Date Published: May 31, 2019
Publisher: Public Library of Science
Author(s): Elisabeth Gasser, Eva Braunwarth, Marina Riedmann, Benno Cardini, Nikolaus Fadinger, Jaroslav Presl, Eckhard Klieser, Philipp Ellmerer, Aurélien Dupré, Katsunori Imai, Hassan Malik, Hideo Baba, Hanno Ulmer, Stefan Schneeberger, Dietmar Öfner, Adam Dinnewitzer, Stefan Stättner, Florian Primavesi, Surinder K. Batra.
Colorectal cancer (CRC) represents a major cause for cancer death and every third patient develops liver metastases (CRLM). Several factors including number and size of metastases and primary tumour lymph-node status have been linked to survival. The primary tumour location along the colo-rectum continuum (sidedness) was analysed in first-line chemotherapy trials, where right-sided CRCs showed decreased survival. This association has not yet been clearly established in patients undergoing resection for CRLM.
Clinicopathological differences in CRLM resections according to sidedness in two Austrian centres (2003–2016) are described and survival is compared through Kaplan-Meier and multivariable analysis. A risk-score is presented with time-dependent receiver operating curve analysis and international validation in two major hepatobiliary centres. Furthermore, a systematic meta-analysis of studies on primary tumour location and survival after CRLM resection was performed.
259 patients underwent hepatectomy. Right-sided CRC patients (n = 59) more often had positive primary tumour lymph-nodes (76.3%/61.3%;p = 0.043) and RAS-mutations (60%/34.9%;p = 0.036). The median overall and disease-free survival was 33.5 and 9.1 months in right-sided versus 55.5 (p = 0.051) and 12.1 months (p = 0.078) in left-sided patients. In multivariable analysis nodal-status (HR 1.52), right-sidedness (HR 1.53), extrahepatic disease (HR 1.71) and bilobar hepatic involvement (HR 1.41) were significantly associated with overall survival. Sidedness was not independently associated with disease-free survival (HR 1.33; p = 0.099). A clinical risk score including right-sidedness, nodal-positivity and extrahepatic involvement significantly predicted overall (p = 0.005) and disease-free survival (p = 0.027), which was confirmed by international validation in 527 patients (p = 0.001 and p = 0.011). Meta-analysis including 10 studies (n = 4312) showed a significant association of right-sidedness with overall survival after resection (HR 1.55;p<0.001). There was no significant association with disease-free survival (HR 1.22;p = 0.077), except when rectal-cancers were excluded (HR 1.39;p = 0.006). Patients with liver metastases from right-sided CRC experience worse survival after hepatic resection. Sidedness is a simple yet effective factor to predict outcome.
Although mortality of colorectal cancer (CRC) is declining within the last years, it still represents the second most common cause of cancer death in Europe  (WHO). About one third of patients develop liver metastases (colorectal liver metastases, CRLM) , but only 10–30% [3, 4] are usually eligible to undergo liver resection due to the extent of the disease. Progressive liver surgery eventually combined with interventional oncology techniques enables increased resectability in specialized centres [5–7], but preoperative risk stratification is essential to limit postoperative complications and achieve adequate long-term survival benefit [8–10]. Even though radical liver resection is a potentially curative treatment, more than 50% of these patients develop intrahepatic recurrence [11, 12] and recently reported five-year overall survival (OS) rates after liver resection are in the range of 25 to 58% [12–16]. Established risk scores such as the”Fong” score from Memorial Sloan Kettering Cancer Centre (MSKCC) or the Basingstoke predictive index are routinely applied by clinicians to select patients suitable for hepatic resection in terms of risk-benefit ratio. [17, 18] These risk scores mainly utilize clinical and pathological factors such as number and size of metastases or tumour markers to predict OS and disease-free survival (DFS) after liver resection. Recently, markers of tumour biology and genetics such as the RAS or BRAF mutational status are more commonly included in clinical risk scores and algorithms for oncosurgical treatment [19–22]. In this new genomic era of cancer treatment, the relevance of primary tumour location (“sidedness”)–a term commonly used in former times of colorectal surgery—emerged with a new livery. The large bowel develops from different embryonic origins and molecular features change along the length of the colon-rectum. Advancements in molecular biology knowledge and insights of embryogenesis lead to revive previous research and to clinically divide CRCs in right- and left-sided tumours, representing two separate distinct entities [23, 24]. Right sided colorectal cancer (RCRC) is commonly defined as a tumour located between the ileocecal junction and the transverse colon and left colorectal cancer (LCRC) includes all tumours located from the splenic flexure to the rectum. RCRCs are more often diploid and hypermutated, frequently present with microsatellite instability (MSI), and more often have deleterious mutations of RAS, BRAF and PI3KCa and a serrated signature [25–28]. LCRCs more often develop from the classical adenoma-carcinoma sequence of carcinogenesis with aneuploidy and chromosomal instability, leading to amplification of regions hosting receptor tyrosine kinases such as epidermal growth factor receptor (EGFR) [29–33].
The present study examined if survival after resection of CRLM is worse in patients with RCRC compared to LCRC through analysis of own data, international validation cohorts and meta-analysis of published studies. First, we evaluated 259 patients undergoing liver surgery in two Austrian University Hospitals, revealing differences in biological behaviour between RCRC and LCRC tumours. RCRC significantly more often had positive lymph nodes and RAS mutations, and patients with RCRC tended to be older than LCRC patients’, which is in line with other studies [15, 54]. In contrast to previous reports, a sex difference with higher incidence of RCRC in women was not seen in our own data [14, 54, 55].
Patients with CRLM of right-sided primary colon cancer experience worse survival after hepatic resection than left-sided CRC patients. While the association with OS has been demonstrated in an own cohort with international validation and through meta-analysis, DFS is only significantly worse in RCRC compared to left-sided tumours when rectal cancer patients are excluded. The difference in survival is accounted for by the more aggressive biological behaviour of RCRC liver metastases with higher rates of mutations in oncogenes such as RAS and BRAF and probably other factors associated with the histological subtype of primary tumour and surgical outcomes of simultaneous colonic resection that have not yet been analysed prospectively in detail by the oncosurgical scientific community. Incorporating primary tumour sidedness into clinical risk stratification along other established variables is an easy and effective way to determine the mCRC patients’ postoperative prognosis in case of planned resection for CRLM.