Clinics and Research in Hepatology and Gastroenterology (2014) 38, 219—225

Available online at

ScienceDirect www.sciencedirect.com

ORIGINAL ARTICLE

Raltitrexed-based chemotherapy for advanced colorectal cancer Y. Liu , W. Wu , W. Hong , X. Sun , J. Wu , Q. Huang ∗ Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, No.2 Fuxue Road, 325000 Wenzhou, Zhejiang Province, PR China Available online 30 December 2013

KEYWORDS Raltitrexed; 5-fluorouracil; Chemotherapy; Advanced colorectal cancer; Meta-analysis

Summary Aims: To evaluate the efficiency and safety profile of raltitrexed-based chemotherapy in the treatment of advanced colorectal cancer. Methods: An electronic search was undertaken to identify randomized controlled trials comparing raltitrexed-based regimen to 5-fluorouracil-based regimen in patients with advanced colorectal cancer. The outcomes included overall survival, overall response rate and toxicities. Results: This meta-analysis included 11 studies with 4622 patients. Overall, there were no significant differences between the two regimens in terms of overall survival (HR = 1.06, 95% CI: 0.96—1.17, P = 0.23) or overall response rate (RR = 1.09, 95% CI: 0.86—1.38, P = 0.47). In subgroup analysis, patients in raltitrexed/oxaliplatin group had significantly higher partial response (RR = 1.53, 95% CI: 1.17—2.00, P = 0.002), overall response rate (RR = 1.42, 95% CI: 1.10—1.82, P = 0.006), disease control rate (RR = 1.16, 95% CI: 1.04—1.29, P = 0.009) and lower progressive disease (RR = 0.61, 95% CI: 0.45—0.84, P = 0.002) when compared to 5fluorouracil/leucovorin/oxaliplatin group. Occurrence of severe anemia (RR = 2.23, 95% CI: 1.38—3.59, P = 0.0001), asthenia (RR = 2.29, 95% CI: 1.36—3.84, P = 0.002), hepatic disorders (RR = 7.51, 95% CI: 1.30—43.56, P = 0.02), and nausea/vomit (RR = 1.70, 95% CI: 1.03—2.81, P = 0.04) were significantly higher with the raltitrexed arm treatment, while frequencies of grade 3/4 alopecia (RR = 0.36, 95% CI: 0.26—0.50, P < 0.00001) and stomatitis/mucositis (RR = 0.14, 95% CI: 0.07—0.31, P < 0.00001) were increased in the 5-fluorouracil group. Conclusions: Raltitrexed-based chemotherapy regimen leads to an equivalent overall survival and response rates with acceptable toxicities compared to traditional 5-fluorouracil-based regimen in patients with advanced colorectal cancer. Raltitrexed can be a treatment option for these patients when 5-fluorouracil-based regimens are not tolerated or inappropriate. © 2013 Elsevier Masson SAS. All rights reserved.

Abbreviations: CI, Confidence interval; CR, Complete response; DCR, Disease control rate; HR, Hazard ratio; ORR, Overall response rate; PD, Progression disease; PR, Partial response; RR, Relative risk; SD, Stable disease. ∗ Corresponding author. Tel.: +86 577 55579185; fax: +86 577 55579185. E-mail address: [email protected] (Q. Huang). 2210-7401/$ – see front matter © 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.clinre.2013.11.006

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Introduction Colorectal cancer (CRC) is a commonly diagnosed malignancy and leading cause of cancer-related death although its incidence decreased worldwide [1]. Despite the notable progress achieved in the management of advanced CRC, the prognosis of patients still remains poor. 5-fluorouracil (5FU), which generally used in combination with leucovorin (LV), remains an important agent in oncologic treatment of advanced non-resectable CRC. Although 5-FU shows advantages in palliative chemotherapy, the gains are relatively modest, and the benefits are obtained at the cost of patients’ inconvenience and morbidity. In recent years, the development of new anticancer drugs with different mechanisms has considerably expanded the CRC therapeutic options. One of the most promising agents was raltitrexed (Tomudex® ; TOM). As a thymidylate synthase inhibitor that easily concentrate in the cell, raltitrexed blocks the production of thymidine monophosphate from deoxyuridine monophosphate, leading to DNA fragmentation and cell death [2]. Its activity was demonstrated in a variety of solid tumors, including gastric cancer [3], head and neck cancer [4], malignant mesothelioma [5], pancreatic cancer [6], as well as colorectal cancer [7,8]. For the treatment of advanced CRC, raltitrexed was approved in many countries and was proposed as a conveniently administered alternative to 5-FU. Compared with repeated and prolonged 5-FU infusions regimens, simple bolus 3-weekly schedules of raltitrexed appeared to be with less complications (e.g. catheter-related thrombosis, infections) and higher levels of acceptability for outpatients [9]. Although several studies showed an improvement of response rates as well as progression-free survival (PFS) or time-to-progression (TTP) with raltitrexed-based chemotherapy for advanced CRC, most trials failed to demonstrate a statistically significant prolongation of survival. To evaluate the efficiency and safety profile of raltitrexed (either as single agent or combined with other therapy) with sufficient statistical power, we conducted a pooledanalysis of all randomized controlled trials (RCTs) comparing raltitrexed-based with 5-FU-based regimen in the treatment of advanced CRC.

Materials and methods Study identification We performed a computerized search of the Medline, EMBASE, Cochrane library, China National Knowledge Infrastructure from January 1985 to July 2013, using combinations of the following keywords ‘‘advanced colorectal cancer’’, ‘‘raltitrexed’’, ‘‘fluorouracil’’, ‘‘chemotherapy’’. The reference lists of pertinent articles were also inspected. No language limits were made.

Selection criteria Trials had to fulfill the following inclusion criteria: • only full-text randomized controlled trials were eligible for inclusion;

Y. Liu et al. • raltitrexed-based regimen and 5-FU-based regimen were compared in patients with advanced colorectal cancer in the trials; • if publications were duplicated or shared in more than one study, the one with multivariate adjusted estimates was included. Exclusion criteria were: • control arm was blank or contaminated with raltitrexed; • data of response, survival outcomes or toxicities were not reported.

Data extraction and synthesis Two of the authors (Y. Liu and W. Wu) independently evaluated the eligibility of all studies retrieved from the databases and reached a consensus on all of the items. The following information was extracted from each enrolled references: study name, publication year, sample size, regimens, outcome measures, and results of studies. The primary outcome measurement was overall survival (OS). The secondary outcomes include overall response rate (ORR) and toxicity. Methodological quality of the trials was assessed using Jadad score (range 0 to 5), including the presence of randomization, double blinding, and withdrawals [10]. All meta-analyses were performed according to intention-to-treat method to minimize a type I error, using Review Manager 5.2 provided by The Cochrane Collaboration. We calculated the relative risk (RR) and hazard ratio (HR); it was expressed by point estimation and 95% confidence interval. P value of < 0.05 was considered statistically significant. Results were defined as heterogeneous for P value ≤ 0.10, determining the use of either fixed-effects or random-effects mode.

Results Characteristics of studies A total of 11 randomized studies involving 4622 patients with advanced colorectal cancer were included in the metaanalysis [11—21]. A total of 2085 patients were treated with raltitrexed-based regimen and 2537 patients with 5FU-based chemotherapy. Table 1 describes the main details of the selected studies.

OS and ORR The main results of the meta-analysis were shown in Table 2. Four trials provided data regarding the overall survival rate. Overall, there were no significant differences between the two regimens in overall survival (HR = 1.06, 95% CI: 0.96—1.17, P = 0.23). Ten trials provided the data for the overall response to chemotherapy. Among the 2701 eligible patients (1133 vs. 1568 patients) in the ten RCTs, the one in the raltitrexed group had no more overall response rate (RR = 1.09, 95% CI: 0.86—1.38, P = 0.47). No significant differences in the two treatments were found in the

Basic characteristics of trials included in the study.

Studies

Years

n

Treatment regimen

Outcomes

Jadad

TOM vs. 5-FU/LV Cunningham et al. [11]

1996

223 216

Raltitrexed 3 mg/m2 (d 1; q 3 wks) Folinic acid 20 mg/m2 + fluorouracil bolus 425 mg/m2 (d 1—5; q 4 wks/q 5 wks)

CR, PR, ORR, OS, TTP,

4

Cocconi et al. [12]

1998

247 248

Raltitrexed 3 mg/m2 (d 1; q 3 wks) Folinic acid 200 mg/m2 + fluorouracil bolus 400 mg/m2 (d 1—5; q 4 wks)

CR, PR, PD, SD, OR, TTP, OS

4

Maughan et al. [13]

2002

301 301 303

Raltitrexed 3 mg/m2 (q 3 wks) Fluorouracil infusion 300 mg/m2 (daily) Folinic acid 200 mg/m2 + fluorouracil bolus 400 mg/m2 + fluorouracil infusion 600 mg/m2 (d 1, 2; q 2 wks)

CR, PR, PD, SD, PFS, OS

5

Ducreux et al. [14]

2006

72 74

CR, PR, PD, SD, PFS, OS

2

73

Raltitrexed 3 mg/m2 (d 1; q 3 wks) Folinic acid 200 mg/m2 + fluorouracil bolus 400 mg/m2 + fluorouracil infusion 600 mg/m2 (d 1, 2; q 2 wks) folinic acid 20 mg/m2 + fluorouracil bolus 400 mg/m2 + fluorouracil infusion 600 mg/m2 (d 1, 2; q 2 wks) Fluorouracil infusion 2600 mg/m2 infusion (d 1; q 6 wks) Raltitrexed 3 mg/m2 (d 1; q 3 wks) Folinic acid 20 mg/m2 + fluorouracil bolus 370—425 mg/m2 (d 1—5; q 4 wks)

RFS, OS

4

75

Popov et al. [15]

2008

952 969

TOMOX vs. FOLFOX Wu et al. [16]

2007

20 20

Raltitrexed 3 mg/m2 + oxaliplatin 130 mg/m2 (d 1; q 3 wks) Oxaliplatin 130 mg/m2 (d 1; q 3 wks) + leucovorin 200 mg/m2 (d 1—5; q 3 wks) + fluorouracil infusion 375∼425 mg/m2 (d 1—5; q 3 wks)

CR, PR, PD, SD, TTP

3

Xue et al. [17]

2011

25 25

Raltitrexed 3 mg/m2 + oxaliplatin 130 mg/m2 (d 1; q 3 wks) Oxaliplatin 130 mg/m2 (d 1; q 3 wks) + leucovorin 200 mg/m2 (d 1—3; q 3 wks) + fluorouracil bolus 400 mg/m2 + fluorouracil infusion 600 mg/m2 (d 1—3; q 3 wks)

CR, PR, PD, SD, PFS

5

Ning et al. [18]

2011

21 20

Raltitrexed 3 mg/m2 + oxaliplatin 130 mg/m2 (d 1; q 3 wks) Oxaliplatin 130 mg/m2 (d 1; q 3 wks) + leucovorin 200 mg/m2 (d 1—5; q 3 wks) + fluorouracil infusion 375∼425 mg/m2 (d 1—5; q 3 wks)

CR, PR, PD, SD, TTP

3

Fu et al. [19]

2012

20 20

Raltitrexed 3 mg/m2 + oxaliplatin 130 mg/m2 (d 1; q 3 wks) Oxaliplatin 130 mg/m2 (d 1; q 3 wks) + leucovorin 200 mg/m2 (d 1—5; q 3 wks) + fluorouracil infusion 375∼425 mg/m2 (d 1—5; q 3 wks)

CR, PR, PD, SD

2

Gravalos et al. [20]

2012

92 91

Raltitrexed 3 mg/m2 + oxaliplatin 130 mg/m2 (d 1; q 3 wks) Oxaliplatin 130 mg/m2 (d 1; q 3 wks) + leucovorin 200 mg/m2 (d 1—5; q 3 wks) + fluorouracil bolus 400 mg/m2 + fluorouracil infusion 600 mg/m2 (d 1, 2; q 3 wks)

CR, PR, PD, SD, RD, OS, PFS, TTP

4

Wang et al. [21]

2012

112 102

Raltitrexed 3 mg/m2 + oxaliplatin 130 mg/m2 (d 1; q 3 wks) Oxaliplatin 130 mg/m2 (d 1; q 3 wks) + leucovorin 200 mg/m2 (d 1—5; q 3 wks) + fluorouracil infusion 375 mg/m2 (d 1—5; q 3 wks)

CR, PR, PD, SD, ORR, DCR, PFS

5

221

CR: complete response; PR: partial response; PD: progressive disease; SD: stable disease; RD: response duration; ORR: overall response rate; DCR: disease control rate; OS: overall survival; PFS: progression-free survival; RFS: recurrence-free survival; TTP: time-to-progression; 5-FU/LV: 5-fluorouracil/leucovorin; d: day; q: quaque; wks: weeks.

Raltitrexed for advanced CRC

Table 1

222

Table 2

Clinical efficacy between raltitrexed-based regimen and 5-FU-based regimen.

Outcome

Raltitrexed-based group vs. 5-FU-based group

Raltitrexed vs. LV5FU2

No. of Events in each group Patients in RR (95% study each group CI)

P

CR

10

25/36

1133/1568

0.82 (0.49, 1.37)

0.45 0.93

3

11/16

620/625

0. 70 (0.33, 1.48)

0.35 0.51

PR

10

221/286

1133/1568

1.14 (0.88, 1.47)

0.32 0.04

3

88/109

620/625

0.81 (0.63, 1.05)

0.12 0.11

SD

9

364/516

910/1352

1.01 (0.91, 1.12)

0.92 0.97

3

251/250

620/625

1.05 (0.84, 1.32)

0.65 0.09

PD

9

209/324

910/1352

0.94 (0.80, 1.09)

0.40 0.20

3

158/144

620/625

1.11 (0.91, 1.35)

0.31 0.89

10

246/322

1133/1568

1.09 (0.86, 1.38)

0.47 0.05

3

99/125

620/625

DCR (CR + PR + SD)

9

567/802

910/1352

1.00 (0.94, 1.07)

0.94 0.21

3

350/375

620/625

0.94 (0.86, 1.03)

0.19 0.40

OS

4



1514/1524

1.06 (0.96, 1.17)

0.23 0.81

3



620/625

1.10 (0.96, 1.27)

0.18 0.48

Outcome

Raltitrexed vs. ldLV5FU2

ORR (CR + PR)

Pheterogeneity No. of Events in Patients in RR (95% CI) study each group each group

P

0.73 (0.46, 1.17)

Pheterogeneity

0.19 0.05

TOMOX vs. FOLFOX

No. of study

Events in each group

Patients in each group

RR (95% CI)

P

Pheterogeneity

No. of study

Events in each group

Patients in each group

RR (95% CI)

P

Pheterogeneity

CR

2

8/9

295/291

0.87 (0.35, 2.17)

0.77

0.54

6

6/9

290/278

0.64 (0.23, 1.77)

0.39

0.68

PR

2

42/43

295/291

0.82 (0.34, 1.99)

0.66

0.06

6

98/62

290/278

1.53 (1.17, 2.00)

0.002

0.89

SD













6

113/109

290/278

0.99 (0.81, 1.21)

0.92

0.94

PD













6

51/79

290/278

0.61 (0.45, 0.84)

0.002

0.96

ORR (CR + PR)

2

50/52

295/291

0.78 (0.32, 1.93)

0.59

0.05

6

104/71

290/278

1.42 (1.10, 1.82)

0.006

0.83

DCR (CR + PR + SD)













6

217/180

290/278

1.16 (1.04, 1.29)

0.009

0.89

OS

3



1247/1260

1.07 (0.96, 1.20)

0.21

0.57













CR: complete response; PR: partial response; SD: stable disease; PD: progression disease; ORR: overall response rate; DCR: disease control rate; OS: overall survival; RR: relative risk; CI: confidence interval; ldLV5FU2: 5-FU/low-dose leucovorin; LV5FU2: 5-FU/high-dose leucovorin; TOMOX: raltitrexed/oxaliplatin; FOLFOX: 5-FU/leucovorin/oxaliplatin.

Y. Liu et al.

Raltitrexed for advanced CRC Table 3

223

Summary of grade 3/4 adverse events by treatment.

Adverse effect

No. of study

No. of patients

Raltitrexedbased arm (No/%)

5-FUbased arm (No/%)

RR (95% CI)

Alopecia Anemia Asthenia Constipation Cutaneous Diarrhea Fever/infection Hepatic disorders Leukopenia Nausea/vomit Neutropenia Pain Stomatitis/mucositis Thrombocytopenia

3 6 3 2 2 5 3 7 5 7 8 2 6 7

3120 2144 1117 480 1199 2316 2654 3586 2316 2397 3648 934 4094 2126

45/3.4 49/5.3 44/7.8 7/2.9 8/2.1 114/12.2 40/3.2 273/15.9 72/7.7 122/12.5 142/8.9 24/5.1 21/1.2 38/4.5

132/7.4 25/2.1 19/3.4 7/3.0 20/2.4 127/9.2 57/4.1 25/1.3 115/8.3 106/7.5 319/15.5 24/5.2 224/9.8 23/1.8

0.36 2.23 2.29 0.97 0.93 1.29 0.74 7.51 1.02 1.70 1.13 0.98 0.14 1.80

(0.26, (1.38, (1.36, (0.34, (0.40, (0.67, (0.50, (1.30, (0.35, (1.03, (0.34, (0.57, (0.07, (0.61,

0.50) 3.59) 3.84) 2.71) 2.13) 2.49) 1.09) 43.56) 2.98) 2.81) 3.69) 1.71) 0.31) 5.32)

P values

P for heterogeneity

< 0.00001 0.001 0.002 0.95 0.86 0.44 0.13 0.02 0.97 0.04 0.85 0.96 < 0.00001 0.29

0.93 0.33 0.65 0.99 0.24 < 0.0001 0.13 < 0.00001 < 0.00001 0.01 < 0.00001 0.21 0.04 0.01

5-FU: 5-fluorouracil; RR: relative risk; CI: confidence interval.

proportion of patients who achieved complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD) or disease control rate (DCR) according to the combined analysis.

Subgroup analysis Table 1 also showed the subgroup analyses including comparisons of raltitrexed single agent versus 5-FU/high-dose leucovorin (LV5FU2), raltitrexed single agent versus 5FU/low-dose leucovorin (ldLV5FU2), raltitrexed/oxaliplatin (TOMOX) versus 5-FU/leucovorin/oxaliplatin (FOLFOX). Six trials provided the data for the comparison of TOMOX vs. FOLFOX (290 vs. 278 patients). Patients in the TOMOX group had significantly higher PR (RR = 1.53, 95% CI: 1.17—2.00, P = 0.002), ORR (RR = 1.42, 95% CI: 1.10—1.82, P = 0.006), DCR (RR = 1.16, 95% CI: 1.04—1.29, P = 0.009) and lower PD (RR = 0.61, 95% CI: 0.45—0.84, P = 0.002) when compared to FOLFOX group using fixed effect model. As to other subgroup analyses comparison, such as raltitrexed vs. ldLV5FU2 (2 trials included, 295 vs. 291 patients), or raltitrexed vs. LV5FU2 (3 trials included, 620 vs. 625 patients), there were no differences between the two regimens for the outcome measures (2 to 6 trials included, all subgroup rates were further described in Table 2).

Toxicity Toxic effects of the included trials according to National Cancer Institute Common Toxicity Criteria were summarized in Table 3 (only grade 3/4 toxicities were presented). Occurrence of severe anemia (RR = 2.23, 95% CI: 1.38—3.59, P = 0.0001), asthenia (RR = 2.29, 95% CI: 1.36—3.84, P = 0.002), hepatic disorders (RR = 7.51, 95% CI: 1.30—43.56, P = 0.02), and nausea/vomit (RR = 1.70, 95% CI: 1.03—2.81, P = 0.04) were significantly higher with the raltitrexed arm treatment, while frequencies of alopecia (RR = 0.36, 95% CI: 0.26—0.50, P < 0.00001) and

stomatitis/mucositis (RR = 0.14, 95% CI: 0.07—0.31, P < 0.00001) were increased in the 5-FU group. No statistically significant differences were found for other toxic effects. Heterogeneity was found for some adverse events, which was possibly due to the use of different agents at various dosages in the studies.

Discussion From present meta-analysis that combined individual data from more than 4000 patients, we found that raltitrexedbased regimen yielded a major response in 21.0% of the patients, while 38.9% obtained at least a stabilization of disease, and tumor control was obtained in 60.5% of the whole series. The final results showed that raltitrexed, either alone or in combination with oxaliplatin, led to an equivalent overall survival and overall response rate compared to 5-FU. Although various dosage of leucovorin (high-dose: 200 mg/m2 ; low-dose: 20 mg/m2 ) were used in 5-FU-based regimens, there appeared to be no significant difference in terms of treatment outcomes in TOM vs. LV5FU2 or TOM vs. ldLV5FU2 comparison. Raltitrexed and oxaliplatin had different mechanisms of action. Oxaliplatin can form intrastrand DNA-platinum adducts/crosslinks, leading to DNA strand breaks and p53dependent apoptosis [22]. Its combination with raltitrexed showed synergistic antineoplastic activities in vitro, which dues to depletion of deoxy-thymidine triphosphate and subsequent interference with the repair process [23]. Based on these mechanisms, TOMOX regimen has been explored in phase I studies [24,25], then in a series of advanced CRC patients, with preliminary results. Previous studies showed that ORR of patients in TOMOX group ranged from 31—54%, while PFS/TTP and OS were within the range of 6.2—7 months and 9—15 months, respectively [26—28]. In general, results from these trials were encouraging and supported the continued investigation of TOMOX regimen. In our analysis, the most promising tumor response advantage was

224 observed in TOMOX vs. FOLFOX comparison. Patients who received TOMOX schedule had significantly higher PR and lower PD when compared to FOLFOX group. There was no heterogeneity within intervention subsets. Although survival advantage seemed to be similar between the two regimens, the results showed a higher ORR and DCR in favor of TOMOX. These findings indicated that the combinations of raltitrexed and oxaliplatin may be effective and beneficial in advanced CRC patients, and provided rationale for further evaluation of TOMOX regimen in the first-line setting. With regards to toxicities, it was reported that the most common adverse events of raltitrexed therapy were elevation of transaminase, anemia and asthenia. In this meta-analysis, we found that raltitrexed and 5-FU have similar tolerability profiles with a few notable exceptions. Anemia occurred more frequently with raltitrexed than 5-FU therapy (5.3% vs. 2.1%), as well as nausea/vomit symptoms (12.5% vs. 7.5%). An elevated transaminase level was more likely to be seen in raltitrexed than 5-FU-treated patients (15.9% vs. 1.3%). On the other hand, stomatitis/mucositis seen in 5-FU recipients was largely absent with raltitrexed (9.8% vs. 1.2%), while a trend toward less alopecia was found in raltitrexed compared with 5-FU group (3.4% vs. 7.4%). Other toxicities such as cutaneous effects were unremarkable for their low incidence and mild intensity. Although raltitrexed-schedules were associated with a statistically significant higher incidence of severe increases in liver transaminases, such changes were usually predictable and curable. As Massacesi et al. once reported, the most important predictive factors of raltitrexed-induced hepatotoxicity were chemotherapy cycles, cumulative dose, baseline transaminases, interval between courses and association with oxaliplatin [29]. The liver injury caused by raltitrexed chemotherapy can be treated with glutathione or ademethionine as hepatoprotectors, without side effects [29]. As for cardiotoxicity, a previous systematic review found its incidence that associated with fluoropyrimidine chemotherapy ranged between 0.5% and 19%, however, no published cases was revealed with raltitrexed [30]. Thus, raltitrexed was proposed to be a suitable option for patients with fluoropyrimidine-induced cardiotoxicity or significant cardiovascular risk factors. However, according to the halfway shutdown PETACC-1 study evaluating raltitrexed versus 5-FU in adjuvant setting, without measuring creatinine clearance for dose-adjustment, or inappropriate use of raltitrexed dose based on creatinine clearance, could result in more deaths 60 day after drug administration [15]. So a careful evaluation of renal function should be warranted before initiating raltitrexed treatment, particularly in the elderly [31]. Based on the above considerations, the fairly use of raltitrexed may depend on the prediction of patients in whom toxicity may occur, and the adoption of ways to reduce toxicity. It should be noticed that most patents in the 5-FU (including FOLFOX) group received mainly bolus 5-FU, not LV5FU2, which has better tolerance and efficacy. It could explain the difference in the alopecia rates, which was very rare with LV5FU2. And it could partly explain the higher PR, ORR, and DCR in TOMOX group when compared to FOLFOX. It should also be pointed that five of the six enrolled studies comparing TOMOX to FOLFOX were performed in Asian countries, in which the population was small and the follow-up time

Y. Liu et al. was short. As overall survival remained the most meaningful measure of treatment efficacy, it should be evaluated as a primary end-point when different regimens were compared. But these studies were aimed to evaluate the short-term outcomes and toxicities, without reporting the survival rate. This might influence the analysis in our study. Moreover, it was not clear that if there was a significant difference in the efficacy and side effects incidence between Asian and non-Asian races. Therefore, large RCTs with longer follow-up duration focusing on TOMOX regimen should be performed in non-Asian countries to further confirm our findings. In addition, data on other treatment efficacy (e.g. PFS, TTP) had also been reported in some researches, most of which showed similar short-term outcomes, although it seemed that PFS may be sooner in 5-FU group [17,21]. However, such analysis was not the intent of our investigations. There were some limitations in our study. Firstly, some of the studies included in the meta-analysis were old, and not all the outcomes data were available. Secondly, this was not a meta-analysis using individual patient data approach. All the outcome estimates were from published reports, so the systematic biases and chance effects will not be minimized [32]. Thirdly, the characteristics of the included studies were varied in terms of the follow-up and dosages. Fourthly, abstracts and unpublished studies were not included in this meta-analysis, which may lead to publication bias and affect the credibility of the results to some extent. Despite the limitations of our research, this metaanalysis demonstrates that raltitrexed-based chemotherapy regimen leads to an equivalent overall survival and response rates with acceptable toxicities compared to traditional 5-FU-based regimen in patients with advanced CRC. Raltitrexed, as single agent or combined with oxaliplatin, should be considered as an efficient intervention for these patients when 5-FU-based regimens are not tolerated or inappropriate. Moreover, the monoclonal antibodies such as cetuximab and bevacizumab, combined with oxaliplatin/5-FU-based chemotherapy are under investigation in clinical trials. Further studies evaluating the combination of raltitrexed and vascular endothelial growth factor (VEGF) or epidermal growth factor receptor (EGFR) inhibitors are required for better use of raltitrexed-based regimens in practice.

Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.

Acknowledgment The authors gratefully acknowledge all the colleagues working in the Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, for their help and kind support.

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Raltitrexed-based chemotherapy for advanced colorectal cancer.

To evaluate the efficiency and safety profile of raltitrexed-based chemotherapy in the treatment of advanced colorectal cancer...
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