Colorectal cancer, like most epithelial tumors, occurs late in life. Of all the common malignancies, its pathogenesis, defined by a stochastic accumulation of genetic and epigenetic events, is most completely understood.[1,2] Furthermore, the time that it takes for these seemingly random events to occur is the single best explanation for why colorectal cancer appears late in life. However, for clinicians treating older patients and for older patients themselves, this understanding of how colon cancer develops and why it is more frequent with age is of little practical value in formulating treatment plans. For this, we generally rely on published reports of well-conducted clinical trials.
Upshot of Clinical Trials
Xiao and Lichtman have provided a compendium of such trials, many of which were evaluated post hoc to discern treatment outcomes with age. Based on this up-to-date review one may conclude that chemotherapy can be safely administered to older patients, both in the adjuvant setting and with palliative intention for those with metastatic disease. The authors point out that older patients treated in these trials had comparable response rates, survival, and toxicities, compared to their younger counterparts. Once again we are reminded that chronologic age should not be considered exclusionary and that we should avoid age-bias when considering chemotherapy.
On the other hand, older patients are more likely to have comorbidities, some of which may be more ominous than the cancer. Furthermore, comorbidities are like children—their impact is more exponential than additive. Comorbidities are associated with decline in function and impaired capacity to sustain the rigors of aggressive therapy.
This brings us to the critical question that we have flirted with for a decade or more but have not truly addressed. What do we do with the "typical" older patient with colon cancer? For example, the 75-year-old with incompletely compensated congestive heart failure, type II diabetes, hypertension, and a serum creatinine of 1.9 mg/dL who is found to have stage III colon cancer? Or stage II? This patient most likely would not have fit any of the trials reviewed by Xiao and Lichtman but certainly is more typical of the age cohort than those that did. Thus, medical oncologists are left in the uncomfortable position of skirting evidence-based medicine, for no reason other than that there is no evidence.
Xiao and Lichtman raise the issue of age bias with regard to treatment of older patients in general as well as with regard to enrollment in clinical trials. They speculate that the latter may be due to reluctance on the part of community physicians to refer older patients to academic centers. Although this is no doubt true to some extent, additional onus must fall on the shoulders of those who design these trials. The fact is, exclusionary criteria will render most 75-year-old patients with colon cancer ineligible for enrollment in most phase III or even phase II trials.
The authors point out that 50% of children are referred for clinical trials, compared to less than 5% of 75-year-olds. That said, it is likely that nearly 100% of children with cancer are eligible for trials, whereas this number would be more like 10% for 75-year-olds. Accordingly, the problem might not be age bias on the part of community physicians or even patient/family reluctance. Rather, it might be related more to a failure of clinical investigators to design trials that would not only include typical older patients but actually answer meaningful questions on how to treat their malignancy in the context of coexisting morbidities, organ dysfunction, and even dependence in one or more of the activities of daily living (ADL). My guess is that community oncologists, patients, and their families would be favorably inclined to participate in such a research effort.
Of course, no one knows this better than Stuart Lichtman. As a founder of the Geriatric Oncology Consortium, he has been instrumental in integrating geriatric concerns within cooperative groups, academic institutions, and national organizations (eg, the American Society of Clinical Oncology). The comprehensive review offered by Xiao and Lichtman provides a clear view of what we know (fit older colorectal cancer patients can be treated effectively and safely) and a startling view of what we don't (there is little data on the treatment of "typical" older patients with colorectal cancer). We have our marching orders.
—William B. Ershler, MD
The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Vogelstein B, Fearon ER, Hamilton SR, et al: Genetic alterations during colorectal-tumor development. N Engl J Med 319:525-532, 1988.
2. Vogelstein B, Kinzler KW: Cancer genes and the pathways they control. Nat Med 10:789-799, 2004.
3. Ershler WB: The influence of advanced age on cancer occurrence and growth. Cancer Treat Res 124:75-87, 2005.