Colorectal cancer

Colorectal cancer (CRC), commonly known as bowel cancer, is a tumour arising from uncontrolled cell growth in the colon or rectum, In the great majority, the histology is adenocarcinoma. The risk factors for CRC overlap with those for type 2 diabetes (T2D), and include: increasing age, male gender, obesity, western diet and sedentary lifestyle, and thus, not surprisingly, T2D is associated with an increased risk of incident CRC. Risk may however be independent of increased body mass index (BMI). There is no link between type 1 diabetes and incident CRC. Glucose-lowering medications may increase (e.g. insulins) or decrease (e.g. metformin) risk, but the evidence for these associations is controversial. After the diagnosis of CRC, the presence of T2D may negatively influence treatment selection and be associated with higher treatment complications rates. Overall mortality seems to be greater in patients with CRC who also have T2D compared with those without T2D, but this may reflect increased risk for non-cancer deaths. There are a number of effective population-level bowel cancer screening modalities, and mixed evidence that patients with T2D under-utilise these programmes. There is currently no evidence to support more intensive colonoscopic screening or surveillance in patients with T2D.

Epidemiology

CRC is the third most commonly diagnosed cancer in the world - 663,000 new cases in men; 571,000 new cases in women in 2008 (GLOBOCAN2008).

Risk factors

Approximately 15% of patients who develop CRC have a family history of this cancer. Risk factors for the remainder of the population include:

  • increasing age
  • male gender
  • obesity
  • western diet
  • sedentary lifestyle[1]
  • Cigarette smoking is also a risk factor but requires typically four decades of observation to reveal the increased risk.

There is overlap between these risk factors and those for T2D. A seminal meta-analysis in 2005 established that T2D is associated with an increased risk of incident CRC[2]. A recent meta-analysis reported these risks are 1.29 (1.19-1.39) for men and 1.34 (1.22-1.47) for women[3].

There are lines of evidence indicating that this risk is independent of, for example, increased BMI. These include:

  1. The risk associations between BMI and CRC are site- (colon>>rectum) and gender-specific (men>>women)[4], whereas associations between T2D and CRC are not.

  2. In studies which adjust for BMI, associations between T2D and CRC remain.

  3. There appears to be an interaction between T2D, smoking and CRC risk[5], which has not been reported for associations between BMI and CRC risk. There is no evidence indicating a link between type 1 diabetes and incident CRC.

Glucose-lowering medications

A seminal paper in 2005 raised the question that the long-term administration of insulin among patients with T2D is associated with an increased risk of CRC[6]. A further series of publications in 2009, and subsequent analyses, failed to show a consistent link between insulin analogues and increased risk of CRC[7]. Parallel epidemiological observations suggested that metformin may be protective for cancer risk, including CRC[8]. However, the evidence that insulins may increase and metformin may reduce cancer risk is controversial – there are several methodological challenges to these analyses, and biases and confounding may not have been fully taken into account [9].

Pathophysiology

The histology of CRC, in the great majority, is adenocarcinoma. Most invasive carcinomas arise from a benign precursor, known as an adenoma (and often manifested clinically as a polyp). There are at least five molecular pathways in the development of invasive CRCs [10]. There is little research to indicate that the diabetes pathway to invasive CRC is along a specific molecular route. Additional mechanisms linking diabetes with CRC include: reduced colonic transit, hyperinsulinaemia, and IGF-IR activation.

Clinical Symptoms

Symptoms of colorectal cancer include change in bowel habit, weight loss, rectal bleeding and anaemia. Approximately 20% of patients with CRC first present as an emergency with large intestinal obstruction or colonic perforation. In patients with newly diagnosed T2D, there is a peak increase in the coincidence of CRC – which probably reflects a detection time bias [11].

CLINICAL MANAGEMENT

Surgery

Surgery is the mainstay of treatment for patients with CRC. The majority of cases are treated by hemi-colectomy for colonic tumours, and anterior resection or abdomino-perineal resection for rectal cancers. Early stage I lesions may be treated by endoscopic resection for colonic cancer, and by transrectal endoscopic micro-dissection in the rectum. There is a recognised 30-day mortality rate of 5% to 10% after major surgery. There is no consistent evidence that the presence of diabetes influences this rate [12].

Radiotherapy

Pre-operative radiotherapy, either alone (known as short-course) or in combination with chemotherapy (known as long-course) is widely used across Europe in patients with rectal cancers. There is evidence from the Eindhoven Tumour Registry that patients with diabetes may receive pre-operative radiotherapy less often than patients without diabetes[13].

Chemotherapy

Chemotherapy is used in patients with CRC in two broad settings: (i) adjuvant chemotherapy after initial surgical resection in patients with high-risk of disease progression (e.g. nodal involvement); and (ii) metastatic disease, where the benefit is one of survival prolongation. The commonest cytotoxic agents are 5-fluorouracil, 5-FU (known as capecitabine in its oral format), oxaliplatin, and irinotecan. Newer agents are known as targeted therapies and include EGFR inhibitors (e.g. cetuximab) and anti-VEGF therapies (e.g. bevacizumab). 5-FU is the traditional agent used in adjuvant chemotherapy trials. Data from one large randomised trial reported that the presence of diabetes at trial entry was associated worse overall survival [14]. However, these result need to be interpreted in the context of the clinical practice of ‘dose capping’, which commonly practiced by oncologists in patients above a BSA (body surface area) > 2 – whether or not mandated by trial protocol – despite evidence that obese patients tolerate well doses based on their body weight [15].

Combinational regimens of 5-FU (or capecitabine) with oxaliplatin are increasingly common, and more effective than 5-FU alone, but tolerance is most commonly limited by the development of peripheral neuropathy. Recent data suggests that patients with T2D are more vulnerable to this complication[16].

Prognosis

The five-year relative survival in patients with a diagnosis of CRC is 50% to 60% in many westernised countries [17]. A systematic review, published in 2010, addressed the influence of T2D on mortality in patients with CRC [18]. The pooled summary from the six included studies reported a 32% increased risk for long-term all-cause mortality, among people with diabetes compared to people without diabetes.

Four studies have evaluated long-term colorectal cancer-specific mortality, but only one found an association between poorly-controlled, pre-existing diabetes mellitus and the risk of death attributed to colorectal cancer[19]. In a number of studies, the presence of diabetes was associated with increased mortality from non-cancer causes. This has been echoed in a more recent cohort analysis of the Cancer Prevention II Study, which found an increased risk of cardiovascular-related death among survivors of CRC with T2D [20].

SCREENING AND PREVENTION

Screening

There are several trial-proven effective approaches to CRC screening – including faecal occult blood testing (FOBT), once-only flexible sigmoidoscopy, and colonoscopy. Population-level national screening programme using quality-assured FOBT reduces cancer-related mortality; endoscopic screening reduces CRC incidence through the detection and removal adenomas, the precursors of invasive carcinoma. There is some, albeit mixed evidence 19, that patients with T2D under-utilise these programmes.

Since T2D is a chronic condition with increased CRC risk, there have been calls to introduce more intensive colonoscopic screening in these patients [21]. However, in absolute terms, the usual threshold required for elevated screening is 1 in 10 life-time risk - for patients with T2D, the CRC risk is closer to 1 in 100.

Prevention

Most CRCs are in theory preventable, through screening and improved lifestyle; modifiable risk factors of high intake of fat, alcohol, red meat, obesity, smoking and a lack of physical exercise should be targeted. For diabetic patients, it is unclear whether removal of some of the additional risk factors such as excessive body weight will prevent CRC – thus, for example, in the largest controlled study of bariatric surgery [22], many of whom had T2D, there were beneficial long-term effects post-surgery on breast and endometrial cancer incidence, but not for CRC cancer incidence.

Nonetheless, there are ethnic differences in CRC risk among patients with T2D (higher in US Blacks compared with US Whites [23]; potential differential risks associated with glucose-lowering medications; and differential cancer treatment selections among patients with T2D, which highlights the need for culturally sensitive approaches to cancer prevention taking into account individual risk patterns [24].

Future Prospects

The key challenge in the next few years is to better define the risks associated with modifiable factors specific to diabetes – for example, glucose control and glucose-lowering medications. This will require the use of complex pharmaco-epidemiological methodologies which take account of time-dependent variables and cumulative exposures 19. Only then, can we truly inform health professionals and our patients with diabetes about the impact of the disease of diabetes and its therapies, for cancer risk and treatment outcome.

References

  1. ^ Cunningham D et al. Colorectal cancer. Lancet, 201;375:1030-47.

  2. ^ Larsson SC et al. Diabetes mellitus and risk of colorectal cancer: a meta-analysis. J Natl Cancer Inst, 2005;97:1679-87.

  3. ^ Kramer HU et al. Type 2 diabetes mellitus and colorectal cancer: meta-analysis on sex-specific differences. Eur J Cancer 2012;48:1269-82.

  4. ^ Renehan A et al. Body mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 2008;371: 569-578.

  5. ^ He J et al. The association of diabetes with colorectal cancer risk: the Multiethnic Cohort. Br J Cancer 2010; 103:120-6.

  6. ^ Yang YX et al. Insulin therapy and colorectal cancer risk among type 2 diabetes mellitus patients. Gastroenterology 2004;127:1044-50.

  7. ^ Clayton PE et al. Growth hormone, the insulin-like growth factor axis, insulin and cancer risk. Nat Rev Endocrinol 2011;7:11-24.

  8. ^ Currie CJ et al. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009;52:1766-77.

  9. ^ Renehan AG. Insulin analogues and cancer risk: the emergence of second-generation studies. Diabetologia 2012;55:7-9.

  10. ^ Jass JR. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 2007;50:113-30.

  11. ^ Johnson JA et al. Time-varying incidence of cancer after the onset of type 2 diabetes: evidence of a potential deection bias. Diabetologia 2011;54:2263-71

  12. ^ Masoomi H et al. Predictive factors of in-hospital mortality in colon and rectal surgery. Am J Coll Surg 2012;215:255-61

  13. ^ van de Poll-Franse et al. Less aggressive treatment and worse overall survival in cancer patients with diabetes: a large population based analysis. Int J Cancer 2007;120:1986-92

  14. ^ Meyerhardt JA et al. Impact of diabetes mellitus on outcomes in patients with colon cancer. J Clin Oncol 2003;21:433-40

  15. ^ Chambers P et al. Chemotherapy dose reductions in obese patients with colorectal cancer. Ann Oncol 2012;23:748-53

  16. ^ Uwah et al. The effect of diabetes on oxaliplatin-induced peripheral neuropathy. Clin Colorectal Cancer, 2012;11:275-9

  17. ^ Coleman MP et al. Cancer survival in Australia, Canada, Denmark, Norway, Sweden and the UK, 1995-2007 (the International Cancer Benchmarking Partnership): an analysis of population-based cancer registry data. Lancet2011;377:127-38

  18. ^ Stein KB et al. Colorectal cancer outcomes, recurrence, and complications in persons with and without diabetes mellitus: a systematic review and meta-analysis. Dig Dis Sci 2010;55:1839-51

  19. ^ Renehan AR et al. Diabetes and cancer (2) evaluating the impact of cancer on mortality in patients with cancer. Diabetologia 2012:55:1619-1632

  20. ^ Campbell PT et al. Diabetes and case-specific mortality in a prospective cohort of one million US adults. Diabetes Care 2012;35:1835-44

  21. ^ Berster JM & Goke B. Type 2 diabetes as a risk factor for colorectal cancer. Arch Physiol Biochem 2008;114:84-98

  22. ^ Sjostrom L et al. Effects of bariatric surgery on cancer incidence in obese patients in Sweden (Swedish Obese Subjects Study): a prospective, controlled intervention trial. Lancet Oncol, 2009;10: 653-62.

  23. ^ Cavicchia PP et al. Racial disparities in colorectal cancer incidence by type 2 diabetes mellitus status. Cancer Causes Control 2013;24:277-285

  24. ^ Renehan AG et al. Foreword: implementing cancer prevention in Europe. Eur J Cancer 2010;46:2523-4

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