Colorectal Cancer in Younger Patients: Any Difference?

Abstract & Commentary

By William B. Ershler, MD

Synopsis: In a review of nine Phase 3 trials enrolling 6,284 patients, data from 793 who were younger than 50 years old were compared to the remainder who were older than 50 years, with attention given to progression-free survival, response rates, and overall survival. Although there was a slightly reduced progression-free survival in younger patients, response rates and overall survival were not statistically different. A failure to demonstrate altered responses in the very young may be a reflection of age-associated variability in enrollment onto clinical trials.

Source: Blanke CD, et al. Impact of young age on treatment efficacy and safety in advanced colorectal cancer: A pooled analysis of patients from nine first-line phase III chemotherapy trials. J Clin Oncol 2011;29:2781-2786.

Colorectal cancer occurs primarily in older people. The median age at diagnosis is 72 years and more than 25% diagnosed are 80 years or older.1 Yet, approximately 5% of patients are 50 years or younger. When colorectal cancer occurs in younger patients, it is more likely to present at a more advanced stage (III or IV).2 The question of whether, stage for stage, younger age confers a negative prognosis remains to be conclusively established.

To address whether age at diagnosis influences treatment response and survival, Blanke and colleagues analyzed individual data on 6,284 patients from nine Phase 3 trials of advanced colorectal cancer (aCRC) that used either fluorouracil-based single-agent or combination chemotherapy. Of these, 793 patients (13%) were younger than 50 years old and 188 (3%) were younger than 40 years old. Stratified Cox and adjusted logistic-regression models were used to test for age effects and age-treatment interactions.

Grade 3 or worse nausea was statistically more common, but severe diarrhea and neutropenia were less common in younger (younger than 50 years) than in older (older than 50 years) patients. Age was prognostic for progression-free survival (PFS), with poorer outcomes occurring in those younger than 50 years (median, 6.0 vs 7.5 months; hazard ratio, 1.10; P ≤ 0.02), but it did not affect response rate (RR) or overall survival (OS). In the subset of monotherapy vs combination chemotherapy trials, the relative benefits of multiagent chemotherapy were similar for young and older patients. Results were comparable when utilizing an age cut point of 40 years.

Commentary

Clinical oncologists are familiar with the heterogeneity in tumor biology with age, and there has been a long-held notion that certain common malignancies (e.g., breast and prostate carcinomas) are less aggressive in the oldest-old. This notion has been difficult to prove by epidemiologic data, perhaps because it is confounded by special problems common to geriatric populations (e.g., comorbidity, "poly-pharmacy," physician or family bias regarding diagnosis and treatment in older patients, and age-associated life stresses) — any or all of which might negatively influence standard "aggressive" management, and thus response rates and survival. Yet, under well-controlled experimental conditions in various tumor models, it has been clearly demonstrated that tumors grow more slowly, are less invasive, and spread less frequently in older animals.3-6 In considering explanations for observed age-associated changes in tumor biology, it is useful to consider the "seed vs. soil" hypothesis. Although the "seed" (tumor cell) may be of the same origin and inherently similar in proliferative potential, the microenvironment ("soil") that provides nutrients and growth factors for proliferating cells may be less fertile in tissues from older hosts. Accordingly, it would come as no surprise to find more aggressive tumors growing in younger patients — this without having to implicate any substantive difference in the tumor itself.

Colorectal cancer occurring in younger patients tends to present at a more advanced state and this remains to be addressed satisfactorily. Perhaps, as the authors suggest, this results from the success of large-scale screening initiatives starting at age 50. Further, a subset of younger patients carry a genetic susceptibility for the development of colorectal cancer, but such patients generally have a better prognosis, perhaps reflecting the greater likelihood of associated microsatellite instability, a known favorable prognostic factor.7,8

Thus, the current study in which young age was only modestly associated with poorer PFS but not OS or RR in comparably treated patients with advanced colorectal cancer was somewhat surprising. However, as the authors suggest, the study reflects patients enrolled in clinical trials and might not be representative of either typical young or old patients with advanced colorectal cancer, many of whom do not make it onto trial for any number of reasons. It is curious that younger patients experienced more nausea with therapy, but less diarrhea and neutropenia. These are findings that will come as no surprise to clinicians but are useful to remember.

The safest conclusion to remember from this report is that both young and old patients derive similar benefits from combination chemotherapy.

References

1. Jemal A, et al. Cancer statistics, 2009. Cancer 2009;59:225-249.

2. O'Connell JB, et al. Do young colon cancer patients have worse outcomes? World J Surg 2004;28:558-562.

3. Ershler WB, et al. Slower B16 melanoma growth but greater pulmonary colonization in calorie-restricted mice. J Natl Cancer Inst 1986;76:81-85.

4. Ershler WB, et al. B16 murine melanoma and aging: Slower growth and longer survival in old mice. J Natl Cancer Inst 1984;72:161-164.

5. Ershler WB, et al. Experimental tumors and aging: Local factors that may account for the observed age advantage in the B16 murine melanoma model. Exp Gerontol 1984;19:367-376.

6. Tsuda T, et al. Role of the thymus and T-cells in slow growth of B16 melanoma in old mice. Cancer Res 1987;47:3097-3100.

7. Popat S, et al. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 2005;23:609-618.

8. Sargent DJ, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 2010;28:3219-3226.