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First-line therapy for mCRC — the influence of primary tumour location on the therapeutic algorithm

Nature Reviews Clinical Oncology volume 14, page 113 (2017)Cite this article

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Many different factors influence the choice of upfront treatment for patients with metastatic colorectal cancer (mCRC). In a Perspectives article published in the October 2015 issue of this journal (First-line chemotherapy for mCRC — a review and evidence-based algorithm. Nat. Rev. Clin. Oncol. 12, 607–619; 2015)1, we presented an algorithm to facilitate the translation of results from clinical trials into daily practice, and to provide physicians with a useful tool to guide their routine treatment decisions. This algorithm summarized our evidence-based philosophy regarding the choice of both the 'most-appropriate' intensity of the chemotherapy backbone and the 'best' targeted agents to add to this backbone. Comprehensive assessment of patient characteristics was placed at the top of the therapeutic algorithm, emphasizing the importance of the patient's general health and condition in determining the intensity of the treatment; the same approach was subsequently endorsed in the 2016 updated ESMO clinical practice guidelines for the management of mCRC2.

In the past few months, however, data highlighting the relevance of primary tumour location as both a prognostic factor and a predictor of benefit from treatment with anti-EGFR monoclonal antibodies have rapidly accumulated. In October 2016, results of a robust meta-analysis3 confirmed previous evidence of a significantly worse patient prognosis associated with right-sided tumours (located up to the proximal two-thirds of the transverse colon) versus left-sided tumours (located within the distal third of the transverse colon or beyond), independent of disease stage — thus demonstrating the importance of including primary tumour location as a stratification factor in clinical trial design. With regard to predicting patient benefit from targeted agents, although findings indicate that no interaction exists between 'sidedness' and the efficacy of anti-VEGF therapy with bevacizumab4, the location of the primary tumour does seem to affect sensitivity to anti-EGFR-antibodies5,6. In this respect, subgroup analyses of six international, randomized, controlled trials in large cohorts of patients with RAS-wild-type mCRC were also reported in October 2016 (Refs 7,8,9), and the results showed clear differences in the efficacy of anti-EGFR therapy in patients with left-sided and right-sided primary tumours (Supplementary information S1 (table)). Overall, the addition of anti-EGFR antibodies to a chemotherapy doublet is associated with a significant overall survival benefit for patients with left-sided tumours (hazard ratio (HR) 0.69, 95% confidence interval (CI) 0.58–0.83), which is essentially absent in those with right-sided tumours (HR 0.96, 95% CI 0.68–1.35; Pinteraction = 0.10)10. Consistent results were reported when comparing the addition of anti-EGFR antibodies versus bevacizumab to doublet chemotherapy according to tumour sidedness: a clear overall survival benefit from the combination with anti-EGFR antibodies was evident for patients with left-sided tumours (HR 0.71, 95% CI 0.58–0.85), whereas doublet chemotherapy plus bevacizumab seems to provide better results in those with right-sided tumours (HR 1.30, 95% CI 0.97–1.74; Pinteraction <0.001)10.

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Figure 1: Updated algorithm for personalized allocation of first-line treatments in patients with mCRC.

References

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Authors and Affiliations

  1. Azienda Ospedaliera-Universitaria Pisana; and at the Department of Translational Research and New Technologies in Medicine and Surgery, Chiara Cremolini, Carlotta Antoniotti, Roberto Moretto, Gianluca Masi and Alfredo Falcone are at the Unit of Medical Oncology 2, University of Pisa, Via Roma, 67, 56126 Pisa, Italy.,

    Chiara Cremolini, Carlotta Antoniotti, Roberto Moretto, Gianluca Masi & Alfredo Falcone

  2. at the Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma, 67, 56126 Pisa, Italy.,

    Chiara Cremolini, Carlotta Antoniotti, Roberto Moretto, Gianluca Masi & Alfredo Falcone

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  1. Chiara Cremolini
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Corresponding author

Correspondence to Chiara Cremolini.

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Competing interests

C.C. has received payment for consultancy and honoraria for speaking from Amgen, Bayer, Eli-Lilly, Merck Serono, and Roche. A.F. has received payment for consultancy and honoraria for speaking from Amgen, Bayer, Celgene, Eli-Lilly, Merck Serono, and Roche. The other authors declare no competing interests.

Supplementary information

Supplementary information S1 (table)

Subgroup analyses of first-line and second-line randomized studies in patients with RAS-wild-type CRC, according to primary tumour location. (PDF 236 kb)

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Cremolini, C., Antoniotti, C., Moretto, R. et al. First-line therapy for mCRC — the influence of primary tumour location on the therapeutic algorithm. Nat Rev Clin Oncol 14, 113 (2017). https://doi.org/10.1038/nrclinonc.2016.219

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