First line chemotherapy in metastatic colorectal cancers: A review

Chemotherapy and Anti-EGFR

To choose the best treatment for healthy patients with unresectable mCRC, it is now mandatory to determine the RAS and BRAF mutational status. RAS mutations should always be ruled out before the use of anti-EGFR because they are poor predictors of their effectiveness. BRAF mutation V600E has a low prevalence and a dismal prognosis. The RAS and BRAF wild type is present in about 40% of patients. The selection of individuals who might benefit from EGFR-targeting strategies is made possible by RAS mutation status [29]. The anti-EGFR monoclonal antibodies cetuximab and panitumumab should only then be used for patients whose tumors are RAS wild type (KRAS exons 2, 3 and 4 and NRAS exons 2, 3 and 4). Patient OS is increased significantly from 20 to 26–28 months by the addition of cetuximab or panitumumab to either FOLFIRI or FOLFOX [15,18]. It is, however, linked to an increase in grade 3–4 toxic events, particularly acneiform rash, infusional reactions, diarrhoea, and hypomagnesemia. Studies comparing Doublet chemotherapy with Cetuximab or Panitumumab, have shown no differences in efficacy and are now regarded as being equivalent. Contrarily, the combination of anti-EGFR antibodies with capecitabine or bolus 5-FU plus oxaliplatin is not advised [16,17]. The use of anti-EGFR drugs in first-line therapy has been assessed in a total of six clinical trials [15,16,17,18,19,20] (Table 1). Most of them were originally planned for the entire mCRC population and then re-examined retrospectively for patients with RAS wild type. In terms of survival, half of them showed a significant improvement. Compared to patients with any RAS mutation, patients with RAS wild type had significantly higher RR and PFS (positive predictive value).

Anti VEGF versus Anti-EGFRs

Bevacizumab and anti-EGFR drugs shouldn't be added, together, to combination CT because they have been shown to have negative effects [30,31]. Data from three first-line trials comparing anti-EGFR to bevacizumab in conjunction with CT doublets for patients with RAS wild-type have been reported (Table 1) [21,22,23]. Results were contradictory and therefore inconclusive. PFS was equal in all three, and none of them met the predetermined endpoint. But with anti-EGFR, there was a rise in RR and a positive trend toward better survival.The primary tumor site may have an impact on the choice of treatment. Results from meta- analysis of trials combining CT and anti-EGFR antibodies revealed a greater benefit in left-sided tumors, while greater benefit was seen for right-sided cancers when CT was given alone or in combination with bevacizumab [32]. Bevacizumab plus CT, regardless of the primary site, should be the first line of treatment for tumors with the RAS mutation.

Doubletsand Triplets chemotherapy

With or without monoclonal antibodies, two-drug regimens,FOLFOX/XELOX and FOLFIRI/XELIRI are used to administer 5-FU, oxaliplatin, and irinotecan. The ideal sequencing has not yet been determined, but some Phase III trials have demonstrated that the FOLFOXIRI regimen, which includes 5-FU, oxaliplatin, and irinotecan, can improve outcomes for patients with metastatic colorectal cancer (mCRC) [14,24,25,26,27] (Table 1). In a recent meta-analysis of eight RCTs, FOLFOXIRI had  better efficacy outcomes, most notably with a 25% increase in survival. The grade 3–4 toxicity of FOLFOXIRI was also elevated [5]. To estimate the benefit of adding bevacizumab to FOLFOXIRI, a phase III randomized study (TRIBE) was conducted comparing FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab. The median progression free survival (P.F.S) was 12.1 months in the experimental arm versus 9.7 in the control arm. The overall survival (O.S) and overall response rate(O.R.R) were 31 months respectively versus 25.8 and 65% versus 53% all in favour of the experimental arm with statistically significant differences[33]. Regarding triplet therapy and anti-EGFR, there is less research available. Recently, a randomized Phase II trial comparing FOLFOXIRI to mFOLFOXIRI plus panitumumab in 96 RAS WT patients was presented. The panitumumab-containing arm's OS demonstrated a trend in favor of increased ORR and secondary metastasis resections, similar PFS, and favorable OS [34]. In TRIBE-2, the sequence of mFOLFOX6 and FOLFIRI doublets in addition to bevacizumab was contrasted with the preplanned strategy of upfront FOLFOXIRI followed by the reintroduction of the same regimen after disease progression. This Phase III trial demonstrated that, in terms of PFS and OS, upfront FOLFOXIRI plus bevacizumab appears to be a more advantageous therapeutic approach [27]. In the majority of clinical trials, the advantages of triplets are more pronounced in healthy, younger patients without comorbidities and without a history of adjuvant oxaliplatin exposure. Multiple recommendations for FOLFOXIRI plus bevacizumab for patients with BRAF mutations were made based on small individual patient data. This suggestion has been contested by a recent meta-analysis [33].

Drivers of treatment

Recent clinical trials have shown that new targeted therapies may be beneficial for small, molecularly selected subgroups of patients with mCRC. Less than 5% of mCRC patients have tumors with high MSI scores or that lack mismatch repair (dMMR). In these situations, immunotherapy is a more effective form of treatment than conventional CT (with or without antiangiogenic or anti-EGFR agents), both in the initial [35] and subsequent lines of treatment [36]. 8–15 percent of cases of mCRC have the V600E BRAF mutation, which is associated with a worse prognosis and resistance to common chemotherapy regimens. Encorafenib and cetuximab, with or without binimetinib, have shown promising results in second and later lines of treatment [37], and their combination is currently being tested in patients receiving less pretreatment. Finally, less than 5% of patients with mCRC exhibit HER2 amplifications (more frequently linked to rectal primaries) or NTRK fusions (more frequently seen in patients with high MSI scores or dMMR). With drugs like trastuzumab [38] or larotrectinib [39], these uncommon alterations can be effectively treated. For first-line treatment of patients with mCRC and MSI-high tumors, only immunotherapy using pembrolizumab is currently approved.