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

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

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

**85**

*Further Therapeutic Options in Heavily Pretreated Colorectal Cancer Patients*

than individuals who received TAS-102 [59]. The same study identified modified GPS before later-line chemotherapy as the strongest predictor of OS in patients with

Nothing has been known about the efficacy and toxicity of TAS-102 in patients treated previously with regorafenib since publication of Kotani et al.'s study. In the latter study, median PFS in patients treated with regorafenib prior to TAS-102 implementation was 2.0 months as compared with 2.1 months in individuals with no history of regorafenib treatment, and median OS in these two groups was 4.7 and 6.2 months, respectively [61]. The toxicity of TAS-102, assessed based on the incidence of at least grade 3 side effects, was similar regardless of the study group [61]. The treatment sequence analysis demonstrated that TAS-102-treated patients had longer PFS and OS after a fluoropyrimidine-based therapy-free interval, 3.1 and 17.7 months, respectively, as compared with 2.2 and 8.1 months, respectively, in persons in whom TAS-102 was implemented immediately after the fluoropyrimidine-based therapy. However, no similar association was found between the efficacy of regorafenib and the time elapsed since fluoropyrimidine-based treatment

The prognosis seems to be also influenced by the sequence of regorafenib and TAS-102 administration. Median OS in patients who received crossover treatment with regorafenib followed by TAS-102 was 11.5 months, as compared with 7.6 months in individuals in whom first TAS-102 and then regorafenib were imple-

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].

**6. Combination of capecitabine and mitomycin C (MMC)**

MMC is a cytotoxic antibiotic which shows moderate efficacy when used as monotherapy in colorectal cancer patients. Upregulation of intra-tumoral

*DOI: http://dx.doi.org/10.5772/intechopen.85027*

metastatic colorectal cancer [59].

discontinuation [62].

**5. Re-challenge chemotherapy**

mented [57].

*Further Therapeutic Options in Heavily Pretreated Colorectal Cancer Patients DOI: http://dx.doi.org/10.5772/intechopen.85027*

than individuals who received TAS-102 [59]. The same study identified modified GPS before later-line chemotherapy as the strongest predictor of OS in patients with metastatic colorectal cancer [59].

Nothing has been known about the efficacy and toxicity of TAS-102 in patients treated previously with regorafenib since publication of Kotani et al.'s study. In the latter study, median PFS in patients treated with regorafenib prior to TAS-102 implementation was 2.0 months as compared with 2.1 months in individuals with no history of regorafenib treatment, and median OS in these two groups was 4.7 and 6.2 months, respectively [61]. The toxicity of TAS-102, assessed based on the incidence of at least grade 3 side effects, was similar regardless of the study group [61]. The treatment sequence analysis demonstrated that TAS-102-treated patients had longer PFS and OS after a fluoropyrimidine-based therapy-free interval, 3.1 and 17.7 months, respectively, as compared with 2.2 and 8.1 months, respectively, in persons in whom TAS-102 was implemented immediately after the fluoropyrimidine-based therapy. However, no similar association was found between the efficacy of regorafenib and the time elapsed since fluoropyrimidine-based treatment discontinuation [62].

The prognosis seems to be also influenced by the sequence of regorafenib and TAS-102 administration. Median OS in patients who received crossover treatment with regorafenib followed by TAS-102 was 11.5 months, as compared with 7.6 months in individuals in whom first TAS-102 and then regorafenib were implemented [57].
