Cancer and Aging

M. Extermann

• Publisher: S. Karger
• Year: 2013
• ISBN:
  9783318023077
• Topic: Medicine
• Subtopic: Endocrinology & Metabolism

Cancer is clearly an age-related disease. Recent research in both aging and cancer has demonstrated the complex interaction between the two phenomena. This affects a wide spectrum of research and practice, anywhere from basic research to health care organization. Core examples of these close associations are addressed in this book. Starting with basic research, the first chapters cover cancer development, mTOR inhibition, senescent cells altering the tumor microenvironment, and immune senescence affecting cancer vaccine response. Taking into account the multidisciplinarity of geriatric oncology, several chapters focus on geriatric and oncologic aspects in patient assessment, treatment options, nursing and exercise programs. The book is rounded off by a discussion on the impact of the metabolic syndrome illustrating the interactions between comorbidity and cancer and a chapter on frailty.This book provides the reader with insights that will hopefully foster his or her reflection in their own research and practice to further the development of this most exciting field. Given the aging of the population worldwide and the high prevalence of cancer, it is essential reading not only for oncologists and geriatricians but for all health practitioners.

Extermann M (ed): Cancer and Aging. From Bench to Clinics.
Interdiscipl Top Gerontol. Basel, Karger, 2013, vol 38, pp 104–123 (DOI: 10.1159/000343618)

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Pharmacology of Aging and Cancer: How Useful Are Pharmacokinetic Tests?

Stuart M. Lichtman

Memorial Sloan-Kettering Cancer Center, Commack, N.Y. and Weill Cornell Medical College, New York, N.Y., USA

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Abstract

The elderly comprise the majority of patients with cancer and are the recipients of the greatest amount of chemotherapy. Unfortunately, there is a lack of data to make evidence-based decisions with regard to chemotherapy. This is due to the minimal participation of older patients in clinical trials and that trials have not systematically evaluated chemotherapy. This chapter reviews the available information with regard to chemotherapy and aging. Due to the lack of prospective data, the conclusions and recommendations made are a consensus of the available information. Extrapolation of data from younger to older patients is necessary, particularly to those patients older than 80 years, for which data is almost entirely lacking. The classes of drugs reviewed include alkylators, antimetabolites, platinum compounds, anthracyclines, taxanes, purine analogues, antimicrotubule agents, camptothecins, and epipodophyllotoxins. Clinical trials need to incorporate an analysis of chemotherapy in terms of the pharmacokinetic and pharmacodynamic effects of aging. In addition, data already accumulated need to be re-analyzed by age to aid in the management of the older cancer patient.

Copyright © 2013 S. Karger AG, Basel

Background

The study of the pharmacokinetics of chemotherapy in older patients has truly been lacking. This has been primarily due to a general exclusion of the elderly from clinical trials. This has been a persistent underrepresentation of older patients from trials which has resulted in the approval of drugs by the Food and Drug Administration [1, 2]. This has led to a paucity of data available to the clinician to make rational treatment decisions. Most, but certainly not all, of the available literature is based on retrospective, subset analyses in which older patients represent a small proportion of the total population. Patients reported generally do not have significant comorbidity and may not be truly representation of the average patient seen in practice. There is very little prospective pharmacokinetic data. Many papers focus on toxicity, which reflects pharmacodynamic changes in the older patient. In addition to age, there have been a number of publications regarding end-organ dysfunction. While this is not specifically for the elderly, the data can be utilized for this purpose as older patients have a higher incidence of comorbidity. Because of the overall lack of data, particularly for patients over the age of 80 years, the clinician will continue to have the task of extrapolating data to fit the individual patient. Clinical judgment will always be important. Modification of toxicity and appropriateness of dosing will also be affected by the use of hematopoietic growth factors and change in the schedule of drug administration [3]. The assessment of renal function is extraordinarily important in dosing chemotherapy. There is controversy which formula is the most accurate in the elderly. It is clear that serum creatinine should not be the sole determinant of renal function in the elderly or in patients with cachexia [4-7].

Should We Study Pharmacokinetics and Pharmacodynamics in Older Patients?

Is there a need to study pharmacokinetics in older patients? If we say that it is not necessary, then we are saying that our current clinical trials structure is adequate for older patients. It is definitely not, as indicated by the underrepresentation of these patients in trials. In terms of drug trials, the pharmacokinetics of current chemotherapy has been primarily studied in the ‘typical’ patients. That is, those patients without significant comorbidity and good performance and functional status. End-organ dysfunction studies have been performed on many drugs such as irinotecan, paclitaxel, gemcitabine, pemetrexed [8-11]. To date, there are few studies which have shown a difference between the ‘typical’ patients and elderly. Few age-related changes have been reported. Pharmacokinetic differences, when present, have not been clinically relevant. In addition, there are virtually no studies which look at changes in pharmacokinetics over multiple cycles. Heterogeneity makes studies in the elderly difficult and results in too much variability to be clinically applicable. Some differences in clinical toxicity have often been a result of drug scheduling, not age [12]. An example, whether 5-fluorouracil (5-FU) toxicity differs if administered weekly, as a bolus monthly or as infusion.

One rationale in the past to do pharmacokinetics studies was the avoidance of toxicity. Hematologic toxicity has been minimized due to hematopoietic growth factors. Dose-limiting toxicity is often due to non-hematologic toxicities which are not related to significant differences in pharmacokinetics, i.e. neuropathy from oxaliplatin.

One main issue is to determine which subset of elderly patients should be chosen to do pharmacokinetic studies. Are they the healthy, vulnerable, frail, anemic, hypoalbuminemic, those dependent in activities of daily living (ADL) or instrumental ADL (IADL) and multiple comorbidities? Many older patients have had previous chemotherapy and radiation for treatment of other cancers. In addition, comorbidity may causes further change in organ function and change the patients’ sensitivity to toxicity, i.e., diabetes-neuropathy, atherosclerotic heart disease-cardiomyopathy. We should be studying pharmacokinetic tests in these different elderly populations. The factors to be studied should also include oral therapy, compliance, biologic therapy, and drug interactions. The other factors which should be included in data acquisition include longitudinal effects of treatment, changes in cognition, changes in function with treatment, dependency, chronic toxicities, scheduling differences which can effect toxicity, and correlation of toxicity and function. The inclusion of pharmacogenomics is also critical [13]. In evaluating toxicity, one question which needs to be answered is: Are our toxicity scales adequate for older patients? Do they capture enough information, particularly function, such as the effect of neuropathy.

Therefore, pharmacokinetics should be studied but the trials need to be novel and include these aforementioned factors. Regulatory agencies should require the inclusion of older patients before drugs can be approved.

The pharmacokinetics of common chemotherapeutic agents are discussed with emphasis on older patients.

Alkylating Agents

Alkylating agents have been the foundation of therapy for decades, particularly for breast cancer and hematologic malignancies. Their main dose-limiting toxicity is the hematologic. The large interindividual variability in bone marrow reserves is well known among older patients depending on comorbidity. Metabolism represents the main route of elimination for most compounds. Hepatic enzymatic processes are often involved [14]. Cytotoxic effects correspond to metabolites rather to parent compounds.

Melphalan

Melphalan is administered to elderly patients for treatment of multiple myeloma. Drug excreted unchanged in the urine represents about one third of the administered dose [15]. Positive correlation has been observed between melphalan area under the curve (AUC) and the degree of renal insufficiency [16, 17]. However, renal insufficiency did lead to a limited decrease in melphalan clearance compared to the interindividual variations in systemic clearance [18, 19].

High-dose chemotherapy is being increasingly utilized for the treatment of multiple myeloma in older patients [20-23]. Doses up to 200 mg/m² by intravenous infusion have become a standard. Higher toxicity, mainly myelosuppression, has been observed in patients over the age of 70 years [23, 24]. There is no recommendation of melphalan dosing based on renal function, but there is a consensus that reduction of the melphalan dose should be considered in patients with a glomerular filtration rate (GFR) of <30 ml/min. There are a number of treatment options available for elderly patients with multiple myeloma ineligible for high-dose chemotherapy [25, 26]. The treatment of myeloma has evolved and there other treatments not involving traditional alkylating agents [27].

Cyclophosphamide

Metabolism of cyclophosphamide to active metabolites is initiated by cytochrome P450 (subfamily 3A and 2B) mainly in the liver. An accumulation of toxic alkylating metabolites is expected in renal insufficiency justifying a dose reduction of 20-30% depending on the degree of the renal insufficiency [28]. Cyclophosphamide is administered in combination with methotrexate and 5-FU (CMF) for treatment of breast cancer. A prospective study in patients over 70 years of age concluded that the dose of CMF in patients over 70 years should not exceed 75% of the standard dose [29]. The combination cyclophosphamide/doxorubicin for the treatment for breast cancer was evaluated [30]. There was moderate evidence of an age-related decrease in the nadir absolute neutrophil count. Pharmacokinetic analyses did not demonstrate age-related differences in the either cyclophosphamide or doxorubicin plasma exposure, but only the pharmacokinetics of the parent drug (unchanged cyclophosphamide) was explored. Overall, regarding the modest ...