Robin McLeod, MD, Division of General Surgery, Mount Sinai Hospital, University of Toronto; Department of Health Policy, Management and Evaluation, University of Toronto; Zane Cohen Digestive Diseases Clinical Research Centre; Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON.
Selina Schmocker, Zane Cohen Digestive Diseases Clinical Research Centre; Toronto General Research Institute, University Health Network, Toronto, ON.
Erin Kennedy, MD, PhD, Division of General Surgery, University Health Network, University of Toronto; Department of Health Policy, Management and Evaluation, University of Toronto; Zane Cohen Digestive Diseases Clinical Research Centre; Toronto General Research Institute, University Health Network, Toronto, ON.

Colorectal cancer is the third most common cancer worldwide, and more than half of those newly diagnosed with colon cancer are over the age of 70 years. Despite the large proportion of patients over the age of 70 diagnosed with colon cancer annually, this age group is significantly underrepresented in clinical trials and, therefore, there is little high-quality evidence on which to base treatment decisions or treatment guidelines. This article reviews the management of primary colon cancer in older adults, including screening, presentation and diagnosis, treatment, and follow-up in this population.
Key words: colon cancer, colorectal cancer, screening, tumour, older adults.

The incidence of colorectal cancer increases with age, with approximately 60% of patients in the US (and similar numbers in Canada) older than 65 years at diagnosis and 40% over the age of 75. As highlighted by McLeod et al in this issue, the management of older patients with colorectal cancer is challenging. The prevailing difficulty is the lack of randomized trial data to support and guide treatment decisions. Pivotal trials establishing the standard of care for this disease have tended to enroll younger patients. For example, the median age of patients enrolled in phase III studies of systemic chemotherapy for metastatic colorectal cancer is commonly 60-64 years,1,2 with fewer than 20% of patients being 70 years and older. In the large colorectal screening studies, older patients are again under-represented, with only 15-17% of randomized patients being 70 years or older.3, 4 Similarly, elderly patients are less likely to be enrolled in surgical trials than younger patients.5 With this absence of prospective data, evidence regarding safety and efficacy of interventions in older patients with colorectal cancer has come mainly from subgroup analyses or meta-analyses of large randomized clinical trials, both in the adjuvant and metastatic disease settings. These analyses suggest that older patients gain similar benefit from chemotherapy as do younger patients, with little difference in the rates of severe toxicity.6 This should be reassuring to clinicians.  The relation between age and outcomes from colorectal cancer surgery is more complex, however. Poorer outcomes in terms of postoperative morbidity and mortality are reported with increasing age, but these are confounded by presentation with more advanced disease stage, a greater frequency of emergency surgery and fewer curative surgeries compared to younger patients.7 All of these analyses suffer from selection bias with patients in these studies generally being fit and of good performance status. Data from randomized studies will ultimately help optimize management of older patients with colorectal cancer. However, careful consideration should be given to the design of these studies.  A growing appreciation of the heterogeneity of this patient population has led to a better understanding and use of geriatric specific assessments. These assessments which evaluate functional status, comorbid medical conditions, cognitive function, psychological state, and social supports may have value in predicting postoperative complications following surgery and may help better predict tolerance to systemic therapies. Incorporation of these assessments into both the clinical trial setting and daily clinical practice is encouraged but challenging due to time constraints in busy practices. Identifying elder-specific clinical predictors of tolerability to various interventions will ultimately lead to a more tailored approach for these patients. The essential principles of managing colon cancer in the elderly are the same as in younger patients, however, as the authors state, an individualized approach is necessary. Frameworks for determining a patient’s remaining life-expectancy, risks of toxicities and operative complications, and quality of life issues must be developed and should ultimately underlie these individualized decisions. No competing financial interests declared. References: 1.    Goldberg RM, Sargent DJ, Morton RF et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004; 22: 23-30. 2.    Seymour MT, Maughan TS, Ledermann JA et al. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet 2007; 370: 143-152. 3.    Hardcastle JD, Chamberlain JO, Robinson MH et al. Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. Lancet 1996; 348: 1472-1477. 4.    Mandel JS, Bond JH, Church TR et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med 1993; 328: 1365-1371. 5.    Stewart JH, Bertoni AG, Staten JL et al. Participation in surgical oncology clinical trials: gender-, race/ethnicity-, and age-based disparities. Ann Surg Oncol 2007; 14: 3328-3334. 6.    Kumar A, Soares HP, Balducci L, Djulbegovic B. Treatment tolerance and efficacy in geriatric oncology: a systematic review of phase III randomized trials conducted by five National Cancer Institute-sponsored cooperative groups. J Clin Oncol 2007; 25: 1272-1276. 7.    Surgery for colorectal cancer in elderly patients: a systematic review. Colorectal Cancer Collaborative Group. Lancet 2000; 356: 968-974.

The Mayo Clinic has reported that patients taking a commonly prescribed treatment for colon cancer are dying at almost three times the rate of patients who took other medications for the same disease. The chemotherapy drug, irinotecan, has been shown to increase life expectancy by about two months for patients with advanced colorectal cancer. However, in the first two months of receiving the drug, 33 out of 1,199 patients died, among patients taking different drugs, only 10 out of 905 patients died within the same period.

The drug is manufactured by Pharmacia and marketed under the name Camptosar. Although the findings are preliminary and not statistically significant, the company has sent letters to doctors in the US advising them of the results. The finding is somewhat controversial, as this effect of the drug has not been seen previously. However, the research group at the Mayo Clinic explains that this may result from the fact that the deaths were spread out among different medical centres, and when data were pooled the effect was seen; it might not have been obvious to individual physicians. Doctors who are conducting the study will be giving the drug in lower doses and will be more aggressive about looking for warning signs of toxicity, including diarrhea, nausea, vomiting and a low white blood cell count.

The results of the study will be published in a letter in an upcoming issue of the New England Journal of Medicine.

A major study by the research group of Dr. Josef Penninger, at the University of Toronto, has identified a protein that, when absent, appears to contribute to the development of colorectal cancer. The protein in question is the p110g catalytic subunit of phosphoinositide-3-OH kinases (PI(3)Ks), a family of proteins that regulate a vast array of fundamental cell responses, including proliferation, transformation, differentiation and protection from apoptosis. Quite by accident, the researchers discovered that genetic inactivation of the p110g subunit leads to the development of invasive colorectal carcinomas in mice. In humans it has been previously found that p110g protein expression is lost in primary colorectal adenocarcinomas and in colon cancer cell lines. Overexpressing wildtype or kinase-dead p110g in human colon cancer cell lines with mutations of tumour suppressors, or with the oncogenes b-catenin and Ki-ras, suppressed tumorigenesis.

Penninger's group was examining genetically altered mice to determine how their white blood cells responded to infection when the mice lost weight, became sick and began to die. It turned out that they were riddled with colon cancer. Turning this discovery into practical medicine for the treatment of colon cancer in humans will obviously require time and a lot more study. However, it is hoped that this knowledge may help in the design of novel strategies for fighting colon cancer.

Colon cancers are the second leading cause of cancer death and it is estimated that 50% of humans develop colon tumours by the age of 70.

Source

1. Sasaki T, et al. Colorectal Carcinomas in Mice Lacking the Catalytic Subunit of PI(3)Kg Nature 2000 (406) 897-902.

91st annual meeting of the American Association for Cancer Research

While a number of analgesics are shown to inhibit tumour growth, anti-cancer properties of acetaminophen appear to work earlier during the neoplastic process. According to the recent research at the New York Medical College in Valhalla, acetaminophen can prevent the beginning of colon cancer by blocking the action of food mutagens. Treatment of rats with acetaminophen prior to the administration of 3,2'dimethyl-4-aminobiphenyl (a carcinogen, similar to the one formed during cooking) "produced a marked cytoprotective effect," Dr. Gary Williams, principal investigator of the study, said at the 91st annual meeting of the American Association for Cancer Research. While these results are very exciting, clinical trials with people at risk for colon cancer are necessary to determine whether administration of acetaminophen would reduce this risk in humans.