Adjuvant Therapy for Colorectal Cancer: Increasingly Complex as Patients Age

The treatment of older patients with colorectal cancer is not always straightforward. As highlighted in the article by Dr. Ades, the heterogeneity of physiologic aging, the increasing prevalence of comorbid disease with age, and changing preferences with aging make counseling about adjuvant therapy more complex for older patients than for younger patients.

Dr. Ades reviews the available data on adjuvant therapy with fluorouracil (5 FU) monotherapy and FOLFOX (5-FU, leucovorin [LV], oxaliplatin [Eloxatin]) from two pooled analyses of phase III clinical trials, showing a similar efficacy with chemotherapy in patients younger and older than age 70.[1,2] The conclusions drawn from these data are supported by evidence in the advanced-disease setting, where older patients treated with first- or second-line FOLFOX and first-line irinotecan/5-FU combinations have the same relative benefit from therapy compared with their younger counterparts.[2,3]

Additionally, data from the Surveillance, Epidemiology and End Results (SEER) and Medicare programs on the effectiveness of adjuvant 5-FU in patients over 65 treated outside of clinical trials are remarkably similarly to the reviewed clinical trial data.[4,5] As summarized by Dr. Ades, the benefit from adjuvant 5-FU in patients aged 65 or older in the SEER database, even after adjustment for factors related to survival, is of similar magnitude to the trial experience.[6]

Age and Toxicity

Toxicity among presumably fit older patients in phase III trials differs only minimally from that observed in younger patients. Hematologic toxicity is most consistently reported to be increased in older patients, yet absolute differences in the incidence of grade 3+ toxicity are small. In the pooled analyses, 5-FU/leucovorin–treated patients had a 4% absolute increase in the incidence of leukopenia (4% vs 8%, P = .05).[1] FOLFOX-treated older patients had a 6% absolute increase in the risk of neutropenia (43% vs 49%) and a 3% absolute increase in thrombocytopenia (2% vs 5%).[2] Cytopenias were not associated with increases in more serious adverse events such as bleeding or infection, in either analysis.

Furthermore, no difference was noted in hematologic toxicity or diarrhea between older and younger patients treated with irinotecan/5-FU combinations. Differences in hematologic toxicity among the elderly might be assumed to result from diminished bone marrow reserve in older patients, which makes it more difficult to deliver full therapeutic doses on schedule. However, in the analysis of FOLFOX therapy in older patients, dose intensity did not vary across age groups.[2]

Paucity of Data

While Dr. Ades focuses on available toxicity data from trials, a paucity of data exist on the adverse effects of chemotherapy experienced by the vast majority of elderly patients. Although data from the phase III trials clearly support a benefit of adjuvant therapy in older patients, the heterogeneity of aging means that many-if not most-patients are not as fit as those enrolled on clinical trials. SEER-Medicare data are limited in their ability to capture toxicity. Crude measures such as hospitalization or emergency room visits during treatment do not vary by age, but given the infrequency of hospitalization for patients receiving colorectal cancer treatments, these outcomes miss more subtle yet important effects of treatment on older patients. Furthermore, as very few patients aged 80 or older enroll on clinical trials, safety data for octogenarians is particularly scant.

Dr. Ades suggests that comorbid conditions are of key importance to risk-stratifying older patients for adjuvant chemotherapy. This is certainly the case for patients who are extremely ill from another condition, with poor performance status and a short life expectancy. However, SEER-Medicare data on the benefit of adjuvant therapy in those with comorbidities suggest that even those with congestive heart failure, obstructive lung disease, and diabetes do benefit with no increase in treatment- or condition-related hospitalization.[7] Thus, while comorbid conditions may affect treatment tolerance, current evidence does not support a practice of basing treatment recommendations on the extent of comorbid disease.

Treatment Options

With regard to specific therapeutic approaches in older patients, Dr. Ades recommends single-agent capecita­bine (Xeloda) or a short course of prolonged infusional 5-FU as acceptable treatment options for frail older patients. While we agree that single-agent fluoropyrimidine therapy is the best alternative for frail older patients, in our experience these regimens are not necessarily the most convenient or the best tolerated monotherapy options. We find that oral chemotherapy requiring a patient to make dosing decisions and toxicity assessments at home can be difficult for many older individuals, particularly for those who have a suboptimal support network. And although capecitabine is often touted as being less toxic than 5-FU/LV, this is only the case when you compare capecitabine to bolus regimens of 5-FU/LV.

As to the recommendation of 3 months of protracted 5-FU infusion, this is a cumbersome method of delivering therapy, and its safety in older patients is uncertain. Furthermore, while a short course of therapy seems attractive in some ways, this strategy has not yet been adequately substantiated. Our own preference for administering single-agent 5-FU for most patients is the infused LV5FU2 regimen (bolus 5-FU at 400 mg/m2 with LV at 200 mg/m2, followed by 5-FU at 2,400 mg/m2 over 46 hours).

For patients who prefer the idea of oral chemotherapy, we often begin with a reduced dose of capecitabine (850–1,000 mg/m2 twice daily) relative to the doses studied in adjuvant trials and escalate if tolerated, but this practice is not necessarily supported by quality evidence. Along these lines, we agree that if one utilizes XELOX (capecitabine, oxaliplatin), the best and safest method is probably to begin with a low dose of capecitabine and escalate if the drug is tolerated. That said, we feel strongly that FOLFOX is a proven regimen and suggest using it preferentially for adjuvant therapy in patients of all ages until definitive data on capecitabine combinations are available.

Concluding Thoughts

Finally, although neither drug currently plays a role in adjuvant therapy in this setting, Dr. Ades’ words of caution about the use of bevacizumab (Avastin) and cetuximab (Erbitux) in older patients are appropriate. Concerns about cetuximab (and the similar epidermal growth factor receptor inhibitor panitumumab [Vectibix]) are particularly timely, given the results of a recent interim analysis of the ongoing US Intergroup adjuvant study N0147 (investigating FOLFOX with or without cetuximab). These results suggest there may be an increased risk of death in patients over 70 who are randomized to receive cetuximab. More data will be available about the safety and efficacy of biologics as data from ongoing clinical trials mature.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Sargent DJ, Goldberg RM, Jacobson SD, et al: A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med 345:1091-1097, 2001.
2. Goldberg RM, Tabah-Fisch I, Bleiberg H, et al: Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol 24:4085-4091, 2006.
3. Folprecht G, Seymour MT, Saltz L, et al: Irinotecan/fluorouracil combination in first-line therapy of older and younger patients with metastatic colorectal cancer: Combined analysis of 2,691 patients in randomized controlled trials. J Clin Oncol 26:1443-1451, 2008.
4. Iwashyna TJ, Lamont EB: Effectiveness of adjuvant fluorouracil in clinical practice: A population-based cohort study of elderly patients with stage III colon cancer. J Clin Oncol 20:3992-3998, 2002.
5. Sundararajan V, Mitra N, Jacobson JS, et al: Survival associated with 5-fluorouracil-based adjuvant chemotherapy among elderly patients with node-positive colon cancer. Ann Intern Med 136:349-357, 2002.
6. Gill S, Loprinzi CL, Sargent DJ, et al: Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: Who benefits and by how much? J Clin Oncol 22:1797-1806, 2004.
7. Gross CP, McAvay GJ, Guo Z, et al: The impact of chronic illnesses on the use and effectiveness of adjuvant chemotherapy for colon cancer. Cancer 109:2410-2419, 2007.