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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 8  |  Issue : 1  |  Page : 7

The efficacy and safety of trifluridine/tipiracil plus bevacizumab compared with trifluridine/tipiracil monotherapy for metastatic colorectal cancer: A meta-analysis


Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China

Date of Submission12-Nov-2021
Date of Decision15-Jan-2022
Date of Acceptance11-Feb-2022
Date of Web Publication21-Apr-2022

Correspondence Address:
Dongying Gu
Department of Oncology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing 210006
China
Xiaowei Wei
Department of Oncology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing 210006
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/digm.digm_44_21

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  Abstract 


Background: Some small sample size studies have yielded slightly inconsistent results for comparing the efficacy and toxicity of trifluridine/tipiracil (TAS-102) with or without bevacizumab. This meta-analysis aims to further investigate the additive effect and safety profile of bevacizumab when combined with TAS-102 in patients receiving a salvage-line treatment for metastatic colorectal cancer (mCRC). Methods: A systematic literature search was conducted using PubMed, Web of Science, Cochrane Library, and some oncological conferences by the end of February 2021. No restrictions were placed on the searches. Two reviewers independently performed the retrieval and selection according to the “Patient, Intervention, Comparison, Outcome, Study design” principle. The outcome endpoints included overall survival (OS), progression-free survival (PFS), disease control rate (DCR), and adverse events (AEs). Results: Six controlled trials which recruited 435 refractory mCRC patients were ultimately taken in. Our results suggested that the regimen of TAS-102 plus bevacizumab had a significant advantage in OS, PFS, and DCR over TAS-102 alone (hazard ratio (HR) = 0.43, 95% confidence interval (CI): 0.27–0.67, P < 0.001; HR = 0.48, 95% CI: 0.39–0.59, P < 0.001; OR = 3.19, 95% CI: 1.56–6.50, P = 0.001; respectively). In general, the incidence of AEs was slightly but not obviously higher in the combination therapy group than the monotherapy group (OR = 1.08; 95% CI: 0.89–1.30; P = 0.458). However, the most frequent grade 3 or worse AE was neutropenia (OR = 2.32; 95% CI: 1.53–3.52; P < 0.001) which was higher in the TAS-102 plus bevacizumab group. Meanwhile, the morbidity of anemia (OR = 0.43; 95% CI: 0.22–0.83; P = 0.013) was significantly higher in TAS-102 monotherapy group. Conclusion: TAS-102 plus bevacizumab has promising activity with a manageable safety profile in a salvage-line treatment for mCRC who are refractory or intolerant to standard chemotherapy.

Keywords: Bevacizumab, Meta-analysis, Metastatic colorectal cancer, Trifluridine/tipiracil


How to cite this article:
Ge Y, Gu D, Wei X. The efficacy and safety of trifluridine/tipiracil plus bevacizumab compared with trifluridine/tipiracil monotherapy for metastatic colorectal cancer: A meta-analysis. Digit Med 2022;8:7

How to cite this URL:
Ge Y, Gu D, Wei X. The efficacy and safety of trifluridine/tipiracil plus bevacizumab compared with trifluridine/tipiracil monotherapy for metastatic colorectal cancer: A meta-analysis. Digit Med [serial online] 2022 [cited 2022 May 17];8:7. Available from: http://www.digitmedicine.com/text.asp?2022/8/1/7/343718




  Introduction Top


According to the latest cancer epidemiological statistics, colorectal cancer (CRC) is the third most common malignant tumor with a high mortality on a global scale, which ranks second in the major causes of cancer in clinical practice at present. On the basis of epidemiological investigations, there were 1900, 000 new confirmed cases of CRC with 935, 000 deaths during 2020.[1] Fluorouracil-based chemotherapy combined with irinotecan or oxaliplatin is the standardized systemic administration for advanced or metastatic colorectal cancer (mCRC). For the sake of ameliorating the medical prognosis of mCRC patients, chemotherapy is usually coupled with targeted therapy like vascular endothelial growth factor (VEGF) antibodies, which include bevacizumab, ramucirumab or ziv-aflibercept (the latter two are only combined with irinotecan-based chemotherapy regimens.[2],[3] Take cetuximab or panitumumab for instance, patients with left-sided RAS and BRAF wild-type mCRC often receive traditional chemotherapy plus epidermal growth factor receptor (EGFR) antibodies. After this mixture of chemotherapy plus targeted therapy, the median overall survival (OS) of sufferers with mCRC can already reach approximately 30.0 months. Nevertheless, many terminal mCRC patients are refractory to or unable to tolerate these agents, so salvage-line medications (e.g., regorafenib, fruquintinib, or Trifluridine/tipiracil (TAS-102)) are recommended for those who are pretreated with fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and EGFR antibodies.[4],[5]

TAS-102 is a neotype anti-tumor drug administered by oral route, which is composed of a thymidine-based nucleoside analog, trifluridine (FTD), and a thymidine phosphorylase inhibitor, tipiracil hydrochloride (TPI), at a molar ratio of 1:0.5. FTD is the active antitumor ingredient of TAS-102. It can be straightforwardly incorporated into DNA instead of thymidine, thereby causing DNA dysfunction after phosphorylation by thymidine kinase1. To maintain the bioavailability of TAS-102, TPI prevents FTD from degrading in the liver and gastrointestinal tract by inhibiting thymidine phosphorylase.[6],[7] TAS-102 has been indeed confirmed to significantly extend OS in refractory mCRC patients as compared to placebo. It was accredited in Japan for using against mCRC based on the findings of a randomized phase 2 trial. It was licensed by the US Food and Drug Administration and European Agency due to the revelations from the international phase 3 RECOURSE study. And then, it was demonstrated in Asian patients with previously treated mCRC according to the conclusions of the Asian phase 3 TERRA trial.[8–10]

As mentioned above, chemotherapy combined with VEGF antibodies can ameliorate patients' prognosis. Besides, in accordance with major clinical practice guidelines, bevacizumab is the preferred combination drug for first- or second-line chemotherapy.[4],[5] Hence, probing into the efficacy and safety of TAS-102 plus bevacizumab is indispensable for us. The antitumor effect of TAS-102 plus bevacizumab was first appraised in a preclinical study in which Tsukihara et al. used CRC xenografts.[11] Then, a single-arm, phase 1/2 trial of TAS-102 plus bevacizumab conducted by Kuboki et al. in Japan which registered 25 participants with mCRC published that the median PFS was 5.6 months (95% confidence interval (CI): 3.4–7.6) and OS was 11.4 months (95%CI: 7.6–13.9). In addition, neutropenia was the most frequent ≥3 grade adverse reaction in their research (specifically 18 [72%] patients).[12] This trial suggested that this combination regimen might have promising activity with manageable and tolerable toxicity, inspiring the publication of many randomized controlled studies and retrospective studies.[13–18]

Although many studies explored the efficacy and safety of TAS-102 plus bevacizumab in mCRC patients, the current results of these studies were rather disputed and controversial. Moreover, the sample size of each study was insufficient, hence the stability and representativeness of the consequences from each study remained to be reasoned. Therefore, in order to augment the sample size and reduce the error, to get a more stable and reliable conclusion, to provide patients with a more effective and less toxic regimen, we conducted this meta-analysis which compared the curative effects and adverse reactions of management with or without bevacizumab in patients with refractory mCRC receiving TAS-102.


  Methods Top


This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.[19]

Search strategy

According to inclusion criteria, two authors (Y Ge and D Gu) searched PubMed, Web of Science and Cochrane Library by the end of February 2021 independently. The searching keywords mainly included the following terms: “metastatic colorectal cancer,” “mCRC,” “advanced colorectal cancer,” “TAS-102,” “Trifluridine/tipiracil” and “bevacizumab.” No restrictions were placed on the retrieval. Irrelevant articles were got rid of by skimming the titles along with abstracts. And then, by perusing the full text we could confirm the final inclusion of papers. Further, the references of retained articles were manually retrieved to obtain relevant studies that can be included. In addition, significant oncological conferences during the past 5 years such as the European Society of Medical Oncology and the American Society of Clinical Oncology (ASCO) were also searched for abstract reports of correlative trials.

Selection criteria

The selection criteria are originally set according to the “Patient, Intervention, Comparison, Outcome, Study design” principle:

  • P: (1) Histopathologically confirmed mCRC; (2) WHO performance status of 0–1 or ECOG performance status of 0–2; (3) refractory or intolerant to fluoropyrimidines, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy (in patients with left-sided RAS and BRAF wild-type mCRC).
  • I/C: Patients in the trial arm were exposed to TAS-102 + bevacizumab regimen, while patients in the control group accepted TAS-102 monotherapy regimen.
  • O: The outcome endpoints reflecting efficacy and safety profile included OS, progression-free survival (PFS), disease control rate (DCR) along with adverse events (AEs). Specifically, OS was restricted to the date from the beginning of therapeutic schedule to the date of all-cause death. Accordingly, PFS could be elaborated as the time from the start of one of therapeutic regimens to the date of advancement of disease or all-cause death. DCR was interpreted as complete or partial response or stable disease (CR + PR + SD).
  • S: The researches were limited to control trials.


Data extraction

Two investigators independently extracted data from the incorporated researches. Any disagreement during the extraction was resolved through consensus by another investigator. The following data we focused on were extracted: (1) Basic information of publication: First author, year of publication, nation, trial type, treatment plans. (2) Demographic baseline characteristics: The number of patients, median age, sex ratio, RAS status, performance status, primary tumor location. (3) Efficacy and safety parameters: OS, PFS, DCR, and AEs.

Quality assessment

All eligible articles were assessed simultaneously for quality by the Downs and Black quality assessment method[20] and the Newcastle-Ottawa Scale (NOS).[21] The Downs and Black score were applied to estimate both randomized controlled trails (RCT) and non-RCT while the NOS was employed to assess non-RCT only. The Downs and Black quality assessment method includes five parts and a total of 27 items. Depending on whether the answer is yes or no or uncertain, we were able to assign exact scores to the included articles. The higher the final scores, the more excellent the quality. The NOS embraces three categories, namely selection, outcome, and comparability. The highest level of NOS is nine stars, and trials with more than six stars are considered relatively high quality.

Statistical analysis

In this meta-analysis, STATA software package (version 15.0 for Mac, Stata Corp LLC, College Station, TX, USA) was employed to analyze and process the entire data. Specifically, dichotomous variables such as DCR and AEs were accessed by odds ratios (ORs) along with 95% CIs and P values. Survival data such as PFS and OS were assessed by hazard ratios (HRs) along with 95% CIs and P values. HRs were obtained firsthand from the original texts or derived indirectly from the Kaplan Meier survival curves. By convention, P < 0.050 was on behalf of the existence of statistically significant differences. Through applying the Cochran's Q-test and the I2 statistics, we could determine whether there remained statistical heterogeneity among those studies being evaluated. When I2 ≥50.0% or P < 0.050, it represented that the heterogeneity among trials could not be overlooked, so that the random-effects model ought to be chosen. Whereas, a fixed-effects model would be used if the heterogeneity was considered acceptable. We controlled and reduced the potential report bias which included publication bias, language bias and multiple publication bias by collecting sufficient clinical trials without language restriction and deleting duplicate papers. A funnel plot was used to qualitatively identify whether there was a publication bias from a subjective point of view. Simultaneously, Begg's Test and Egger's Test were employed for quantitatively assessment. The trim and fill method were yardstick to further identify and deal with publication bias. For the sake of assessing the heterogeneity and stability of these trials, sensitivity analysis was also implemented.


  Results Top


Literature search and quality assessment

Initially, we retrieved 238 relevant records from all searched electronic databases. The details of the retrievals are listed in the flowchart in [Figure 1]. Finally, six articles which met all the inclusion criteria finally enrolled 435 patients with chemorefractory mCRC.[13–18] Among these patients, 220 patients received TAS-102+ bevacizumab regimen, while 215 patients were exposed to TAS-102 monotherapy regimen. [Table 1] exhibits the baseline characteristics of these six trials. For the Downs and Black score, all studies were over 15, and the RCT was over 20. In addition, all trials had scores seven stars for NOS.
Figure 1: A flowchart of the literature search and selection strategy.

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Table 1: Baseline characteristics of the 6 included trials in the meta-analysis.

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Overall survival for patients treated with trifluridine/tipiracil plus bevacizumab versus trifluridine/tipiracil alone

The OS data were available in five trials, but only four studies explicitly mentioned the HRs and 95% CIs in the original articles.[13],[15],[16],[17] The HR and 95% CI from the Yoichiro Yoshida et al. were derived indirectly from the corresponding Kaplan-Meier plot.[18] Because of a moderate heterogeneity detected among these five studies (I2 = 64.8%; P = 0.023), a random-effects analysis was applied to aggregate the data, which showed that TAS-102 plus bevacizumab significantly improved OS (HR = 0.43; 95% CI: 0.27–0.67; P < 0.001) more than TAS-102 alone in mCRC patients in [Figure 2]a. As represented by OS, we performed a subgroup analysis. Two studies[13],[16] reported subgroup data for sex, RAS mutations, primary tumor location, and history of bevacizumab. Combination therapy did not significantly prolong OS in men (HR = 0.87, 95% CI: 0.57–1.33, P = 0.527), right-sided tumor (HR = 0.67, 95% CI: 0.30–1.49, P = 0.327), RAS wild-type (HR = 0.80, 95% CI: 0.48–1.34, P = 0.391) and patients without a history of bevacizumab treatment (HR = 0.52, 95%CI: 0.14–1.97, P = 0.337); but did in women (HR = 0.46, 95% CI: 0.26-0.81, P = 0.007), left-sided tumor (HR = 0.63, 95% CI: 0.43-0.93, P = 0.018), RAS mutant-type (HR = 0.59, 95% CI: 0.38–0.93, P = 0.022), and patients with a history of bevacizumab treatment (HR = 0.66, 95% CI: 0.47–0.94, P = 0.022).
Figure 2: Forest plots showing hazard ratio (HR) or odds ratio (OR) for overall survival (OS), progression free survival (PFS) and disease control rate (DCR). (a) The forest plot of OS for patients treated with trifluridine/tipiracil plus bevacizumab versus trifluridine/tipiracil alone. (b) The forest plot of PFS for patients treated with trifluridine/tipiracil plus bevacizumab versus trifluridine/tipiracil alone. (c) The forest plot of DCR for patients treated with trifluridine/tipiracil plus bevacizumab versus trifluridine/tipiracil alone. Caption: T: Trifluridine/tipiracil alone; T-B: Trifluridine/tipiracil plus bevacizumab; CI: Confidence interval.

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Progression free survival for patients treated with trifluridine/tipiracil plus bevacizumab versus trifluridine/tipiracil alone

There were five trials mentioning the PFS data. Among them, three trials mentioned the specific value of the HRs and CIs directly in the paper,[13],[15],[16] while the data of other two studies were obtained second-hand from the Kaplan-Meier survival curve.[14],[18] Taking the nonsignificant heterogeneity among trials (I2 = 47.0%; P = 0.110) into consideration, we employed a fixed-effects model to pool the PFS data, which demonstrated that the combination chemotherapy regimen significantly prolonged PFS (HR = 0.48; 95% CI: 0.39–0.59; P < 0.001) compared with TAS-102 alone in [Figure 2]b.

Disease control rate for patients treated with trifluridine/tipiracil plus bevacizumab versus trifluridine/tipiracil alone

DCR data were reported in five trials.[13],[14],[16],[17],[18] The aggregated data indicated that there was a moderate degree of heterogeneity among these five trials (I2 = 59.2%; P = 0.044). Therefore, a random-effects model was carried out. Compared with TAS-102 monotherapy, the combination therapy showed a statistically significant improvement in DCR (OR = 3.19; 95% CI: 1.56–6.50; P = 0.001), according to the results of the meta-analysis in [Figure 2]c.

Adverse events

Meanwhile, we also analyzed the difference between the AEs of the two arms. No significant heterogeneity between trials was detected (I2 = 19.8%; P = 0.165), so a fixed-effects model was utilized. In general, the incidence of AEs was slightly but not significantly higher in the combination therapy group than the monotherapy group (OR = 1.08; 95% CI: 0.89–1.30; P = 0.458). Specifically, the risk of hematological toxicity was slightly higher in the TAS-102 plus bevacizumab group (OR = 1.31; 95% CI: 0.98–1.75; P = 0.065). In contrast, the incidence of non-hematological toxicity was mildly higher in the TAS-102 group (OR = 0.91; 95% CI: 0.70–1.19; P = 0.497). Of these, thrombocytopenia (OR = 1.78; 95% CI: 1.09–2.93; P = 0.022) was the only significant outcome. Furthermore, we detected significantly higher incidence of grade 3/4 AEs for neutropenia (OR = 2.32; 95% CI: 1.53–3.52; P < 0.001) in the TAS-102 plus bevacizumab group, while the application of this combination administration of TAS-102 plus bevacizumab did not result in enhanced risk of anemia (OR = 0.43; 95% CI: 0.22–0.83; P = 0.013). The analysis also exhibited lower risks for nausea (OR = 0.23; 95% CI: 0.04–1.43; P = 0.115), diarrhea (OR = 0.86; 95% CI: 0.27–2.76; P = 0.805), fatigue (OR = 0.49; 95% CI: 0.17–1.41; P = 0.189), and febrile neutropenia (OR = 0.63; 95% CI: 0.21–1.87; P = 0.406), and showed higher incidence for thrombocytopenia (OR = 2.27; 95% CI: 0.63–8.18; P = 0.209), in spite of no statistical significance in [Table 2]a and [Table 2]b.
Table 2: AEs of TAS-102 plus bevacizumab compared with TAS-102.

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Sensitivity analysis

Our study took one RCT and five retrospective trials into the analysis. To detect the stability of our analysis, we removed the RCT and re-analyzed the rest of five studies. The outcomes of meta-analysis did not change significantly in [Table 3], indicating that the inclusion of this RCT had a rare impact on the stability of our meta-analysis results. In addition, we also carried out influence analysis. The results of the studies were basically concentrated and tended to be consistent in [Figure 3]a,[Figure 3]b,[Figure 3]c, so the results of meta-analysis were stable.
Figure 3: Influence analyses for overall survival (OS), progression free survival (PFS) and disease control rate (DCR). (a) Influence analysis of OS. (b) Influence analysis of PFS. (c) Influence analysis of DCR. Caption: CI: Confidence interval.

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Table 3: Sensitivity analysis.

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Report bias

Five studies[13],[15],[16],[17],[18] reported the OS of combination therapy group compared with monotherapy group. The results of publication bias were as follows: Begg's test: Z =1.22, P = 0.221 and Egger's test: P = 0.063; both of them were >0.05, indicating no existence of significant publication bias. Five studies[13],[14],[15],[16],[18] reported the PFS of TAS-102 plus bevacizumab group compared with TAS-102 monotherapy group, so we investigated its publication bias. The results were as follows: Begg's test: Z = 1.22, P = 0.221 and Egger's test: P = 0.061; both of them were >0.05, suggesting no existence of obvious publication bias. Five studies[13],[14],[16],[17],[18] reported the DCR of combination regimen group compared with monotherapy group. The results of publication bias were as follows: Begg's test: Z =1.22, P = 0.221 and Egger's test: P = 0.015; the outcome of Egger's test was <0.05, indicating the possible existence of publication bias. The publication bias of DCR in the five articles was further identified by trim and fill method. Before trim and fill method, the combined effect size and confidence interval of these five trials were as follows: fixed OR = 2.59, 95% CI: 1.68–3.98; random OR = 3.19, 95% CI: 1.56–6.50. The linear method was applied to estimate the number of absent trials, and a meta-analysis of seven studies was performed again. The results were as follows: Fixed OR = 1.99, 95% CI: 1.35–2.94; random OR = 2.14, 95% CI: 1.05–4.39. There were no major changes existing in the conclusion (the statistical differences in OR existed neither before nor after the trim and fill method), manifesting that the outcomes of DCR in these studies were stable. The corresponding funnel plots of all endpoints are displayed in [Figure 4]a,[Figure 4]b,[Figure 4]c.
Figure 4: The funnel plots for overall survival (OS), progression free survival (PFS) and disease control rate (DCR). (a) The funnel plot of OS for patients treated with trifluridine/tipiracil plus bevacizumab versus trifluridine/tipiracil alone. (b) The funnel plot of PFS for patients treated with trifluridine/tipiracil plus bevacizumab versus trifluridine/tipiracil alone. (c) The funnel plot of DCR for patients treated with trifluridine/tipiracil plus bevacizumab versus trifluridine/tipiracil alone. Caption: SE: Standard error, log/ln: Logarithm, HR: Hazard ratio, OR: Odds ratio.

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  Discussion Top


This meta-analysis reported the survival benefit and safety of TAS-102 plus bevacizumab compared with TAS-102 in a salvage-line treatment for mCRC. The combination of TAS-102 plus bevacizumab has shown the survival benefit in the single-arm trials such as C-TASK FORCE study (PFS: 3.7 months; OS: 11.4 months) and the TAS-CC3 study (PFS: 4.5 months; OS: 9.2 months).[12],[22] In a researcher-initiated, open-label, randomized, phase 2 trial, Per Pfeiffer et al. reported that the regimen of TAS-102 plus bevacizumab significantly improved PFS (4.6 vs. 2.6 months; HR = 0.45; 95% CI: 0.29–0.72; P = 0.001) and OS (9.4 vs. 6.7 months; HR = 0.55; 95% CI: 0.32–0.94; P = 0.028) compared with TAS-102 monotherapy in patients with advanced progressive CRC who have undergone multiple chemotherapy.[13] The pooled results of our meta-analysis are consistent with this RCT's finding. There were also several reports of such combination regimen of TAS-102 plus bevacizumab in retrospective studies.[14–18] Consequently, before this paper, there had never been a meta-analysis of TAS-102 plus bevacizumab combination therapy compared with TAS-102 monotherapy. Current researches indicated that in clinical practice, this combination administration had clinical benefits with controllable AEs and had the potential to be a new lease of life for pretreated advanced CRC patients.

In our study, compared with TAS-102 monotherapy regimen, the combination regimen of TAS-102 plus bevacizumab significantly prolonged OS and PFS, and also remarkably ameliorated DCR. Thus, it can be seen that combination therapy is promising and set the stage for further researches on mCRC. Taking OS for instance to perform subgroup analysis on the data, subgroup analysis failed to detect the origin of heterogeneity. The result of subgroup analysis indicated that the combination therapy significantly prolonged OS especially in women, left-sided tumor, RAS mutant-type, and patients with a history of bevacizumab treatment.

Distinguished from normal blood vessels, tumor vessels are typically unstructured and non-functional.[23] Anti-angiogenic therapy is able to increase the oxygen supply as well as plasma concentration by inhibiting angiogenesis and reshaping or normalizing tumor vasculature, in order to augment trifluridine accumulation and its phosphorylation in the tumor.[24] The highest tolerable FTD exposure provides the highest antitumor effect.[25] Thus, the combination of TAS-102 plus bevacizumab might prolong survival by increasing trifluridine concentrations in the DNA of tumor. However, it was reported that VEGF antibodies were associated with incremental risks of neutropenia, thrombocytopenia, and febrile neutropenia when combined with chemotherapy.[26]

Overall, with the addition of bevacizumab, the incidence rate of grade 1–4 AEs did not substantially differ from the TAS-102 alone. Respectively, there were relatively more hematological side effects occurring in the combination treatment group, while nonhematological toxicities took place in the TAS-102 monotherapy group more frequently. Although only a few articles reported grade 3–4 AEs, we could roughly draw the following ultimateness: in the combined therapy group, the incidence of grade 3–4 AEs not only did not multiple significantly, but even slight augment in the monotherapy group. Whereas, we must pay attention that the addition of bevacizumab was related to a significant elevating in the morbidity of grade 3–4 neutropenia, which was also the most common grade 3–4 AE. While the incidence rate of grade 3–4 anemia was significantly promoted in the monotherapy group, our results were roughly consistent with the conclusion drawn by Fabio A. B. Schutz et al.[26] Therefore, it is obligatory for physicians and patients to be care of these AEs and conduct a hematological monitoring more frequently during combination regimen, preferably 1–2 times a week. Only in this way can we determine whether bone marrow suppression has occurred and correct it in time. Once AEs occur, they can be well managed in an outpatient by dose reduction, temporary dose interruptions, and appropriate supportive intervention with G-CSF or other relevant drugs. To sum up, the overall AEs of the combination regimen are controllable and easily treatable, but we must regularly monitor hematological toxicities, especially grade 3–4 neutropenia. Fortunately, Yoichiro Yoshida et al. are currently performing a prospective study[27] (The TASCC4 study) in which grade 3 or 4 neutropenia can be suppressed by changing the administration schedule of TAS-102. Therefore, neutropenia is predicted to be reduced.

Our study was the first meta-analysis to evaluate the curative effect and safety profile of TAS-102 plus bevacizumab versus TAS-102 monotherapy in patients receiving refractory therapy for mCRC. Our results indicated that bevacizumab might be an excellent partner for TAS-102. In other words, the combination therapy is a promising and potential option for patients with refractory mCRC. Further investigations should be carried out to verify the antitumor activity or safety of this regimen for earlier treatment lines in patients with mCRC. For example, the combination regimen showed significantly and clinically relevant benefit in first-line unresectable mCRC patients who were not suitable for high-intensity therapy, with a controllable safety profile in TASCO1 study.[28] More information on first-line treatment can be expected from the underway randomized, open-label, global Phase III SOLSTICE trial (NCT03869892).[29] Clinical trial exploring the second-line combination regimen for mCRC, such as TRUSTY study is also ongoing (JapicCTI-173618).[30] In addition to exploring combination treatment with bevacizumab, further study has been launched to probe into the combination with other biological targeted agents, such as panitumumab (Clinicaltrials.govNCT02613221)

(APOLLON study) or cytotoxic drugs such as oxaliplatin.[31] Several guidelines recommend TAS-102 as a new potential option for mCRC. Its role in the treatment of other tumors is also being continuously evaluated. For example, a study of TAS-102 plus nano-liposomal irinotecan in gastrointestinal cancers (NCT03368963) is underway.

Some limitations existed in our meta-analysis. First of all, only six studies that met the requirements had been retrieved, resulting in a limited sample size. Second, there were several reports of TAS-102 plus bevacizumab therapy in retrospective studies, but only one RCT, a Denmark trial, has been included. Hence, a few studies were able to accurately conduct blinding and concealed allocation. Third, five of six studies took place in Japan, so there was a certain degree of bias. Therefore, we need even more large sample size, high-quality randomized double-blind controlled studies to be included.


  Conclusion Top


TAS-102 plus bevacizumab has promising activity with a manageable safety profile in a salvage-line treatment for mCRC who are refractory or intolerant to standard chemotherapy.

Acknowledgments

The authors are grateful to Dr. Wei and Dr. Gu for their supervision and revision of this article.

Financial support and sponsorship

This article was supported by the Grants from the National Natural Science Foundation of China (Grant No. 81773240 and 81773516). The Natural Science Foundation of Jiangsu Province (Grant No. BK20181118). Nanjing Medical Science and technique Development Foundation (Grant No. QRX17062).

Conflicts of interest

There are no conflicts of interest.



 
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