Pharmacology of Anticancer Agents in the Elderly: The Pharmacist’s Perspective

In this issue of ONCOLOGY, Balducci[1] reviews principles for treating elderly patients with antineoplastic therapy. This paper begins by defining baseline terminology such as age and frailty, while providing an overview of applied techniques of discerning a patient’s functional impairment or disability. Establishing these terms is clearly helpful for clinicians when evaluating primary literature for the elderly population. One of the most critical underpinnings of the difference in drug response and toxicity is the difference in pharmacokinetic characteristics in elderly patients.

The author reviews specific differences in absorption, distribution, metabolism, and excretion that affect specific chemotherapy drugs. These pharmacokinetic differences in the elderly become more unpredictable-relative to the general population-when concomitant medications that modify endogenous drug-metabolizing enzymes, such as the cytochrome P-450 (CYP450) system, are administered. For example, the tyrosine kinase inhibitor class of drugs (imatinib [Gleevec], erlotinib [Tarceva], sorafenib [Nexavar], etc) inhibits multiple CYP450 isoenzymes and is a substrate for the most prolific drug metabolizing CYP450 isoenzyme 3A4. Multiple classes of medications that are commonplace in the elderly (such as antihypertensives, oral hypoglycemics, antibiotics/antifungals, and antihyperlipidemics, among others) will make prediction of efficacy and toxicity of a CYP450 antineoplastic agent less certain.

Tumor Biology

The author points out that tumor biology evolves with age and cites examples with several hematologic malignancies. This phenomenon has a cytogenetic basis in acute lymphocytic leukemia, with the incidence of Philadelphia chromosome positivity (t[9;22]) increasing with age.

Evidence is accumulating at the gene mutation level in acute myeloid leukemia (AML) that the presence of a specific mutation may influence drug response in the elderly. An elderly patient population with AML was studied in a German cooperative group trial for a response to all-trans retinoic acid (ATRA) in combination with conventional cytotoxic chemotherapy, which demonstrated a significant benefit in the ATRA arm for complete response, event-free survival, and overall survival rates.[2] Schlenck and colleagues theorized that this benefit was restricted to a subgroup based on genotype.[3] These authors found that the presence of the nucleophosmin-1 mutation (NPM-1) with the absence of the FLT3-ITD mutation were the only patients who benefited from ATRA.

With the high-profile discovery of K-ras mutation status predicting response to cetuximab (Erbitux) in colorectal cancer, this avenue of research will continue to expand and guide oncologists’ selection of therapy.[4] The benefit of individualizing antineoplastic therapy will continue to be particularly important from the standpoint of efficacy, toxicity, and cost.

Chemotherapy-Associated Toxicities

This article proceeds to review prominent chemotherapy-associated toxicities in the elderly including myelosuppression, mucositis, and cardiomyopathy, among others. The author summarizes the deleterious effect of advancing age on the risk of neutropenia and anemia following chemotherapy. Chemotherapy-associated neutropenia increases the risk of infection-related morbidity and hospitalization in patients aged 65 years and older. Accordingly, the American Society of Clinical Oncology (ASCO) practice guidelines recommend that consideration be given to use of myeloid colony-stimulating factors as prophylaxis starting with the first cycle of chemotherapy.[5] Chemotherapy-associated anemia is commonplace in elderly patients, and use of erythroid colony-stimulating factors (ESAs) has been an accepted clinical intervention, with the primary benefit being reduced transfusion requirements. Controversy has erupted over the past 2 years regarding the toxicity associated with ESAs in cancer patients. Risk of thromboembolism, proliferation of tumor cells for selected malignancies, and an increased risk of death in randomized trials have forced clinicians to reevaluate use of these agents in cancer patients. The US Food and Drug Administration has changed the labeling of marketed ESAs, and ASCO published a revised clinical guideline to reflect these concerns.[6] Practitioners are cautioned to consider the newly recognized risks vs realization of tangible benefit when prescribing these agents.

The well documented anthracycline-associated toxicity of cardiomyopathy is also discussed in this paper. The author cites limitations of the use of dexrazoxane with respect to toxicity and potential blunting of the anticancer effect of anthracyclines. Other limitations include the fact that the definitive trials for dexrazoxane have been done in breast cancer, limiting extrapolation of these data to other tumor types, and the need for data in trastuzumab (Herceptin)/anthracycline-treated patients.

Concluding Thoughts

The author concludes this paper by offering a sober assessment of where current clinical practice for administering antineoplastic therapy stands in the elderly population. The guidelines advocated by the National Comprehensive Cancer Network (NCCN) are cited as a basis for state-of-the-art practice for this patient group. An ambitious research agenda follows, highlighting clinical trial directives such as an examination of the effect of cancer treatment on active life expectancy, phase II trials designed for patients aged 70 years and older, and the role of comorbidity and concomitant medications on treatment outcome in cancer. Additional measures that researchers may consider is stratification of patients 70 and older in large, phase III clinical trials, phenotypic assessment of a patient’s hepatic enzyme capacity, and more precise estimates for evaluation of renal function that are validated in the elderly population.

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

References:

1. Balducci L: Pharmacology of antineoplastic medications in older cancer patients. Oncology (Williston Park) 23:78-85, 2009.
2. Schlenk RF, Frohling S, Haremann F, et al: Phase III trial of all-trans retinoic acid in previously untreated patients 61 years or older with AML. Leukemia 18:1798-1803, 2004.
3. Schlenk RF, Dohner K, Kneba M, et al: Gene mutations and response to treatment with all-trans retinoic acid in elderly patients with acute myeloid leukemia. Results from the AMLSG Trial AML HD98B. Haematologica Dec 4, 2008 (epub ahead of print).
4. Karapetis CS, Khambata-Ford S, Jonker DJ, et al: K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359:1757-1765, 2008.
5. Smith TJ, Khatcheressian J, Lyman GH, et al: 2006 update of recommendations for the use of white blood cell growth factors: An evidence-based clinical practice guideline. J Clin Oncol 24:3187-3205, 2006.
6. Rizzo JD, Sommerfield MR, Hagerty KL, et al: Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology and American Society of Hematology clinical practice guideline update. J Clin Oncol 26:132-149, 2008.