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

Introduction

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

Combination chemotherapy, FOLFOX/ XELOX and FOLFIRI/ XELIRI regimes, are the backbone for mCRC treatment.

Median overall survival (OS) for combination chemotherapy only. Leucovorin (LV)-modulated single-agent 5-FU regimens of Saltz, Douillard, and de Gramont achieved a median overall survival (OS) of 15 months while combination chemotherapy regimens of FOLFOX and FOLFIRI consistently lead to median survivals in the 15- to 20-month range (RM Goldberg, 2006). 

Improving survival

Biologic agents (anti-VEGF, anti-EGFR) were later added to the combination chemotherapy regimes, resulting in longest survival ever seen for metastatic colorectal cancer.

• The first successful trial was combining bevacizumab (anti-VEGF) 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 (due to study population not RAS WT-enriched).

Laterality of Colorectal Cancer (CRC)

The right-sided CRC are tumours from ceacum, 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.

Right-sided (midgut) vs left-sided (hindgut), both with different embryonic origins

The prognosis for stage IV/ metastatic colorectal cancer is better for left-sided primary tumours than right-sided primary tumor (JM Loree, 2018).

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.

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)

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

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. For left-sided metastatic colorectal cancer RAS wild type (WT), addition of anti-EGFR significantly improve survival and deliver superior median overall survival up to 3 years. For right-sided metastatic colorectal cancer RAS WT, there is no significant statistical difference median overall survival with addition of anti-EGFR or anti-VEGF, although numerically, it seemed like addition of anti-VEGF conferred slight advantage. Anti-EGFR (cetuximab, panitumumab), anti-VEGF (bevacizumab).

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

Treatment with an anti-EGFR antibody in first-line setting left-sided mCRC RAS WT leads to a significantly longer median overall survival compared with patients treated with bevacizumab.

In patients with right-sided mCRC RAS WT, both anti-EGFR and anti-VEGF improve median overall survival and there was no significant difference, statistically, between both biologic agents.

Summary

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).

If there is RAS mutation, anti-VEGF is NOT effective. Addition of anti-VEGF will be beneficial instead.

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

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