Metastatic Colorectal Cancer (mCRC): Improving Survival (Left-sided vs Right-sided).

Introduction

In metastatic colorectal cancer (mCRC), treatment in the first-line setting is very important to achieve longest survival.

Combination chemotherapy, FOLFOX or FOLFIRI regimes, are the backbone for mCRC treatment.

Biologic agents (anti-VEGR, anti-EGFR) were developed and used together with chemotherapy to improve survival.

  • The first successful trial was combining bevacizumab with FOLFIRI, yielding around 5 months increase in survival (H Hurwitz, 2004).
  • In 2009, CRYSTAL phase 3 trial with cetuximab (anti-EGFR) were publish, showing improvement of survival also, albeit around 2 months only.

Lately, more analysis were done using data from previously conducted clinical trials to understand if laterality (left-sided, right-sided) of metastatic colorectal cancer affect survival, especially with concomitant use of biologic agents (anti-EGFR, anti-VEGF).

Laterality of Colorectal Cancer

Screen Shot 2018-08-16 at 5.08.16 PM
Right-sided (midgut) vs left-sided (hindgut), both with different embryonic origins

The right-sided CRC are tumours from cecum, ascending colon, hepatic flexure, and transverse colon.

The left-sided CRC are tumours from splenic flexure, descending colon, sigmoid, and rectum.

Majority of the CRC are left-sided.

Screen Shot 2018-08-16 at 5.29.14 PM
Hazard ratio for overall survival based on primary tumor location and non-location based variables in relative to rectum. Example: a hazard ratio of 2 means that the odd of dying is twice in comparison with cancer at rectum.

The prognosis for stage IV/ mCRC was better for left-sided primary tumours than right-sided primary tumor (JM Loree, 2018).

However, for early stage I and II colorectal cancer, a population-based Surveillance, Epidemiology and End Results (SEER) analysis showed that prognosis was slightly better for right-sided CRC in term of overall survival and cancer-specific survival. Stage III CRC showed similar prognosis for both left-sided CRC and right-sided CRC (R Warschkow, ‎2016).

Addition of biologic agents (anti-EGFR, anti-VEGF)

Screen Shot 2018-08-17 at 12.05.43 AM.png
Median overall survival (OS) in metastatic colorectal cancer RAS WT (wild type) according to the laterality (right-sided/ left-sided) of the colorectal tumour and biologic agents (anti-EGFR, anti-VEGF) used. Anti-EGFR (cetuximab, panitumumab), anti-VEGF (bevacizumab).

In stage IV/ mCRC, addition of biologic therapy is able to improve average/ median overall survival, especially in patients with left-sided metastatic CRC.

colonimage1.jpg

Treatment with an anti-EGFR antibody in first-line setting left-sided mCRC leads to a significantly longer median OS compared with patients treated with bevacizumab, whereas in patient with right-sided mCRC, there is no or only a minor difference between patients treated with bevacizumab or cetuximab.

Finally

It is important to check RAS mutation status early in metastatic colorectal cancer (mCRC).

Anti-EGFR can ONLY be used is there is NO RAS mutation (RAS WT/ wild type)

The use of anti-EGFR together with chemotherapy in first-line setting improve overall survival.

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