Overview of Chemotherapeutic Considerations for Older Patients

Overview of Chemotherapeutic Considerations for Older Patients

Preface

I would like to introduce a new series of E-updates that will cover the area of geriatric oncology. There has been an epidemiologic shift occurring with the aging of our society. It has long been recognized that the most significant risk factor for the development of cancer is aging. This, together with the epidemiologic shift, has resulted in a marked increase in the number of older patients with cancer. All the subspecialties of oncology are rapidly becoming a field that will be primarily concerned with the care of older patients.

Cancer and its treatment may appear as a prime cause of disability, not only mortality, in older individuals. The traditional ways in which cancer is studied, ie, clinical trials focusing on younger, healthier patients, have left us with a void in available data to manage the older patients in an evidence-based fashion. Not only do these trials fail to establish the validity of cancer treatment in the elderly, they also fail to provide information related to the long-term complications of treatment, including decline in function.

Over the past 10 to 15 years, studies of older cancer patients have revealed a significant amount of important clinical information, including the degree and severity of comorbidity and its effect on treatment, the role of polypharmacy, and the various social and financial problems facing older patients with cancer. The underrepresentation of older patients in clinical trials has been amply documented.1 The adverse outcomes of inadequate dosing and supportive care in both curative and palliative treatments have been demonstrated in a number of treatment settings.2 Even when clinical trials are available, barriers to participation of older patients have shown to be primarily due to reluctance by physicians due to fear of toxicity, limited expectation of benefit, or ageism.3

A number of important strides have been made in the evaluation of older patients through various methodologies of geriatric assessment. The comprehensive geriatric assessment (CGA) developed by geriatricians is a multidisciplinary evaluation of the older patient encompassing a number of important clinical domains.4 Researchers in this area have shown that traditional oncology measures of performance are not adequate in older patients and that geriatric-specific measures (ie, Activities of Daily Living and Instrumental Activities of Daily Living) have a much greater predictive value.5

There has been major interest in this area by a number of professional oncology societies and organizations. In 1995, the Cancer and Leukemia Group B organized a Cancer in the Elderly Committee.6 The other national cooperative groups have also developed geriatric oncology interest groups. The American Society of Clinical Oncology (ASCO) sponsored a clinical practice forum in 2000, a symposium at the Annual Meeting in 2002, and a publication “Cancer Care in the Older Patient” as part of its curriculum series. The ASCO annual meeting has included a number of educational sessions and oral presentations emphasizing geriatric oncology. In the US, the National Comprehensive Cancer Network (NCCN) has published practice guidelines for Senior Adult Oncology,7 and the Geriatric Oncology Consortium (GOC; www.thegoc.org) has been founded to initiate clinical trials and raise awareness of problems in elderly patients.

Our European colleagues have been among the first to bring the needs of the elderly to the attention of the medical community.8,9 Many of the clinically significant prospective trials in older cancer patients have originated in Europe.10-12 The International Society of Geriatric Oncology (SIOG; www.cancerworld.org/siog), with its headquarters in Switzerland, has implemented a number of taskforces to evaluate the current literature and to make treatment recommendations.13-16

This E-update series will consist of four publications. The first focuses on the use of chemotherapy in the elderly and offers an algorithm for decision-making. There will be subsequent articles on breast, lung, and colorectal cancers. Each will provide data and help guide clinicians in making meaningful decisions for their elderly patients. I hope this series will also stimulate interest in further research in the area of geriatric oncology. Because older patients will become the majority of the patients we evaluate and treat, they need to become the focus of our endeavors.

Stuart M. Lichtman, MD Associate Attending Clinical Geriatric Program Memorial Sloan-Kettering Cancer Center Commack and New York, NY lichtmas@mskcc.org

References

1. Hutchins LF, Unger JM, Crowley JJ, Coltman CA Jr, Albain KS: Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 1999;341:2061-2067.

2. Dixon DO, Neilan B, Jones SE, et al: Effect of age on therapeutic outcome in advanced diffuse histiocytic lymphoma: The Southwest Oncology Group experience. J Clin Oncol 1986;4:295-305.

3. Kemeny MM, Peterson BL, Kornblith AB, et al: Barriers to clinical trial participation by older women with breast cancer. J Clin Oncol 2003;21:2268-2275.

4. Cohen HJ, Feussner JR, Weinberger M, et al: A controlled trial of inpatient and outpatient geriatric evaluation and management. N Engl J Med 2002;346:905-912.

5. Extermann M, Overcash J, Lyman GH, Parr J, Balducci L: Comorbidity and functional status are independent in older cancer patients. J Clin Oncol 1998;16:1582-1587.

6. Cohen HJ, Muss HB: The cancer and leukemia group B cancer in the elderly committee: Addressing a major cancer need. Clin Cancer Res 2006;12:3606s-3611s.

7. Balducci L: NCCN Clinical Practice Guidelines in Oncology. Senior Adult Oncology. Available at: http://www.nccn.org/professionals/physicians_gls/f_guidelines.asp?button=1+Agree#care. Accessed June 27, 2007.

8. Fentiman IS, Tirelli U, Monfardini S, et al: Cancer in the elderly: Why so badly treated? Lancet 1990;355:1020-1022.

9. Monfardini S, Chabner B: Joint NCI-EORTC consensus meeting on neoplasia in the elderly, San Servolo Island, Venice, 15-16, October 1990. Eur J Cancer 1991;27:653-654.

10. Feugier P, Van Hoof A, Sebban C, et al: Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: A study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 2005;23:4117-4126.

11. Gridelli C: The ELVIS trial: A phase III study of single-agent vinorelbine as first-line treatment in elderly patients with advanced non-small cell lung cancer. Elderly Lung Cancer Vinorelbine Italian Study. Oncologist 2001;6(suppl 1):4-7.

12. Gridelli C, Aapro M, Ardizzoni A, et al: Treatment of advanced non-small-cell lung cancer in the elderly: Results of an international expert panel. J Clin Oncol 2005;23:3125-3137.

13. Audisio RA, Bozzetti F, Gennari R, et al: The surgical management of elderly cancer patients: Recommendations of the SIOG surgical task force. Eur J Cancer 2004;40:926-938.

14. Repetto L, Carreca I, Maraninchi D, Aapro M, Calabresi P, Balducci L: Use of growth factors in the elderly patient with cancer: A report from the Second International Society for Geriatric Oncology (SIOG) 2001 meeting. Crit Rev Oncol Hematol 2003;45:123-128.

15. Extermann M, Aapro M, Bernabei R, et al: Use of comprehensive geriatric assessment in older cancer patients: Recommendations from the task force on CGA of the International Society of Geriatric Oncology (SIOG). Crit Rev Oncol Hematol 2005;55:241-252.

16. Aapro M, Launay-Vacher V, Lichtman S, Chatelut E, Wildiers H: A Report from a SIOG Task Force on Renal Safety in the Elderly. Available at: www.cancerworld.org/cancerworldadmin/getStaticModFile.aspx?id=893. Accessed July 11, 2007.

Physiologic Changes in the Aging Patient and Their Effect on Chemotherapy

Physiologic changes that occur with increasing age affect the pharmacokinetic characteristics of chemotherapy in a number of ways.2 Changes within the gastrointestinal system can result in reduced drug absorption, decreased gastrointestinal motility, reduced splanchnic blood flow and secretion of digestive enzymes, and mucosal atrophy.5 Aging also affects body composition; fat content can double in the elderly, and intracellular water levels decrease.

Because the volume of distribution (Vd) of drugs is a function of body composition and the concentration of plasma proteins,5 these changes can result in a decreased Vd of water-soluble drugs and an increased Vd of lipid-soluble drugs.5 The Vd of drugs can also be affected by anemia, which often occurs in aging patients, along with an associated decrease in albumin levels. Treatment of anemia, which is the only component of Vd that can be manipulated,6 is beneficial in these patients, especially when drugs that bind to red blood cells are prescribed.

The liver is the main site of drug metabolism. There seem to be no significant age-related changes in liver function and drug metabolism. Phase 1 metabolism occurs primarily via the cytochrome P450 microsomal system and exhibits genetic variability.7 Due to the large number of drugs elderly patients use, the potential for drug interactions is high, particularly with the CYP3A4 enzyme.8,9

Renal function also gradually declines with age, as evidenced by a reduced glomerular filtration rate in elderly patients.10 This reduced renal excretion, however, does not result in increased serum creatinine levels because of the simultaneous loss of muscle mass. Serum creatinine levels alone should not be used as a measure of renal function. Various equations, such as the Cockroft-Gault, Jelliffe, and Wright equations, can be used to calculate renal clearance in patients of all ages11; the most practical clinical measure of renal function is the Cockroft-Gault equation. The dosing modifications recommended for older patients with renal impairment to avoid toxicity are discussed elsewhere.12

Comorbidity, Functional Status, and Geriatric Assessment

Comorbidity is a key factor in the overall survival of patients, and it influences the benefits and toxicity of therapy (Table 1).13 In cancer patients, higher comorbidity index scores result in a stepwise increase in cumulative mortality.14 In elderly patients, the presence of comorbidities greatly limits survival.15 Cognitive impairment has a significant effect and is associated with a higher prevalence of depression and more severe comorbidities.15,16 These data must be taken into consideration in treatment planning, especially for patients with limited-stage cancer.16

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Functional status is a significant issue. Comorbidity and functional status need to be assessed independently in older cancer patients before treatment decisions are made.17 Traditional oncology measures, such as the Karnofsky Performance Status and Eastern Cooperative Oncology Group scale, are inadequate means of assessment of overall functional status in the elderly.

In this population, the degree of dependency and geriatric functional scores can be useful in planning treatment.18 A “fit, elderly” patient can often tolerate a standard dose and schedule of chemotherapeutic medications with no additional adverse events and obtain the same benefit as a younger patient. A “frail elderly” patient, on the other hand, might be a good candidate for palliative treatment only.19

Geriatric assessment is a multidimensional, multidisciplinary diagnostic process used to determine the medical, functional, and psychosocial problems and capabilities in elderly patients to arrive at a comprehensive plan for therapy and long-term follow-up. Comprehensive geriatric assessment generally includes patient evaluation in several domains, most commonly the physical, mental, social, economic, functional, and environmental. Functional assessment is a key part of the comprehensive geriatric assessment that focuses on the patient’s ability to handle activities of daily living.

Function is usually determined by two common geriatric scales: Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL). The ADL scale is a measure of simple functions (transfer, bathing, grooming, toileting, dressing, feeding, appropriate behavior).The IADL scale requires more complexity and interaction with the external environment (cooking, cleaning, laundry, using the telephone, using transportation, managing money, taking medications). Geriatric assessment may be part of an extensive comprehensive program, and many components can be self-administered.20,21

Comprehensive geriatric assessment has been used effectively in general geriatric medicine to the benefit of elderly patients.20 Data from randomized clinical trials seem to support the use of such assessments. There are ongoing efforts by Cancer and Leukemia Group B and the International Society of Geriatric Oncology (SIOG) to develop validated scales to help clinicians make treatment decisions for older patients. Such decisions can be made by recognizing which patients will benefit from aggressive treatments and which are better suited for palliative therapy.22-25 The National Comprehensive Cancer Network (NCCN) has developed Senior Adult Oncology guidelines, which recommend a number of assessment tools (including the Vulnerable Elders Survey).26

The treatment of patients with dementia is a significant issue in oncology. In a tertiary cancer center, 18% of patients screened positive for dementia on the Mini Mental Status Examination (MMSE),17 although this is likely an underestimate of its overall incidence. Patients with dementia and other cognitive impairments have markedly reduced survival compared with nonimpaired patients.15 Despite this finding, the median projected survival is 69.7 months. Therefore, consideration should be given for potential life-extending therapy in these patients, but it should be balanced against potential toxicities. In a review of the Surveillance, Epidemiology, and End Results (SEER) colon cancer database,27 patients with dementia were less like to have undergone histologic diagnosis, to be offered surgical resection, and to be considered for adjuvant chemotherapy than other patients. The immediate support of a caregiver is imperative if therapy is to be offered.

The risk of toxicities that can cause delirium, such as diarrhea, dehydration, or febrile episodes, is higher in impaired patients than in those without such impairment,28 and these problems should be addressed immediately. Chemotherapeutic agents that commonly cause these toxicities should be avoided or at least used with extreme care, with special attention given to dosing and adjunctive supportive care measures (eg, growth factors and hydration). Delirium as a complication of surgery has also been recognized in older patients.28 Elective surgery is associated with improved outcome, including markedly decreased mortality, when compared with emergency surgery.29

Hematopoiesis

Stem cell reserve appears to be compromised with advancing age, which might explain the increased hematologic toxicity seen in elderly patients.30 The incidence of anemia increases significantly with age and frailty.31 The adverse effect of anemia on survival and functional status has been evaluated.31,32 In addition, chemotherapy-induced neutropenia appears to be more common and more severe in elderly individuals; it is associated with infectious complications, more hospitalizations, and a higher mortality rate.33 A study in elderly patients with non-Hodgkin’s lymphoma showed that granulopoietic growth factors should be used as primary prophylaxis after intensive chemotherapy, because many of the infectious and life-threatening complications occur early in the course of therapy.34 Primary prophylaxis in the treatment of some older cancer patients has been addressed by guidelines for the use of white blood cell growth factors published by the American Society of Clinical Oncology.1,35

Noteworthy Clinical Factors

The choice of chemotherapy for an elderly patient is dependent on a number of clinical factors and the availability of effective therapy. Patient factors, which include physiology, comorbidity, functional status, and performance status, can help to predict tolerance to treatment and the ability to complete the prescribed regimen.

Toxicity is often difficult to predict in older patients. Unfortunately, much of the data available in the literature on toxicity are based on patients 10 to 15 years younger than the patients who are 70+ years old. Extermann and colleagues have developed a methodology to help predict toxicity.36 The MAX2 index, a convenient and reproducible way of comparing the average per patient risk for toxicity from chemotherapy across several regimens, was developed from the literature in patients over 70 years of age. It is being incorporated prospectively into trials to validate its clinical utility.36

A comprehensive review of chemotherapy in the elderly recently published summarizes pharmacokinetic data and toxicity in older patients.37 Although there is little evidence of clinically significant age-related changes in pharmacokinetic parameters, much of these data have been accumulated in fit elderly patients, particularly those eligible for clinical trials. There are few data on the frail or vulnerable elderly. A summary of the pharmacokinetic parameters of chemotherapeutic drugs is listed in Table 2.38

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Renal Dysfunction

A decreasing glomerular filtration rate is a normal consequence of aging. In addition, comorbidity can lead to further decline in function. As mentioned previously, there are a number of formulae that can aid in the dosing of chemotherapy in older patients. Dose modifications should be made in situations where renal excretion is a significant proportion of overall drug elimination.12 Hematopoietic growth factors should be used in cases where myelosuppression is a potentially significant toxicity and dose modifications are inexact. Suggestions for dose modifications are given in Table 3.39

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Liver Impairment

The liver is the main site of drug metabolism. Hepatic metabolism involves two types of reactions. Type I reactions are dependent on cytochrome P450 mixed-function oxidase systems. Type II reactions are conjugation reactions, which may involve glucuronidation and lead to inactive compounds, excretable through the biliary system. There is no consensus regarding age-related changes in hepatic drug-metabolizing capacity. However, there seems to be general agreement that liver size decreases with age.40 Liver blood flow is reduced at a rate of 0.3% to 1.5% per year after the age of 25. This reduction in blood flow in the liver may lead to lower clearances of drugs, which are highly dependent on blood flow for elimination.

The cytochrome P450 system contains heme-based enzymes that are located primarily in the liver and additional locations in the small bowel, kidneys, lungs, and brain to a much lesser extent. Despite large numbers of various enzymes, genetic variability accounts for differing levels of enzymatic activity through various pathways, which may lead to clinically important pharmacodynamic differences among individuals.41-43

The potential for drug interactions is relatively high in the elderly due to polypharmacy, particularly with the CYP3A4 enzyme. This enzyme is inhibited by a variety of commonly prescribed medications and is involved in the metabolism of an assortment of anticancer agents. Cyclophosphamide, ifosfamide, (Ifex), paclitaxel, etoposide, teniposide (Vumon), vincristine, vinblastine, busulfan (Myleran), and tamoxifen are all substrates of CYP3A4 and may be significantly affected by common enzyme inhibitors of this enzyme.44 The biliary excretion of drugs has been studied, but no age-related alterations have been noted.45 Some examples of dose adjustments that may be required in older patients with hepatic dysfunction are noted in Table 4.1,38

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General Decision-Making Considerations

The algorithm in Figure 1 can be developed to assist in decision-making regarding chemotherapy for older patients. Due to a lack of evidence-based data, this guideline is still largely empiric, although extrapolation of data from existing studies may be helpful. A patient’s age, comorbidity, performance status, and functional status can form the basis of assessing his or her life expectancy. This information should be combined with the data predicting life expectancy based on a patient’s health status13,46 and then compared with the potential survival rates for the type of cancer. If a patient’s life expectancy is limited due to the general health status or the malignancy being treated, palliation should be the goal of therapy. If the potential life expectancy is longer than the potential survival from cancer, standard, and possibly curative, therapy, if available, should be prescribed. Clearly, these are always estimates, and clinical judgment is crucial. However, decisions regarding palliation or therapy with significant efficacy should not be based on age alone.

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Conclusion

The size of the elderly population is increasing globally. People in this age group are known to be at high risk of developing cancer. Clinical trials directed toward characterizing the needs and goals of therapy in elderly cancer patients are under way. Methods for identifying those people who are at a particularly high risk of developing side effects from chemotherapy are being established.

Optimizing therapeutic strategies for cancer patients who are over 65 years of age remains a challenge. Choosing the correct regimen and dose for older patients can be extremely difficult, as there are no accepted algorithms to guide management decisions for this patient group. These decisions should be based on a patient’s performance status, functional status, and life expectancy. Older cancer patients who have an adequate performance status and functional status, and a reasonable life expectancy, should receive the same therapies as younger patients. For older patients with a poor performance status or functional status, single-agent, reduced-dose chemotherapy options and nonchemotherapeutic approaches should be considered, together with palliative and supportive care. Hematopoietic growth factor support will allow us to treat elderly cancer patients more effectively and safely while decreasing transfusion requirements and the incidence of neutropenia and its sequelae. As mentioned, the NCCN has published Senior Adult Oncology guidelines, which can greatly aid physicians in treating older patients.47

Key Points

Chronologic age alone should not be the sole criterion for making treatment decisions.

Physiologic changes with age, comorbidity, and functional status need to be incorporated into treatment decisions.

Some form of geriatric assessment should be considered in patients over 70 years of age.

Renal function needs to be assessed when chemotherapy with predominant renal excretion is utilized.

Serum creatinine levels should not be used alone as an assessment of renal function. Calculations with one of the published formulae should be made.

CME Post-Test and Evaluation

Continuing Medical Education InformationOverview of Chemotherapeutic Considerations for Older Patients Activity Release Date: July 15, 2007 Activity Expiration Date: July 15, 2008

About the Activity This activity is based on a brief article developed as part of the E-Update Series and posted on the Web. The series is geared to oncologists and addresses new treatments of cancer or modifications thereof.

This activity has been developed and approved under the direction of Beam Institute.

Activity Learning Objectives After reading this article, participants should be able to:

(a) Explore the physiologic changes in the elderly patient that affect the pharmacokinetics of chemotherapy agents.

(b) Review the multidimensional components of geriatric assessment.

(c) Discuss the effects of renal dysfunction and liver impairment on elderly patients receiving chemotherapy.

(d) Identify what makes an elderly patient a good candidate for chemotherapy.

Target Audience This activity targets physicians in the fields of oncology and hematology.

Accreditation This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Beam Institute and The Oncology Group. Beam Institute is accredited by the ACCME to provide continuing medical education for physicians

Continuing Education CreditAMA PRA Category 1 Credit™ The Beam Institute designates this educational activity for a maximum of 2 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Compliance Statement This activity is an independent educational activity under the direction of Beam Institute. The activity was planned and implemented in accordance with the Essential Areas and policies of the ACCME, the Ethical Opinions/Guidelines of the AMA, the FDA, the OIG, and the PhRMA Code on Interactions with Healthcare Professionals, thus assuring the highest degree of independence, fair balance, scientific rigor, and objectivity.

However, Beam Institute, the Grantor, and CMPMedica shall in no way be liable for the currency of information or for any errors, omissions, or inaccuracies in the activity. Discussions concerning drugs, dosages, and procedures may reflect the clinical experience of the author(s) or may be derived from the professional literature or other sources and may suggest uses that are investigational in nature and not approved labeling or indications. Activity participants are encouraged to refer to primary references or full prescribing information resources. The opinions and recommendations presented herein are those of the author(s) and do not necessarily reflect the views of the provider or producer.

Financial Disclosures

Dr. Lichtman has no financial relationships with any manufacturers or providers.

Copyright Copyrights owned by Beam Institute, a division of CME LLC. Copyright 2007, CME LLC. All rights reserved.

Contact Information We would like to hear your comments regarding this or other activities provided by Beam Institute. In addition, suggestions for future activities are welcome. Contact us at:

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Disclosures:

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.

References:

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