**2.3 Toxicity**

*Multidisciplinary Approach for Colorectal Cancer*

are not reimbursed.

**2. Regorafenib**

drug intolerance, whichever first.

therapy.

**2.1 Trials**

respectively [5].

**2.2 Predictive markers**

Importantly, the time elapsed since completion of the primary treatment to the re-induction should not be shorter than 9 months. Finally, patients with metastatic colorectal cancer can receive chemotherapy with mitomycin C plus capecitabine. This generally neglected treatment option seems particularly reasonable in the case of countries in which regorafenib and trifluridine/tipiracil have been registered but

The aim of this review paper is to discuss the therapeutic options that could be used in metastatic colorectal cancer patients after three or more lines of systemic

Regorafenib (BAY 73-4506) is a low-molecular-weight diphenylurea multikinase inhibitor of VEGFR1-3, c-KIT, TIE-2, PDGFR-β, FGFR-1, RET, RAF-1, BRAF, and p38 MAP kinase for oral administration. This agent has been registered for patients with pretreated metastatic colorectal cancers and refractory gastrointestinal

stromal tumors (GIST) [1, 2]. Regorafenib is administered at 160 mg daily (q.d.) for 3 weeks of each 4-week cycle (3 week *on*, 1 week *off*), until disease progression or

In a registration phase III trial, CORRECT (regorafenib monotherapy for previously treated metastatic colorectal cancer), 760 patients were randomized in a 2:1 ratio to receive regorafenib or placebo. The majority of patients were Caucasians (the study included only 111 Asians). Median OS turned out to be significantly longer in the regorafenib group than in the placebo group (6.4 vs. 5.0 months) [3]. In another randomized double-blind phase III trial, CONCUR, 204 patients with metastatic colorectal cancer after at least two lines of systemic therapy were randomized in a 2:1 ratio to receive regorafenib or placebo. All patients were

Asians. Median OS in the regorafenib arm and placebo arm was 8.8 and 6.3 months, respectively. The results of this trial confirmed previous observations about the regorafenib efficacy. Toxicity profiles of regorafenib in both studies mentioned above were essentially similar [4]. However, these promising findings were not confirmed in another trial, PREVIUM, including patients with KRAS- or BRAFpositive metastatic colorectal cancer treated previously with FOLFOXIRI plus bevacizumab; median OS and median PFS in this group were 3.3 and 2.2 months,

According to Komori et al., colorectal cancer patients who showed early decrease in carbohydrate antigen 19-9 (Ca19-9) levels had significantly longer PFS after regorafenib than individuals in whom this marker remained elevated (3.7 vs. 2.0 months). Multivariate analysis confirmed that early decrease in Ca19-9 level was a significant independent predictor of better response to regorafenib [6].

status of the tumor and survival. The study demonstrated that the presence of KRAS-wild type and PIK3CA-wild type in primary tumor was a biomarker of PFS benefit [7]. In another study, conducted by Ma et al., the lack of EGFR expression turned out to be associated with longer PFS and OS (14 vs. 2.5 months and 19.7 vs. 9.6 months, respectively). While the presence of KRAS-wild type correlated with

The authors of the CORRECT study analyzed an association between mutational

**80**

Adverse event (AE) profile of regorafenib is similar as in the case of other tyrosine multikinase inhibitors, and the AEs of this agent are generally manageable. The most common non-hematological toxicity, which may worsen patient's quality of life, is hand-foot skin reaction (HFSR) (54%) [10–12]. Hence, many patients who experienced this AE may require treatment modification [10]. Interestingly, the incidence of HFSR seems to vary by primary tumor type. According to literature, HFSR symptoms can be found in up to 50% of regorafenib-treated patients with hepatocellular carcinoma, 60.2% of individuals with GIST, and 46.6% of persons with metastatic colorectal cancer [11]. The second most common AE in regorafenib-treated patients is arterial hypertension. Based on the data from five clinical trials, the overall incidence of arterial hypertension in regorafenib-treated patients can be estimated at 44.4% and the incidence of high-grade (G3 and higher) hypertension at 12.5%. Similar to HFSR, the risk of this AE seems to vary according to tumor type [13].

Treatment with regorafenib may also contribute to all-grade hepatotoxicity (bilirubin, AST, ALT, and ALP elevation), an AE observed in approximately one-third of patients treated with this anticancer agent [14].

Other AEs frequently associated with regorafenib treatment are oral mucositis, fatigue, nausea, weight loss, and diarrhea [12, 15]. All-grade anorexia was shown to occur more often in patients who had been previously treated with tyrosine multikinase inhibitors. On the other hand, patients from this group less commonly presented with a high-grade AST elevation [12].

The incidence of hematologic toxicities, such as thrombocytopenia, anemia, neutropenia, and leukopenia, varies between 22% (thrombocytopenia) and 13% (leukopenia). However, high-grade (G3 or higher) hematologic toxicities are relatively rarely observed in regorafenib-treated patients [16].
