Published online May 24, 2020. doi: 10.5306/wjco.v11.i5.294
Peer-review started: December 31, 2019
First decision: March 15, 2020
Revised: May 9, 2020
Accepted: May 14, 2020
Article in press: May 14, 2020
Published online: May 24, 2020
Colorectal cancer (CRC) is the third most common cause of cancer related death with liver being the most common metastatic site. It has been long suggested that left and right sided primary tumours exhibit different behaviour but relatively little has been written about how this relates specifically to outcomes in colorectal cancer with liver metastases (CRCLM).
To improve current understanding regarding the impact of PTL on CRCLM given the relative paucity of information in this area. This in turn could have a significant impact on patient morbidity and mortality.
To ascertain whether there is a significant difference in oncological outcome in patients with CRCLM depending on PTL and to present some hypotheses that may explain any differences found. This systematic review demonstrates a significant difference in outcomes based on PTL with inferior oncological outcome for patients with right-sided CRC. . Further work is needed to better characterise the mechanisms responsible for this variation in order to inform clinical decision making.
A systematic review of Medline, Cochrane and Embase using the Terms “The medical subject heading terms and key words used are as follows: “Colon” or “rectal cancer”, “liver metastasis” or “liver metastases” or “hepatic metastasis” or “hepatic metastases” and “left” and “Right”. This search was combined with a bibliographic search to find the relevant publications and extract data from these papers. The methodology was based around the Preferred Reporting Items for Systematic Reviews and Meta-Analyses’ recommendations for systematic reviews
Twenty-one studies with a total of 18203 patients showed a statistically significant trend of improved overall survival in patient with left sided primary tumours undergoing treatment for colorectal cancer liver metastases (l-CRCLM). Four studies including 3013 patients showed improved disease free survival (DFS) in l-CRCLM. Only five publications provided data on progression free survival (PFS). These studies including 2805 patients showed significantly improved PFS in l-CRCLM vs r-CRCLM. The findings of this review are congruent with the accepted premise of superior survival in left sided colorectal cancer, and uniquely show that this remains true in the context of metastatic liver disease. We highlight a number of factors that may contribute to this, including KRAS/BRAF mutational status, presence of mucinous elements, and impaired chemosensitivy –all which are shown to be associated with right-sided PTL. The exact interplay between these known factors, PTL, and the emerging new mutations and molecular markers is yet to be determined and work needs to be done to determine the importance of PTL within the conglomeration.
The findings of this review indicate that PTL may have a role as an independent prognostic factor when determining treatment and disease surveillance strategies specifically in colorectal cancer that has metastasised to the liver. We find improved survival for both resected and unresectable l-CRCLM as well as a maintained trend after addition of biologics to established chemotherapy regimens. Hepatic recurrence after treatment of CRCLM appears to occur more aggressively with right-sided CRC, conferring significantly reduced survival. Explaining these variations in oncological outcome requires a deeper understanding of the underlying molecular and embryological differences associated with primary tumour sidedness. Microsatellite instability, interestingly, whilst more common in right-sided tumours, has been shown to be independently associated with improved survival – a finding somewhat incongruent with the overall picture of inferior survival in r-CRCLM. This suggests alternative mechanisms beyond MMR and microsatellite instability are likely to be involved. KRAS and BRAF mutational status, mucinous adenocarcinoma, and impaired chemosensitivity are all known to be significantly associated with right-sided CRC, and we show here that this association and the accompanying inferior survival persists in r-CRCLM. A better understanding of the role of PTL in the oncological outcomes of metastatic CRC may allow for improved risk stratification and redesigned patient pathways.
There is a considerable amount of data available on the oncological outcomes of patients undergoing liver resection for CRCLM, as related to PTL. This shows with convincing evidence that outcomes are superior for patients with l-CRCLM. Future research should be focused on gathering associated molecular and genetic data as related to PTL to better understand the tumour biology of right-sided CRC. This may allow the determination of ideal molecular markers, both for risk stratification/prognostication, and that may be used as potential therapeutic targets.