**5. Re-challenge chemotherapy**

*Multidisciplinary Approach for Colorectal Cancer*

safe agent to be used in daily clinical practice.

(≥65 years) and younger (<65 years) patients [48].

**3.4 TAS-102 combined with other anticancer drugs**

therapy with TAS-102, which implies that this agent might constitute a reasonable option for patients with cardiovascular contraindications for 5-FU treatment [47]. Based on available evidence, TAS-102 seems to be a convenient, manageable, and

According to the data from the RECOURSE and J003 trials, severe AEs (SAEs)

Finally, the occurrence of AEs had no significant impact on the quality of life and performance status of patients participating in the RECOURSE trial, even in those in whom TAS-102 had to be discontinued because of its toxicity [49].

In preclinical studies, TAS-102 combined with cytotoxic drugs (oxaliplatin, irinotecan) showed enhanced activity against recurrent and chemo-naïve colorectal cancers [50, 51]. Also, the regimes including TAS-102 and targeted therapies (cetuximab, panitumumab) or antiangiogenic agents (nintedanib, bevacizumab) were shown to be effective against colorectal cancer in preclinical studies [52, 53]. One phase I/II study demonstrated a promising efficacy and moderate toxicity of TAS-102 plus bevacizumab in patients with metastatic and refractory colorectal

The aim of currently ongoing **TR**iflUridine/tipiracil in **S**econd-line s**T**ud**Y** phase

II/III study, the results of which will be available in 2022, is to determine DCR, response rate (RR), OS, PFS, safety profile, and time to treatment failure of trifluridine/tipiracil plus bevacizumab and irinotecan, fluoropyrimidine plus bevacizumab as the second-line treatments in patients with metastatic colorectal cancer who

An indirect comparison of regorafenib and TAS-102 based on published evidence from PubMed, Cochrane, and other databases suggests that these two agents did not differ in terms of PFS and OS benefit. However, regorafenib seems to produce all-grade toxicity more often than TAS-102 [56]. The most common forms of grade ≥3 toxicity found in regorafenib-treated patients were hepatotoxicity and palmar-plantar erythema, whereas individuals who received TAS-102 most often suffered from neutropenia [57, 58]. The similar efficacy of regorafenib and TAS-102 was confirmed in REGOTAS study (regorafenib vs. TAS-102 as salvage-line in patients with colorectal cancer refractory to standard chemotherapies: a multicenter observational study, UMIN 000020416) which showed no significant differences in

A subgroup analysis conducted within the framework of a retrospective study of Asian patients demonstrated that regorafenib was significantly more efficacious in individuals younger than 65 years, whereas TAS-102 provided greater OS benefit in persons aged 65 years or older [60]. Those findings are consistent with the results of the REGOTAS trial in which regorafenib-treated patients ≥65 years of age, with modified Glasgow Prognostic Score equal to 2 (GPS 2), had shorter OS and PFS

failed to respond to the first-line oxaliplatin-based therapy [55].

OS and PFS of patients treated with one of those agents [59].

occurred in 27.7% of patients treated with TAS-102. In more than 50% of the patients, the toxicity necessitated a delay or interruption of TAS-102 therapy or dose reduction [41]. However, the incidence of SAEs and AEs leading to treatment discontinuation in TAS-102 and placebo arms was essentially similar, and fatal AEs turned out to be more common in the placebo group [41]. Furthermore, in an open-label expanded-access program, TAS-102 had similar safety profiles in older

**84**

cancer [54].

**4. Regorafenib vs. TAS-102**

Another therapeutic option in heavily pretreated patients with metastatic colorectal cancer is re-challenge chemotherapy/re-initiation chemotherapy. Re-challenge chemotherapy is defined as the re-introduction of previously used chemotherapy with oxaliplatin or irinotecan-based regimens at least 9 months after the end of the initial exposure. Re-challenge chemotherapy constitutes an important option in patients who still present with good performance status and organ function reserve, especially in those in whom the initial chemotherapy was discontinued before progression of the disease (e.g., due to cumulative toxicities) [63–65]. Such approach did not shorten the period of the best supportive care and, more importantly, might prolong OS [65]. According to Chambers et al., clinical benefit rate (defined as the proportion of patients with partial response or stable disease) after re-challenge chemotherapy was 75.5% and time to progression equaled 6.5 months [63]. Moreover, re-challenge chemotherapy after regorafenib treatment seems to be a good strategy in heavily pretreated patients with metastatic colorectal cancer. According to literature, PFS after re-challenge chemotherapy varied between 0.5 and 3.5 months, and 6-month OS reached up to 27.3%. In some researchers' opinion, regorafenib could resensitize cancer patients to previously given chemotherapy, but this hypothesis still needs to be verified empirically [66].

Some authors reported the use of re-initiation chemotherapy or second rechallenge chemotherapy after the development of resistance, but none of these approaches is a standard of oncological treatment [63, 64].
