embase to find relevant articles published from 20 September 2009 to 20 September 2019 in English using the main search terms “bevacizumab”, “cetuximab”, “XELOX” and “colorectal cancer”. Considering the incomplete development of real-world research methods, the database search was limited to last 10 years of research. In addition, references for secondary research were manually retrieved to supplement the original research literature. Specific search strategies show in Table 1.

Table 1. Search strategy.

No. Search strategy
1 (colorectal cancer or CRC or Colorectal carcinoma or Colorectal neoplasms).ti,ab,ot,hw,rn.
2 (Cetuxim* or Erbitux).ti,ab,ot,hw,rn.
3 (Bevacizum$b or CAPOX-B).ti,ab,ot,hw,rn.
4 (Oxaliplatin or L-OHP or OXA).ti,ab,ot,hw,rn.
5 (capecitabine or Xeloda or ECX).ti,ab,ot,hw,rn.
6 4 and 5
7 XELOX or CapeOX.ti,ab,ot,hw,rn.
8 Or/6-7
9 Or/2,3,8
10 1 and 9
11 limit 10 to yr=“2009-current”
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Study selection

Titles and abstracts of all retrieved literature were imported into the NoteExpress V3.2.0. The repeat literature was removed. Two reviewers (XZ and SF) independently performed the study selection, including screening titles and abstracts, and evaluating full-text eligibility of potentially eligible studies. Discussion or negotiation with a third party was implemented if there were divergences. If necessary, we contacted the original authors by email or phone to obtain unidentified information.

Included studies need to meet the following criteria: (I) studies that enrolled patients with CRC treated with BEV, CET or XELOX; (II) studies that reported on at least one of the following clinical outcomes: (i) primary outcomes: progression-free survival (PFS), overall survival (OS); (ii) secondary outcomes: response rate (RR) including disease control rate (DCR), objective response rate (ORR), complete response rate (CR), partial response rate (PR), and stable disease (SD) based on the measurement of cancer antigen 125 levels confirmed by radiological examination results or by combined Gynecologic Cancer InterGroup criteria.

Studies not meeting the inclusion criteria were excluded. Other exclusion criteria were: (I) studies in which BEV, CET or XELOX was used as neoadjuvant treatments; (II) studies with a sample size of less than 30; (III) non-English studies.

Data extraction

Data from each included paper were extracted into a standardized spreadsheet developed for this project by two reviewers independently with adjudication by a third reviewer: study characteristics (e.g., title, author, publication year, study design, country, study horizon, follow-up time, trial name, and registration number); treatments (e.g., drug, dose, frequency, and cycle); patient characteristics (e.g., sample size, age, gender, Eastern Cooperative Oncology Group (ECOG), treatment line, tumor location, and transfer); treatment effects (e.g., PFS, OS, RR, DCR, ORR, CR, PR, and SD). We extracted frequency number and percentages. All patients included in the study were fully enrolled in the primary studies, and no witching over treatment or treatment discontinuation.

Data synthesis and statistical analysis

Data on patient baseline characteristics (age, proportions of male, proportion of patients with ECOG ≥2, proportion of patients with second-line and above second-line treatment) and treatment effects (PFS, OS, ORR, DCR) were finally analyzed. The ORR = CR + PR and DCR = ORR + SD were used to process the tumor response results. The methods described by Wan et al. (21) were used to convert the mean and range of continuous variables such as age, PFS, and OS into mean and standard deviation, whereas the other variables were presented as ratios. We first combine the baseline characteristics and treatment effects of CRC patients in RCTs and RWS using random-effect meta-analyses, and subsequently to compare the difference of the combined results.

We used meta-regression analyses to assess the heterogeneity by including the baseline characteristics as covariates, the study design as a dichotomous covariate, and treatment effects as dependent variables. We used restricted maximum-likelihood estimation to assess between-study variance (tau-squared) and applied the Knapp-Hartung adjustment (22).

Considering the follow-up time, treatment cycle and duration would have a major impact on the treatment effects, a comparative analysis of follow up time, treatment cycle and duration between RCT and RWS was added. All analyses were done in the Stata SE15.

Results

Characteristics of included studies

We identified 6,147 records through database searching, and 2 potentially eligible studies through other sources. After duplicate checking and title and abstract screening, 369 full-text articles assessed for eligibility. Finally, 369 full-text articles assessed for eligibility. Finally, 201 articles were eventually included: 117 RCTs including 94 phase II clinical trials, 6 phase III clinical trials, and 17 unknown phase clinical trials; 84 RWS including 36 case series, 13 registry, 20 cohort, and 15 unknown category of studies. There were 102 studies on BEV treatment, 54 studies on CET treatment, and 45 studies on XELOX treatment. A total of 37,479 patients were included, with 13,889 patients in RCTs and 23,590 patients in RWS. The process and results of article selection show in Figure 1. The main characteristics of all studies show in Tables 2,3.

Figure 1.

Figure 1

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Flow chart. RCT, randomized controlled trial; RWS, real-world studies; BEV, bevacizumab; CET, cetuximab; XELOX, oxaliplatin combined with capecitabine.

Table 2. Baseline characteristics of RCTs.

No. Reference Year Study phase Country/region Sample size Drug Characteristics Outcomes Registration number
1 Kim et al. (23) 2019 Phrase II Korea 60 BEV 1,2,3,4 5,7,8 NCT02026583
2 Cremolini et al. (24) 2019 Phrase II Italy 117 BEV 1,2,4 5,7,8 NCT02271464
3 Suzuki et al. (25) 2019 Phrase II Japan 51 BEV 1,2,3,4 6,8 UMIN 000009280
4 Nakayama et al. (26) 2018 Phrase II Japan 54 BEV 1,2,4 5,6,7,8 UMIN000006478
5 Oki et al. (27) 2018 Phrase II Japan 69 BEV 1,2,3,4 5,6,7 NCT02246049
6 Jonker et al. (28) 2018 Phrase II Canada 51 BEV 1,2,3,4 8 NA
7 Satake et al. (29) 2018 Phrase II Japan 62 BEV 1,2,3,4 5,6,7 NA
8 Matsuda et al. (30) 2018 Phrase II Japan 51 BEV 2,3,4 5,6,8 NA
9 Ulivi et al. (31) 2018 Phrase I/II Italy 65 BEV 1,2,4 5,7,8 NA
10 Venook et al. (32) 2017 NA USA 559 BEV 1,2,3,4 5,8 NCT00265850
11 Nakayama et al. (33) 2017 Phrase II Japan 52 BEV 1,2,3,4 5 UMIN000006478
12 Apsangikar et al. (34) 2017 NA India 33 BEV 2,3,4 5,8 NA
13 Zhao et al. (35) 2017 Phrase II China 122 BEV 1,2,3,4 5,8 NA
14 Baba et al. (36) 2017 Phrase I/II Japan 256 BEV 4 7,8 NA
15 Matsui et al. (37) 2016 Phrase II Japan 51 BEV 1,2,3,4 5,7 NA
16 Ogata et al. (38) 2016 NA Japan 47 BEV 1,2,3,4 5,6,7 NA
17 Yamazaki et al. (39) 2016 Phrase I/II Japan 197 BEV 1,2,3,4 8 UMIN000001396
18 van Hazel et al. (40) 2016 Phrase I/II Australia 263 BEV 1,2,3,4 5 NA
19 Stintzing et al. (41) 2016 Phrase I/II Germany 201 BEV 2,3,4 5,7,8 NA
20 Shitara et al. (42) 2016 Phrase II Japan 58 BEV 1,2,3,4 8 NA
21 Hagman et al. (43) 2016 NA Sweden 35 BEV 1,2,3,4 8 NCT01229813
22 Benson et al. (44) 2016 Phrase II USA 88 BEV 2,3,4 5 NCT01478594
23 Shimomura et al. (45) 2016 Phrase II Japan 55 BEV 1,2,3,4 5,6,7,8 NA
24 Passardi et al. (46) 2015 Phrase I/II Italy 176 BEV 1,2,4 5,7,8 NCT01878422
25 Antonuzzo et al. (47) 2015 Phrase I/II Italy 197 BEV 1,2,3,4 5,7,8 NCT00577031
26 Iwamoto et al. (48) 2015 Phrase I/II Japan 181 BEV 1,2,3,4 – UMIN000002557
27 Hegewisch et al. (49) 2015 Phrase I/II Germany 158 BEV 1,2,3,4 8 NCT00973609
28 Masi et al. (50) 2015 Phrase I/II Italy 92 BEV 1,2,3,4 5,6,8 NCT00720512
29 Cao et al. (51) 2015 Phrase II China 65 BEV 1,2,4 5,6,8 NA
30 Wang et al. (52) 2015 NA China 114 BEV 1,2,3,4 5,6,8 NA
31 Garcia et al. (53) 2015 Phrase II Spain 77 BEV 1,2,3,4 5,6,7,8 NCT00875771
32 Liu et al. (54) 2015 Phrase II China 30 BEV 1,2,3,4 5,8 NA
33 Nakayama et al. (55) 2015 Phrase II Japan 40 BEV 1,2,3,4 5,6,7,8 UMIN000001127
34 Heinemann et al. (56) 2014 Phrase I/II Germany 295 BEV 1,2,3,4 5,7,8 NCT00433927
35 Duran et al. (57) 2014 NA Turkey 298 BEV 2,3,4 5,7,8 NA
36 O'Neil et al. (58) 2014 Phrase II USA 49 BEV 1,2,3,4 5 NA
37 Uygun et al. (59) 2013 NA Japan 64 BEV 1,2,3,4 5,8 NA
38 Schmiegel et al. (60) 2013 Phrase II Germany 127 BEV 1,2,3,4 7,8 NA
39 Kochi et al. (61) 2013 Phrase II Japan 39 BEV 1,2,3,4 5,6,7 NA
40 Bennouna et al. (62) 2013 Phrase I/II France 409 BEV 1,2,3,4 5,8 NCT00700102
41 Ducreux et al. (63) 2013 Phrase II France 72 BEV 1,2,3,4 5,7,8 NA
42 Cunningham et al. (64) 2013 NA UK 66 BEV 2,3,4 5,8 NA
43 Yalcin et al. (65) 2013 Phrase I/II Turkey 62 BEV 1,2,3,4 5,7,8 NA
44 Johnsson et al. (66) 2013 Phrase I/II Sweden 80 BEV 1,2,3,4 8 NCT00598156
45 Hong et al. (67) 2013 Phrase II Korea 57 BEV 1,2,3,4 5,8 NA
46 Stintzing et al. (68) 2012 NA Germany 46 BEV 1,2,3,4 5,6,7,8 NCT00433927
47 Pectasides et al. (69) 2012 Phrase I/II Australia, New Zealand 143 BEV 1,2,3,4 5,7,8 NA
48 Díaz-Rubio et al. (70) 2012 Phrase I/II Spain 241 BEV 1,2,3,4 5,7,8 NA
49 Hurwitz et al. (71) 2012 Phrase II USA 217 BEV 2,3,4 5,8 NCT00159432
50 Renouf et al. (72) 2012 Phrase II Canada 50 BEV 1,2,3 5,6 NA
51 Wolff et al. (73) 2012 Phrase II USA 58 BEV 1,2,3,4 – NA
52 Tang et al. (74) 2012 Phrase II NA 51 BEV 1,2,3 8 NA
53 Yamada et al. (75) 2012 Phrase II Japan 51 BEV 1,2,3 5,6 NA
54 Wong et al. (76) 2011 Phrase I/II NA 31 BEV 2 – NA
55 Guan et al. (77) 2011 Phrase I/II China 139 BEV 1,2,3,4 5,7,8 NCT00642577
56 Altomare et al. (78) 2011 Phrase II USA 50 BEV 1,2,4 8 NCT00597506
57 Kopetz et al. (79) 2010 Phrase II USA 43 BEV 1,2,4 5,8 NA
58 Bruera et al. (80) 2010 Phrase II NA 50 BEV 1,2,4 5,8 NA
59 Masi et al. (81) 2010 Phrase II Italy 57 BEV 1,2,3,4 5,6,7,8 NCT01163396
60 Tebbutt et al. (82) 2010 Phrase I/II Australia, New Zealand 157 BEV 1,2,3,4 5,7,8 NA
61 Aranda et al. (83) 2018 Phrase II NA 129 CET 1,2,3,4 7 NA
62 Kotake et al. (84) 2017 Phrase II Japan 60 CET 1,2,3,4 5,6,7 NA
63 Kataoka et al. (85) 2017 Phrase II Japan 32 CET 2,3,4 5,6 NA
64 Stintzing et al. (41) 2016 Phrase I/II NA 199 CET 2,3 5,8 NA
65 Hazama et al. (86) 2016 Phrase II Japan 40 CET 1,2,3,4 5,6,7,8 NA
66 Bowles et al. (87) 2016 Phrase II NA 43 CET 1,2,3 5,6,8 NA
67 Ciardiello et al. (88) 2016 Phrase II Italy 74 CET 1,2,4 5,6,8 NA
68 Eng et al. (89) 2016 Phrase II NA 60 CET 1,2,3,4 5,6,7,8 NA
69 Soda et al. (90) 2015 Phrase II Japan 62 CET 1,2,3,4 5,6,7,8 NA
70 Sclafani et al. (91) 2015 Phrase I/II UK 119 CET 2,3,4 5,6 NA
71 Do et al. (92) 2015 Phrase II USA 30 CET 1,2,4 5,7 NA
72 Élez et al. (93) 2015 NA NA 72 CET 1,2,3 5,8 NA
73 Fernandez et al. (94) 2014 Phrase II Spain 99 CET 1,2,3,4 5,6,7,8 NA
74 Heinemann et al. (56) 2014 Phrase I/II Germany 297 CET 1,2,3,4 5,6,7,8 NA
75 Iwamoto et al. (95) 2014 Phrase II Japan 60 CET 1,2,3,4 5,6,8 NA
76 Douillard et al. (96) 2014 Phrase II USA 150 CET 1,2,3,4 5,6,7,8 NA
77 Ye et al. (97) 2014 Phrase II NA 70 CET 1,2,3 5,6,8 NA
78 Siu et al. (98) 2013 NA China 374 CET 1,2,3 5,6,8 NA
79 Brodowicz et al. (99) 2013 NA NA 75 CET 1,2,4 5,6,7,8 NA
80 Hong et al. (100) 2013 NA NA 40 CET 1,2,3,4 5,6,8 NA
81 Assenat et al. (101) 2011 Phrase II France 42 CET 1,2,3,4 5,6,7 NA
82 Kullmann et al. (102) 2011 Phrase II NA 62 CET 1,2,4 5,6,7,8 NA
83 Lim et al. (103) 2011 Phrase II Asian, Australia 123 CET 1,2,4 5,6,8 NA
84 Van et al. (104) 2011 Phrase I/II Europe 599 CET 1,2,3,4 5,6,7,8 NA
85 Moosmann et al. (105) 2011 Phrase II Germany 89 CET 1,2,4 5,6 NA
86 Wong et al. (106) 2011 Phrase II USA 30 CET 1,2,3 5,8 NA
87 Shitara et al. (107) 2011 NA NA 30 CET 1,2,3,4 5,6,7 NA
88 Saridaki et al. (108) 2012 Phrase II USA 30 CET 1,2,3 5,6,8 NA
89 Stintzing et al. (68) 2012 Phrase I/II Germany 50 CET 1,2,3,4 5,6,7,8 NA
90 Shitara et al. (109) 2012 Phrase II Japan 30 CET 1,2,3,4 5,6 NA
91 Tveit et al. (110) 2012 Phrase I/II Europe 194 CET 1,2,3,4 5,7,8 NA
92 Mrabti et al. (111) 2009 Phrase I/II Morocco 32 CET 1,2,4 5 NA
93 Mizushima et al. (112) 2019 Phrase II Japan 107 XELOX 1,2,3 – NA
94 Yoshimatsu et al. (113) 2019 Phrase II Japan 57 XELOX 1,2 – ID:000005427
95 Nishimura et al. (114) 2018 Phrase II Japan 42 XELOX 1,2,3 – NA
96 Larsen et al. (115) 2017 Phrase II NA 52 XELOX 1,2,3 – NCT00964457
97 Danno et al. (116) 2017 Phrase II Japan 190 XELOX 1,2,3 5 ID:000006742
98 Azria et al. (117) 2017 NA France 291 XELOX 1,2 – NA
99 Liu et al. (118) 2016 Phrase II China 47 XELOX 1,2 5,6 NCT02415829
100 Pilanci et al. (119) 2016 Phrase II Turkey 30 XELOX 1,2,3 5,8 NO:44140529
101 Feng et al. (120) 2016 Phrase III China 224 XELOX 1,2 – NCT00714077
102 Sclafani et al. (121) 2016 Phrase II UK 50 XELOX 1,2,3 – NCT00958737
103 Kim et al. (122) 2015 Phrase II Korea 44 XELOX 1,2,3,4 5,7,8 NCT00677144
104 Wong et al. (123) 2015 Phrase II USA 52 XELOX 1,2,3 – NA
105 Kim et al. (124) 2014 Phrase III Korea 172 XELOX 2,3 – NCT00677443
106 Zhu et al. (111) 2013 Phrase II China 32 XELOX 1,2,4 7,8 NA
107 Gérard et al. (125) 2012 NA France 299 XELOX – – NA
108 Salazar et al. (126) 2012 Phrase II Spain 45 XELOX 1,2,3 5,6 NA
109 Arbea et al. (127) 2012 Phrase II Spain 100 XELOX 1,2 – NA
110 Schou et al. (128) 2012 NA Denmark 84 XELOX 1,2,3 – NA
111 Ducreux et al. (129) 2011 Phrase III France 156 XELOX 1,2,3,4 5,7,8 NA
112 Haller et al. (130) 2011 Phrase III 29countries 944 XELOX 1,2,3 – NO16968
113 Waddell et al. (131) 2011 Phrase II UK 45 XELOX 1,2,3 5,6,8 NA
114 Baraniskin et al. (132) 2011 Phrase III Germany 190 XELOX 2,4 5,7,8 NA
115 Cassidy et al. (133) 2011 Phrase III UK 317 XELOX 1,2,3,4 8 NO16966
116 Li et al. (134) 2010 Phrase II China 124 XELOX 1,2,3,4 5,7,8 NA
117 Qvortrup et al. (135) 2010 Phrase II Denmark 70 XELOX 1,2,3,4 8 NA
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Age =1; gender =2; ECOG =3; treat-line =4; ORR =5; DCR =6; PFS =7; OS =8. UK, United Kingdom; USA, the United States of America; NA, not available; BEV, bevacizumab; CET, cetuximab; XELOX, oxaliplatin combined with capecitabine; ECOG, Eastern Cooperative Oncology Group.

Table 3. Baseline characteristics of RWS.

No. Reference Year Study design Country/region Sample size Drug Characteristics Outcomes
1 Houts et al. (136) 2019 Case series USA 264 BEV 2,4 7,8
2 Degirmencioglu et al. (137) 2019 Case series Turkey 114 BEV 4 –
3 Khakoo et al. (138) 2019 Case series UK 714 BEV 1,2,3,4 7,8
4 Ogata et al. (139) 2019 NA Japan 55 BEV 1,2,3,4 5,6,8
5 Ottaiano et al. (140) 2019 Registry NA 31 BEV 1,2,3,4 5,6,8
6 Devaux et al. (141) 2019 NA France 99 BEV 1,2,3,4 5,6,8
7 Turpin et al. (142) 2018 NA France 216 BEV 1,2,4 7,8
8 Matsusaka et al. (143) 2017 NA Japan 424 BEV 1,2,4 8
9 Hasegawa et al. (144) 2017 NA Japan 58 BEV 1,2,4 5,8
10 Sun et al. (145) 2017 Case series China 217 BEV 2,3,4 5,6,8
11 Bennouna et al. (146) 2017 Cohort France 521 BEV 1,2,3,4 8
12 Chapman et al. (147) 2016 Case series Australia 292 BEV 2,4 8
13 Bai et al. (148) 2016 Registry China 188 BEV 1,2,3,4 5,7,8
14 Dionísio de Sousa et al. (149) 2016 Case series France 41 BEV 1,2,4 5,8
15 Kotaka et al. (150) 2016 Cohort Japan 40 BEV 1,2,3,4 5
16 Wong et al. (151) 2016 Registry Australia 206 BEV 2,3,4 –
17 Cabart et al. (152) 2016 NA France 164 BEV 1,2,3,4 8
18 Kocakova et al. (153) 2015 Registry Czech 357 BEV 1,2,3,4 6,8
19 Hammerman et al. (154) 2015 Cohort Israel 1,052 BEV 2,4 8
20 Stein et al. (155) 2015 Cohort Germany 1,777 BEV 1,2,3,4 5,6,8
21 Bai et al. (156) 2015 Cohort China 175 BEV 1,2,3,4 5,6,8
22 Bencsikova et al. (157) 2015 NA Czech 964 BEV 1,2,3,4 7,8
23 Tahover et al. (158) 2015 Cohort Israel 216 BEV 1,2,4 5,6,7,8
24 Kubáčková et al. (159) 2015 Registry Czech 981 BEV 1,2,4 5,6,7,8
25 Cheng et al. (160) 2015 NA China 69 BEV 2,4 5,6,8
26 Ohhara et al. (161) 2015 Cohort Japan 85 BEV 1,2,4 5,6
27 Yang et al. (162) 2014 Case series Taiwan 95 BEV 2,4 5,6,8
28 Fourrier-Réglat et al. (163) 2014 Cohort France 411 BEV 1,2,3,4 5,7,8
29 Hofheinz et al. (164) 2014 Cohort Germany 1,297 BEV 1,2,3,4 –
30 Suenaga et al. (165) 2014 Cohort Japan 85 BEV 1,2,4 5,6,7,8
31 Uchima et al. (166) 2014 NA Japan 40 BEV 1,2,4 5,6,7
32 Yin et al. (167) 2014 Case series China 87 BEV 1,2,4 7
33 Hurwitz et al. (168) 2014 Cohort USA 1,550 BEV 1,2,3,4 7,8
34 Kiss et al. (169) 2014 Registry Czech 3,990 BEV 1,2,4 5,7,8
35 Turan et al. (170) 2014 Case series Turkey 52 BEV 2 –
36 Moscetti et al. (171) 2013 Case series NA 220 BEV 1,2,3,4 5
37 Cvetanovic et al. (172) 2013 Case series NA 51 BEV 2,4 6,7
38 Wu et al. (173) 2013 Case series China 36 BEV 1,2,3,4 6,7,8
39 Meyerhardt et al. (174) 2012 Registry USA 1,589 BEV 2,3,4 5,8
40 Ghiringhelli et al. (175) 2012 Case series France 49 BEV 1,2,3 8
41 Yildiz et al. (176) 2010 NA NA 40 BEV 2,3 5,8
42 Dranitsaris et al. (177) 2010 Case series Holland 43 BEV 1,2,4 8
43 Rouyer et al. (178) 2018 Cohort France 389 CET 1,2,3,4 7,8
44 Wu et al. (179) 2018 Case series China 34 CET 1,2,4 5,7,8
45 Chapman et al. (147) 2017 Case series Australia 134 CET 2 8
46 Jerzak, et al. (180) 2017 Registry Canada 278 CET 2,4 8
47 Kim et al. (181) 2017 NA Korea 147 CET 1,2,4 8
48 Ozaslan et al. (182) 2017 Case series NA 40 CET 1,2,4 5,6,8
49 Bai et al. (148) 2016 Registry China 101 CET 1,2,3,4 5,6,7,8
50 Derangère et al. (183) 2016 Cohort France 52 CET 2,3 –
51 Pinto et al. (184) 2016 Case series Italy 225 CET 2,3,4 5,6,7,8
52 Uemura et al. (185) 2016 Case series Japan 64 CET 1,2,3,4 5,6
53 Yamaguchi et al. (186) 2016 Case series Japan 97 CET 1,2,3,4 5,8
54 Feng et al. (187) 2016 Cohort China 102 CET 2,3,4 5,6,8
55 Sato et al. (188) 2015 NA Japan 109 CET 1,2,4 8
56 Wang et al. (189) 2015 NA China 110 CET 2,3,4 5,6
57 Giampieri et al. (190) 2015 Case series Italy 46 CET 2 5,6,8
58 Yang et al. (162) 2014 Case series Taiwan 63 CET 2,4 5,6,7,8
59 Jehn et al. (191) 2014 Registry Germany 247 CET 2 5,6
60 Kennecke et al. (192) 2013 Registry Canada 37 CET 1,2,3 8
61 Chen et al. (193) 2013 Case series Taiwan 50 CET 1,2,4 5,6
62 Santos-Ramos et al. (194) 2013 Case series Spain 81 CET 2,3,4 –
63 Jehn et al. (195) 2012 NA Germany 309 CET 1,2,3,4 –
64 Bouchahda et al. (196) 2011 Case series Europe 91 CET 1,2,3,4 5,8
65 Xu et al. (197) 2019 Case series NA 108 XELOX 1,2 –
66 Loree et al. (198) 2018 Registry Canada 151 XELOX 1,2,3 –
67 Sha et al. (199) 2018 NA NA 95 XELOX 2,3 –
68 van et al. (200) 2017 Case series Holland 191 XELOX 2 –
69 Nakanishi et al. (201) 2016 Case series Japan 53 XELOX 1,2 –
70 Karin et al. (202) 2016 Registry NA 51 XELOX 2 8
71 Spada et al. (203) 2016 Case series Italy 78 XELOX 1,2,3 5,8
72 Osawa et al. (204) 2014 Case series Japan 41 XELOX 1,2,3 –
73 Osawa et al. (204) 2014 Case series Japan 41 XELOX 1,2 –
74 Loree et al. (205) 2014 Cohort Canada 83 XELOX 2,3 8
75 Chiu et al. (206) 2014 Case series Hong Kong 110 XELOX 1,2,3 –
76 Loree et al. (207) 2014 Cohort Canada 76 XELOX 1,2 –
77 Boisen et al. (208) 2014 Cohort Denmark 211 XELOX 1,2,3 8
78 Qiu et al. (209) 2014 Cohort China 64 XELOX 1,2,4 7,8
79 Fukuchi et al. (210) 2013 Case series Japan 108 XELOX 1,2,3 5,6
80 Constantinidou et al. (211) 2013 Case series UK 34 XELOX 1,2 –
81 Hansen et al. (212) 2012 Cohort Denmark 89 XELOX 2 –
82 Satram-Hoang et al. (213) 2013 Cohort USA 122 XELOX 2 8
83 Hansen et al. (212) 2012 Case series Denmark 89 XELOX 2,4 8
84 Karacetin et al. (214) 2009 Case series Turkey 34 XELOX 1,2,3 8
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Age =1; gender =2; ECOG =3; treat-line =4; ORR =5; DCR =6; PFS =7; OS =8. UK, United Kingdom; USA, the United States of America; NA, not available; BEV, bevacizumab; CET, cetuximab; XELOX, oxaliplatin combined with capecitabine; ECOG, Eastern Cooperative Oncology Group.

Comparison of patient characteristics

Compared with patients enrolled in RWS, the proportion of male patients in RCTs was 0.032 higher (0.613, 0.598 to 0.628 vs. 0.581, 0.565 to 0.597; P=0.004), the proportion of patients with ECOG ≥2 was 0.085 less (0.005, 0.003 to 0.006 vs. 0.090, 0.078 to 0.103; P<0.001). No significant differences in age and treatment line were found (Figure 2).

Figure 2.

Figure 2

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Comparison of patient characteristics. (A) Age; (B) gender; (C) ECOG ≥2; (D) treat-line ≥2. ECOG, Eastern Cooperative Oncology Group; RCT, randomized controlled trial; RWS, real-world studies; BEV, bevacizumab; CET, cetuximab; XELOX, oxaliplatin combined with capecitabine; ES, effect size; CI, confidence interval.

Subgroup analysis by drug showed that differences generally were in the same direction for the three drugs: the proportion of male patients in RCTs was 0.060 higher than those in RWS (0.622, 0.580 to 0.664 vs. 0.562, 0.524 to 0.600; P=0.038) in the XELOX group; the proportion of patients with ECOG ≥2 in RCTs was 0.075 less than those in RWS (0.006, 0.003 to 0.008 vs. 0.081, 0.065 to 0.98; P<0.001) in the BEV group, and similar results was also found in the CET group [0.175 less than those in RWS (0.006, 0.003 to 0.009 vs. 0.181, 0.118 to 0.245; P<0.001)]. Furthermore, patients in RCTs were 1.304 years older than those in RWS (59.205, 58.520 to 59.890 vs. 57.901, 56.839 to 58.963; P=0.043) in the BEV group; the proportion of patients with second-line and above second-line treatment in RCTs was 0.350 lower than those in RWS (0.281, 0.136 to 0.427 vs. 0.631, 0.403 to 0860; P=0.012) in the CET group (Figure 2). More detailed results show in Table S1 and Figures S1−S8.

Comparison of treatment effects

Primary outcomes

No significant differences were found in OS and PFS between RCTs and RWS by overall analysis. The results of subgroup analysis by drug were mostly consistent with the overall analysis, no significant differences were found in the BEV group and XELOX group, but patients in the CET group of RCTs had an OS of 4.184 months higher than that of patients in the CET group of RWS (17.432 months, 15.118 to 19.745 vs. 13.248, 11.281 to 15.215; P=0.023) (Figure 3).

Figure 3.

Figure 3

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Comparison of treatment effects. (A) PFS; (B) OS; (C) ORR; (D) DCR. PFS, progression-free survival; OS, overall survival; ORR, objective response rate; DCR, disease control rate; RCT, randomized controlled trial; RWS, real-world studies; BEV, bevacizumab; CET, cetuximab; XELOX, oxaliplatin combined with capecitabine; ES, effect size; CI, confidence interval.

Secondary outcomes

No differences in ORR and DCR were found between RCTs and RWS by overall analysis and subgroup analysis in the BEV group and CET group. However, in the XELOX group, the ORR of patients in RCTs was 0.251 higher than that of patients in RWS (0.563, 0.457 to 0.669 vs. 0.312, 0.214 to 0.410; P=0.001), and DCR was also 20.6% higher than that of patients in RWS (0.936, 0.857 to 1.016 vs. 0.730, 0.646 to 0.814; P=0.001) (Figure 3). More detailed results show in Table S2 and Figures S9−S16.

Meta-regression analyses result

According to the meta-analysis results, there were OS differences between RCT and RWS in the CET group, and ORR and DCR differences in the XELOX group. Based on the previous analysis, we found no differences in age, gender, ethnicity and other baseline characteristics of the CET group, except for ECOG and treatment line. To explore the reason for OS differences, we performed meta-regression analysis by including ECOG and treatment line as covariates, OS as dependent variables in the CET group. We extracted the proportion of patients with ECOG score ≥2, and the proportion of patients with second-line or above treatment, based on baseline data from the original study. And there were only gender differences in the XELOX group, so we included the proportion of male patients as covariates, ORR and DCR as the dependent variable in the XELOX group. To explore the impact of study design on results, included the study design as a dichotomous covariate in both groups.

The regression results showed that OS differences in the CET group were related to the difference of treatment line and were not related to ECOG and study type (Table 4). In the XELOX group, differences in treatment outcomes were independent of baseline characteristics and study type (Tables 5,6).

Table 4. Regression analyses of OS in the CET group.

OS Coef. Std. Err. t P 95% CI
Study type 2.924438 2.812611 1.04 0.314 –3.038031 to 8.886906
Treatment line 10.29738 2.341684 –4.4 0.000 –15.26153 to –5.333236
ECOG 2.644013 10.23937 –0.26 0.800 –24.3505 to 19.06248
_cons 21.47765 1.143907 18.78 0.000 19.05267 to 23.90262
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OS, overall survival; CET, cetuximab; Coef., coefficient; Std. Err., standard error; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group.

Table 5. Regression analyses of ORR in the XELOX group.

ORR Coef. Std. Err. t P 95% CI
Study type –0.2529 0.112954 –2.24 0.052 –0.50842 to 0.002623
Gender 0.422701 0.484584 0.87 0.406 –0.673505 to 1.518906
_cons 0.262381 0.294841 0.89 0.397 –0.404595 to 0.929357
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ORR, objective response rate; XELOX, oxaliplatin combined with capecitabine; Coef., coefficient; Std. Err., standard error; CI, confidence interval.

Table 6. Regression analyses of DCR in the XELOX group.

DCR Coef. Std. Err. t P 95% CI
Study type 0.0055461 0.0924147 0.06 0.962 –1.168694 to 1.179786
Gender 1.428532 0.4492353 3.18 0.194 –4.279555 to 7.136596
_cons 0.1183735 0.3428134 –0.35 0.788 –4.475501 to 4.238754
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DCR, disease control rate; XELOX, oxaliplatin combined with capecitabine; Coef., coefficient; Std. Err., standard error; CI, confidence interval.

In addition, although the case number of RWS reporting follow-up time, treatment cycle, and duration was lower than that of RCT, the t-test results for mean follow-up time, treatment cycle, and duration between RCT and RWS showed no significant difference (Table 7).

Table 7. T-test of follow up time, treatment cycle and duration.

T-test Study type Case number Mean SD P value
Follow up time/month RCT 56 29.6352 16.40549 2.19228
RWS 38 26.0416 11.32764 0.244
Treatment cycle RCT 35 7.37143 2.587705 0.212
RWS 18 7.31383 2.624251 0.939
Treatment duration/month RCT 24 4.8875 2.47607 0.940
RWS 12 5.7408 4.23496 0.449
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RCT, randomized controlled trial; RWS, real-world study; SD, standard.

Discussion

Key findings

In this systematic review and meta-analysis, we found that there were slight systematic differences in patient characteristics between RCTs and RWS in CRC. The differences in baseline characteristics mainly included a higher proportion of male patients, a lower proportion of patients with ECOG score ≥2, and a lower proportion of second-line and above-second-line treatments in RCT. The reasons for these differences may be as follows: For gender, data on CRC patients collected from the Medicare database show that the proportion of men with CRC is generally higher than that of women, however, as the sample size increases, the difference will be narrowed, since the sample size of RWS is much larger than that of RCT, the proportion of male patients in RWS is closer to 50%. In addition, according to a study, men are more likely to participate in RCTs than women (215), which also leaded to a higher proportion of male patients in RCT than RWS. For ECOG score and treatment line, RCT has more strict inclusion and exclusion criteria for patients. Patients with high ECOG score and above-second-line treatments may be excluded due to poor health status and complex medical history. Therefore, the proportion of patients with ECOG score ≥2 and second-line and above-second-line treatments in RCT is lower.

Although there were slight differences in baseline characteristics, it did not lead to any difference in treatment outcomes by overall analysis, indicating that the results of RCT and RWS were highly consistent. As for the partial differences in subgroup analysis, a further meta-regression analysis showed that the higher OS value in the CET group of RCTs were due to the inclusion of more patients who are treated in frontlines, that can be reasonably interpreted as patients treated in frontlines were in better health. But no reason was found for the difference between ORR and DCR in XELOX group due to the small number of studies and the serious lack of clinical outcome data. We suggest conducting high-quality XELOX RWS for CRC patients in the future to supplement the deficiencies of the existing research.

Strengths and implications

This comparative study focused on cancer, the anticancer treatment process had relatively high standardization in drug regimens, drug compliance, and strict monitoring measures of toxicity and adverse reaction (216,217), which greatly reduced the differences in intervention measures and patients’ drug compliance and also lowered the bias of the results. Compared with several studies in the past, regression analysis was added in this study to determine the correlation between differences in baseline characteristics and differences in treatment effects, and rule out the effect of study design on the results. We believe that the differences between RCTs and RWS in different disease areas cannot be generalized. This study will be more applicable to clarify the external validity of RCTs results for CRC in real-world applications, help understanding the current status in CRC, improving research design and providing decision-making references for health decision-making departments.

Limitations

Given that this study mainly focused on the differences in patient characteristics between RCTs and RWS rather than the results of clinical trials, we did not perform quality assessment on the literature, the RWS across different countries may result in potential confounding factors. Since the OS value did not reach the upper limit in some studies, we used conservative estimation in the analysis to assume the OS values as the longest follow-up time in this study, which may lead to the underestimation of the OS values. Due to the limitations of study time, study number, and quality of the included studies, the conclusion herein need further verification.

Conclusions

No efficacy-effectiveness gap was found in CRC between RCTs and RWS. The treatment effects of RCTs and RWS in CRC patients were highly consistent, and the results of RCTs have high external validity.

Acknowledgments

We thank our colleagues at Center for Pharmacoeconomics and Outcomes Research of China pharmaceutical university, for their scientific advice, assistance in data analysis and contribution to translation the paper.

Funding: None.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Footnotes

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at http://dx.doi.org/10.21037/tcr-20-2303

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr-20-2303). The authors have no conflicts of interest to declare.

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