Abstract
The achievements in the treatment of metastatic colorectal cancer during recent years are based on a better understanding of the disease and individualized regimen planning. In adjuvant treatment, the highly important IDEA (International Duration Evaluation of Adjuvant Chemotherapy) study has shown that treatment duration can safely be reduced in selected patient populations. In patients with pN1 and pT1-pT3 tumors, 3 months of treatment with 5-fluorouracil and oxaliplatin is comparable with respect to 3-year survival rate to 6 months of treatment. For patients with N2 tumors, 6 months of treatment should stay the standard of care. The limitation of the duration of the adjuvant treatment is significantly reducing the chemotherapy-induced morbidity. New studies will explore the use of immune-checkpoint inhibitors in the adjuvant setting in microsatellite-instable (MSI) tumors. In metastatic disease, next to the required molecular testing for RAS and BRAF mutations, MSI testing is recommended. In the rare group of patients with a MSI tumor, immune-checkpoint inhibition is changing the course of the disease dramatically. Therefore, it is important to identify those patients early. For the RAS-mutant cases, no new and targeted treatment options have been identified yet. An optimal treatment strategy for those patients is urgently needed. RAS wild-type patients with tumors derived from the left side of the colon (splenic flexure to rectum) should be treated in first line with epithelial growth factor receptor (EGFR) antibodies. This selection by a molecular and a clinical marker increased the benefit derived by EGFR antibodies dramatically and defined the most effective treatment option for those patients. New selection criteria based on gene expression, methylation, and other molecular changes are explored and will further influence our therapeutic strategies in the future.
Highlights
During recent years, the treatment of colorectal cancer (CRC) has changed because of a better understanding of the biology of the disease and because of implementation of molecular and clinical biomarkers guiding clinical decisions
After years without any progress in the adjuvant setting, the IDEA (International Duration Evaluation of Adjuvant Chemotherapy) study collaboration challenged the duration of adjuvant treatment and encouraged clinicians to use a more individualized approach for patients with Union for International Cancer Control (UICC) stage III tumors
Data from the head-to-head trials CALGB 80405 (Alliance/SWOG)[1] and FIRE-32 comparing anti-epithelial growth factor receptor (EGFR) and anti-VEGF strategies in combination with a doublet chemotherapy in the first-line treatment of metastatic CRC gave us a better understanding of who will most likely benefit from an anti-EGFR strategy and influenced the current guidelines
Summary
The treatment of colorectal cancer (CRC) has changed because of a better understanding of the biology of the disease and because of implementation of molecular and clinical biomarkers guiding clinical decisions. The EGFR antibodies cetuximab and panitumumab have been shown to significantly increase tumor response rates (objective response rate, or ORR), PFS, and OS when added to firstline chemotherapy in patients with RAS wild-type tumors[18,19] Both drugs have been approved for the combination with FOLFOX (5-FU, folinic acid, and oxaliplatin) or FOLFIRI or as single-agent therapy. Two meta-analyses using the available data on sidedness for panitumumab-, cetuximab-, and bevacizumab-based trials showed that, for RAS wild-type tumors, left-sided primaries benefit with regard to ORR, PFS, and OS when treated in first line with EGFR antibodies[26,28]. For first-line treatment of mCRC, ESMO guidelines recommend EGFR antibodies in combination with chemotherapy for patients with left-sided, RAS wild-type primaries. HER2 overexpression remains a rare event in mCRC with a frequency of about 5.5% of all mCRC cases[38]
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