Bjørn S. Nedrebø

Stage at diagnosis and colorectal cancer survival in six high-income countries: A population-based study of patients diagnosed during 2000–2007

Abstract Background. Large international differences in colorectal cancer survival exist, even between countries with similar healthcare. We investigate the extent to which stage at diagnosis explains these differences. Methods. Data from population-based cancer registries in Australia, Canada, Denmark, Norway, Sweden and the UK were analysed for 313 852 patients diagnosed with colon or rectal cancer during 2000–2007. We compared the distributions of stage at diagnosis. We estimated both stage-specific net survival and the excess hazard of death up to three years after diagnosis, using flexible parametric models on the log-cumulative excess hazard scale. Results. International differences in colon and rectal cancer stage distributions were wide: Denmark showed a distribution skewed towards later-stage disease, while Australia, Norway and the UK showed high proportions of ‘regional’ disease. One-year colon cancer survival was 67% in the UK and ranged between 71% (Denmark) and 80% (Australia and Sweden) elsewhere. For rectal cancer, one-year survival was also low in the UK (75%), compared to 79% in Denmark and 82–84% elsewhere. International survival differences were also evident for each stage of disease, with the UK showing consistently lowest survival at one and three years. Conclusion. Differences in stage at diagnosis partly explain international differences in colorectal cancer survival, with a more adverse stage distribution contributing to comparatively low survival in Denmark. Differences in stage distribution could arise because of differences in diagnostic delay and awareness of symptoms, or in the thoroughness of staging procedures. Nevertheless, survival differences also exist for each stage of disease, suggesting unequal access to optimal treatment, particularly in the UK.

Evolving molecular classification by genomic and proteomic biomarkers in colorectal cancer: Potential implications for the surgical oncologist

Colorectal cancer (CRC) is one of the most frequent cancers in the Western world and represents a major health burden. CRC development is a multi-step process that spans 10-15years, thereby providing an opportunity for early detection and even prevention. As almost half of all patients undergoing surgery develop recurrent disease, surveillance is advocated, albeit with various means and intervals. Current screening and surveillance efforts have so far only had limited impact due to suboptimal compliance. Currently, CEA is the only biomarker in clinical use for CRC, but has suboptimal sensitivity and specificity. New and better biomarkers are therefore strongly needed. Non-invasive biomarkers may develop through the understanding of colorectal carcinogenesis. Three main pathways occur in CRC, including chromosomal instability (CIN), microsatellite instability (MSI) and epigenetic silencing through the CpG Island Methylator Phenotype (CIMP). These pathways have distinct clinical, pathological, and genetic characteristics, which can be used for molecular classification and comprehensive tumour profiling for improved diagnostics, prognosis and treatment in CRC. Molecular-biological research has advanced with the sequencing of the human genome and the availability of genomic and proteomic high-throughput technologies using different chip platforms, such as tissue microarrays, DNA microarrays, and mass spectrometry. This review aims to give an overview of the evolving biomarker concepts in CRC, with concerns on methods, and potential for clinical implications for the surgical oncologist.

Survival effect of implementing national treatment strategies for curatively resected colonic and rectal cancer

The surgical management of rectal cancer has changed substantially over the past decade. There are limited data on the long‐term outcome of implementing systematic management strategies.

Risk factors associated with poor lymph node harvest after colon cancer surgery in a national cohort.

Evaluation of ≥ 12 lymph nodes (LNs) is recommended after surgery for colon cancer. A harvest of ≤ 8 is considered poor, but few reports have evaluated risk factors associated with a poor harvest. This aims of this study were to analyse the clinical, surgical and pathological factors associated with poor LN harvest (LNH), the total number of examined nodes and the effect of LN number on stage.

Influence of Microsatellite Instability and KRAS and BRAF Mutations on Lymph Node Harvest in Stage I–III Colon Cancers

Lymph node (LN) harvest is influenced by several factors, including tumor genetics. Microsatellite instability (MSI) is associated with improved node harvest, but the association to other genetic factors is largely unknown. Research methods included a prospective series of stage I-III colon cancer patients undergoing ex vivo sentinel-node sampling. The presence of MSI, KRAS mutations in codons 12 and 13, and BRAFV600E mutations was analyzed. Uni- and multivariate regression models for node sampling were adjusted for clinical, pathological and molecular features. Of 204 patients, 67% had an adequate harvest (≥12 nodes). Adequate harvest was highest in patients whose tumors exhibited MSI (79%; odds ratio (OR) 2.5, 95% confidence interval (CI) 1.2–4.9; P = 0.007) or were located in the proximal colon (73%; 2.8, 1.5–5.3; P = 0.002). In multiple linear regression, MSI was a significant predictor of the total LN count (P= 0.02). Total node count was highest for cancers with MSI and no KRAS/BRAF mutations. The independent association between MSI and a high LN count persisted for stage I and II cancers (P= 0.04). Tumor location in the proximal colon was the only significant predictor of an adequate LN harvest (adjusted OR 2.4, 95% CI 1.2–4.9; P = 0.01). An increase in the total number of nodes harvested was not associated with an increase in nodal metastasis. In conclusion, number of nodes harvested is highest for cancers of the proximal colon and with MSI. The nodal harvest associated with MSI is influenced by BRAF and KRAS genotypes, even for cancers of proximal location. Mechanisms behind the molecular diversity and node yield should be further explored.

Endoscopy, morphology, morphometry and molecular markers: predicting cancer risk in colorectal adenoma

The evaluation of short- and long-term risk for developing cancer in patients with colorectal adenomas is controversial. Good, reliable predictors of cancer risk in any adenoma are currently lacking and are limited to adenoma size, number and histologic type. In fact, the evaluation of any adenoma or precancer lesion (e.g., hyperplastic polyps, serrated adenoma or aberrant crypt foci) within the colorectum may be assessed by a number of techniques ranging from direct visualization through the endoscope, to microscopic assessment, and to evaluation at the molecular level. Emerging techniques may yield improved methods of adenoma risk-assessment in the near future. For one, newer endoscopy technologies include chromoendoscopy or endocytoscopy, which now render endoscopists able to resolve the surface and subsurface mucosa at cellular resolution in vivo and in real time – thus, bringing the microscope to the patient’s bedside. This new era in endoscopic imaging is dubbed ‘histoendoscopy’. Further, while traditional views of classifying protruding and sessile lesions include those of Haggitt, the sm-classification, the Japanese and the so-called Vienna classifications to evaluate neoplasia, the development of new molecular techniques may give way to new methods of classifying preneoplasia and precancerous lesions. This review discusses some pros and cons of risk evaluation technologies in the colorectal tract by endoscopy, microscopy, and quantitative and molecular features. The morphometry-based studies performed over the past decades for the quantitative assessment of cellular and nuclear features within adenomas have failed to yield results amenable for clinical translation and are unlikely to improve further and gain widespread use with current technology. Rather, emerging knowledge of pathway-specific markers through the outlining of a molecular classification will likely be the basis for improved detection and diagnosis. The emerging genomic and proteomic technologies allowing for noninvasive tests to detect (asymptomatic) cancer and neoplasia are discussed. Lastly, the importance of recognizing bias and pitfalls and the adherence to guidelines for biomarker research are addressed.

Excess mortality after curative surgery for colorectal cancer changes over time and differs for patients with colon versus rectal cancer

Abstract Background. Improved management of colorectal cancer patients has resulted in better five-year survival for rectal cancer compared with colon cancer. We compared excess mortality rates in various time intervals after surgery in patients with colon and rectal cancer. Material and methods. We analysed all patients with curative resection of colorectal cancers reported in the Cancer Registry of Norway before (1994–1996) and after (2001–2003) national treatment guidelines were introduced. Excess mortality was analysed in different postoperative time intervals within the five-year follow-up periods for patients treated in 1994–1996 vs. 2001–2003. Results. A total of 11 437 patients that underwent curative resection were included. For patients treated from 1994 to 1996, excess mortality was similar in colon and rectal cancer patients in all time intervals. For those treated from 2001 to 2003, excess mortality was significantly lower in rectal cancer patients than in colon cancer patients perioperatively (in the first 60 days: excess mortality ratio = 0.46, p = 0.007) and during the first two postoperative years (2–12 months: excess mortality ratio = 0.54, p = 0.010; 1–2 years: excess mortality ratio = 0.60, p = 0.009). Excess mortality in rectal cancer patients was significantly greater than in colon cancer patients 4–5 years postoperatively (excess mortality ratio = 2.18, p = 0.003). Conclusion. Excess mortality for colon and rectal cancer changed substantially after the introduction of national treatment guidelines. Short-term excess mortality rates was higher in colon cancer compared to rectal cancer for patients treated in 2001–2003, while excess mortality rates for rectal cancer patients was significantly higher later in the follow-up period. This suggests that future research should focus on these differences of excess mortality in patients curatively treated for cancer of the colon and rectum.

Number of Lymph Nodes and MSI in Colon Cancer Surgery: Reply to Letter

We appreciate the interest in and comments on our recent article [1] by Dr. Hottenrott [2]. We agree that cancer in general, and colorectal cancer in particular [3, 4], is a highly complicated and heterogeneous disease for which it might be an oversimplification to believe that by measuring lymph nodes, or lymph node ratio (LNR), it would be possible to predict accurately oncologic outcomes in individual patients with colorectal cancers. Our study was not designed for, nor did it try to answer, what should be the best indicator, predictor, or prognosticator in colon cancer. In fact, we question the additional clinical value of LNR to the traditional TNM staging in our study [1]. Obviously, our understanding of quality indicators in colon surgery is in flux, and evidence is evolving with time [5, 6]. We recognize that our study was undertaken before laparoscopic colon cancer surgery was introduced and performed as a standard in our institution. As we state in the article [1], we believe that the standards achieved at the time (with only slightly more than one third having more than 12 nodes harvested) is reflective of that in the general literature on the subject at the same time period, and that the results should be viewed against these standards and not those of the current era. Consequently, replicating the results in other studies would be needed to confirm the validity and reliability of the findings. Nonetheless, as we cannot improve surgical care for patients with colorectal cancer without understanding the tumor biology and how this may affect predictive and prognostic factors, we found it of utmost interest to investigate the effect of microsatellite instability (MSI) on the number of nodes harvested in this population [1]. The association of the right-sided colocation of MSI with higher numbers of lymph nodes is a novel finding in our study [1] and one that has not been reported previously to the best of our knowledge. When further elaborated in clinical series that include current standards of cancer surgery, the influence of tumor biology may further enlighten our understanding of quality indicators, predictors, and prognosticators in patients with colorectal cancer.