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The Impact of Aging on Chemotherapy
commentar y The Impact of Aging on Chemotherapy Shakun M. Malik, MD Lombardi Cancer Center Georgetown University Washington, DC
Advancing age is a severe risk for cancer in both sexes: the risk is 8%-9% in patients 40-59 years of age compared with 20%-30% at ages > 60 years. According to Surveillance, Epidemiology and End Results data, nearly 60% of all newly diagnosed malignant tumors and 70% of all cancer deaths are in persons ≥ 65 years of age, and the number is expected to increase. Lung cancer is the second most common cancer and leading cause of cancer death among men and women, and its incidence increases with age.1 Carcinogenesis is linked to progressive damage to DNA. It is related to cumulative exposure to exogenous carcinogens and age-related decreases in host defenses associated with decreased protection against oxidative damage and decreased immune defenses. Increased cancer incidence and mortality in elderly patients compared with adults ≤ 65 years of age has been attributed to host factors. Aging may impact chemotherapy effectiveness and toxicity. Decreased effectiveness of chemotherapy is thought to result from increased expression of the multidrug resistance gene, decreased apoptosis, tumor anoxia, and tumor indolence. Elderly patients have more indolent breast and non–small-cell lung cancer (NSCLC), shorter duration of remission in non-Hodgkin’s lymphoma, and resistance to chemotherapy in acute myelogenous leukemia. Increased toxicity, conversely, may be related to pharmacokinetic changes in elderly patients caused by decreased volume of distribution, decreased glomerular filtration rate, and decreased hepatic metabolism. Elderly Patients Chemotherapy for advanced lung cancer, especially in elderly patients, has been controversial. Fear of severe toxicity may lead to undertreatment in this group of patients. Age bias was noted in Great Britain by Crook et al when only 11% of
clinicians would recommend chemotherapy in patients > 50 years of age, compared with 26% in patients ≤ 50 years of age.2 A Medicare survey conducted by Earle et al indicated that only 22% of patients > 65 years of age with NSCLC receive chemotherapy.3 Elderly patients are underrepresented in clinical research trials evaluating new treatments in advanced disease.4 Age should not be a contraindication to full-dose chemotherapy, even though tolerance to chemotherapy may worsen with age. Elderly patients are at increased risk of neutropenia and infection, mucositis, cardiac toxicity, neurologic toxicity, and anemia. Tolerance is related more to functional status than to age. The main factors limiting chemotherapy effectiveness are poor overall health and functional status and presence of comorbidities. Clinical evidence supports standard-dose chemotherapy in healthy elderly patients. Chemotherapy yields comparable outcomes in younger and older patients with lung and other cancers.5-7 However, the likelihood of receiving full-dose chemotherapy decreases with age. Oral Chemotherapy The use of orally administered anticancer therapy is an attractive alternative to intravenous therapy, especially in elderly patients. This type of therapy may become even more common with the development of newer targeted therapies. Patients prefer the convenience of oral therapy as long as efficacy is not compromised.8 Patient adherence and bioavailability is the main concern about oral anticancer drugs. Oral chemotherapy can be effective only if adherence is optimized and methods of measurement of adherence are developed.9 For bioavailability, formal pharmacokinetic (PK) studies of sufficient size to permit statistical comparisons between older and younger patients are needed. Effects on PK parameters of influences related to impairment of excretory (renal) and metabolic (hepatic) function and drug–drug interaction can affect any age
group, but are more common in elderly patients. It is therefore important to determine whether the PK behavior of a drug is different in elderly patients than in younger adults. Vinorelbine is one of the drugs available in oral and intravenous forms. The Elderly Lung Cancer Vinorelbine Study was the first randomized trial that showed that single-agent vinorelbine prolonged survival and improved quality of life in elderly patients with NSCLC compared with supportive care alone.10 Similar results were noted by Crawford et al when randomization was made between single-agent vinorelbine and 5-fluorouracil/leucovorin in patients with stage IV NSCLC.11 The Multicenter Italian Lung Cancer in the Elderly Study compared vinorelbine versus gemcitabine versus the combination of the 2 agents and found no difference in response or survival among the singleagent and combination arms.12 Increased toxicity, especially myelosuppression, was noted on the combination-therapy arm. Single-agent chemotherapy has therefore been proposed for patients > 70 years of age. Multiple PK studies comparing oral and intravenous vinorelbine have found the oral form to be 40% bioavailable, and thus a bioequivalent area under the concentration–time curve was demonstrated between oral and intravenous recommended dosages.13-15 In the phase II trial in this issue of Clinical Lung Cancer, Puozzo and Gridelli studied PK parameters of oral vinorelbine in an elderly patient population.16 In the analysis of drug safety and efficacy, a population PK model was developed from a PK database of vinorelbine from phase I/II clinical trials and a limited sampling strategy was defined. A population PK approach offers the possibility of gaining integrated information on pharmacokinetics not only from relatively sparse data obtained from study subjects but also from relatively dense data or a combination of both. This has been an interest of the US Food and Drug Administration and the pharmaceutical industry.17 In the study
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of Puozzo and Gridelli, there was no statistically significant correlation between age and oral vinorelbine total clearance and PK parameters.16 The authors therefore do not recommend dose reduction for oral vinorelbine in elderly patients based on these PK studies. This study is important for future trials and as a reference to the fact that bioavailability in elderly patients may not be statistically different from that in younger people despite concerns of lower clearance. This may further help oncologists in their rethinking of withholding chemotherapy from fit elderly patient populations. Patient adherence remains a concern with oral chemotherapy. Convenience of administration of oral chemotherapy by physicians is especially relevant in elderly patients with frail veins; however, oral chemotherapy adherence should be optimized and methods of measurement developed. Comprehensive Geriatric Assessment Toxicity-induced loss of independence is a major concern for patients and their families. Physicians must base their decisions in the management of elderly patients with chemotherapy on cellular type and staging of cancer and on overall fitness, comorbidities, functional status, mental status, and family/social support of the patient. Comprehensive geriatric
244
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assessment has been found to be helpful in treatment decision making. The use of chemotherapy in this population requires special consideration because of the frequency of comorbid conditions and concomitant drug therapy and the consequent risk of drug interactions. Formulating guidelines based on renal or hepatic function may have significant potential applicability to elderly patients. Elderly patients should be included in clinical trials, especially phase III trials, in meaningful numbers. This subgroup should be represented sufficiently to permit comparison of their drug responses with those of younger patients. Inclusion of both groups in the same studies has the advantage of allowing direct comparisons of older and younger patients using data collection in similar ways. Such comparison is more difficult when separate studies of older and younger patients are undertaken. However, studies more relevant to elderly patients, such as those of cognitive assessment, can best be accomplished in separate studies 1. Lee-Chiong TL Jr, Matthay RA. Lung cancer in the elderly patient. Clin Chest Med 1993; 14:453-478. 2. Crook A, Duffy A, Girling DJ, et al. Survey on the treatment of non-small cell lung cancer (NSCLC) in England and Wales. Eur Respir J 1997; 10: 1552-1558. 3. Earle CC, Venditti LN, Neumann PJ, et al. Who gets chemotherapy for metastatic lung cancer? Chest 2000; 117:1239-1246. 4. Hutchins LF, Unger JM, Crowley JJ, et al. Underrepresentation of patients 65 years of age or older in cancer-
treatment trials. N Engl J Med 1999; 341:2061-2067. 5. Langer CJ, Manola J, Bernardo P, et al. Cisplatinbased therapy for elderly patients with advanced nonsmall cell lung cancer: J Natl Cancer Inst 2002; 94:173-181. 6. Finkelstein DM, Ettinger DS, Ruckdeschel JC. Longterm survivors in metastatic non-small cell lung cancer: an Eastern Cooperative Oncology Group Study. J Clin Oncol 1986; 4:702-709. 7. Jiroutek M, Johnson D, Blum R, et al. Prognostic factors in advanced non-small cell lung cancer (NSCLC): analysis of Eastern Cooperative Oncology Group (ECOG) trials from 1981-1992. Proc Am Soc Clin Oncol 1998; 17:461a (Abstract #1774). 8. Liu G, Franssen E, Fitch MI, et al. Patient preference for oral versus intravenous palliative chemotherapy. J Clin Oncol 1997; 15:110-115. 9. Partridge AH, Avorn J, Wang PS, et al. Adherence to therapy with oral antineoplastic agents. J Natl Cancer Inst 2002; 94:652-661. 10. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small cell lung cancer. The Elderly Lung Cancer Vinorelbine Italian Study Group. J Natl Cancer Inst 1999; 91:66-72. 11. Crawford J, O’Rourke M, Schiller JH, et al. Randomized trial of vinorelbine compared with fluorouracil plus leucovorin in patients with stage IV non-small cell lung cancer. J Clin Oncol 1996; 14:2774-2784. 12. Gridelli C, Perrone F, Gallo C, et al. Chemotherapy for elderly patients with advanced non-small-cell lung cancer, the Multicenter Italian Lung Cancer in Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst 2003; 95:362-372. 13. Marty M, Fumoleau P, Adenis A, et al. Oral vinorelbine pharmacokinetics and absolute bioavailability study in patients with solid tumors. Ann Oncol 2001; 12:1643-1649. 14. Variol P, Bonneterre J, Marty M, et al. Pharmacokinetic/pharmacodynamic relationships of IV and oral navelbine in phase I patients. Proc Am Soc Clin Oncol 2001; 20:110a (Abstract #435). 15. Puozzo C, Zorza G, Guimbaud R, et al. Metabolism of vinorelbine in human clinical application. Proc Am Soc Cancer Res 2000; 41:280 (Abstract #1781). 16. Puozzo C, Gridelli C. Non–small-cell lung cancer in elderly patients: influence of age on vinorelbine oral pharmacokintics. Clin Lung Cancer 2004; 5:237-242. 17. Peck C, Barr W, Benet L, et al. Opportunities for integration of pharmacokinetics, pharmacodynamics and toxikinetics in rational drug development. Clin Pharmacol Ther 1992; 51:465-473.
Advancing age is a severe risk for cancer in both sexes: the risk is 8%-9% in patients 40-59 years of age compared with 20%-30% at ages > 60 years. According to Surveillance, Epidemiology and End Results data, nearly 60% of all newly diagnosed malignant tumors and 70% of all cancer deaths are in persons ≥ 65 years of age, and the number is expected to increase. Lung cancer is the second most common cancer and leading cause of cancer death among men and women, and its incidence increases with age.1 Carcinogenesis is linked to progressive damage to DNA. It is related to cumulative exposure to exogenous carcinogens and age-related decreases in host defenses associated with decreased protection against oxidative damage and decreased immune defenses. Increased cancer incidence and mortality in elderly patients compared with adults ≤ 65 years of age has been attributed to host factors. Aging may impact chemotherapy effectiveness and toxicity. Decreased effectiveness of chemotherapy is thought to result from increased expression of the multidrug resistance gene, decreased apoptosis, tumor anoxia, and tumor indolence. Elderly patients have more indolent breast and non–small-cell lung cancer (NSCLC), shorter duration of remission in non-Hodgkin’s lymphoma, and resistance to chemotherapy in acute myelogenous leukemia. Increased toxicity, conversely, may be related to pharmacokinetic changes in elderly patients caused by decreased volume of distribution, decreased glomerular filtration rate, and decreased hepatic metabolism. Elderly Patients Chemotherapy for advanced lung cancer, especially in elderly patients, has been controversial. Fear of severe toxicity may lead to undertreatment in this group of patients. Age bias was noted in Great Britain by Crook et al when only 11% of
clinicians would recommend chemotherapy in patients > 50 years of age, compared with 26% in patients ≤ 50 years of age.2 A Medicare survey conducted by Earle et al indicated that only 22% of patients > 65 years of age with NSCLC receive chemotherapy.3 Elderly patients are underrepresented in clinical research trials evaluating new treatments in advanced disease.4 Age should not be a contraindication to full-dose chemotherapy, even though tolerance to chemotherapy may worsen with age. Elderly patients are at increased risk of neutropenia and infection, mucositis, cardiac toxicity, neurologic toxicity, and anemia. Tolerance is related more to functional status than to age. The main factors limiting chemotherapy effectiveness are poor overall health and functional status and presence of comorbidities. Clinical evidence supports standard-dose chemotherapy in healthy elderly patients. Chemotherapy yields comparable outcomes in younger and older patients with lung and other cancers.5-7 However, the likelihood of receiving full-dose chemotherapy decreases with age. Oral Chemotherapy The use of orally administered anticancer therapy is an attractive alternative to intravenous therapy, especially in elderly patients. This type of therapy may become even more common with the development of newer targeted therapies. Patients prefer the convenience of oral therapy as long as efficacy is not compromised.8 Patient adherence and bioavailability is the main concern about oral anticancer drugs. Oral chemotherapy can be effective only if adherence is optimized and methods of measurement of adherence are developed.9 For bioavailability, formal pharmacokinetic (PK) studies of sufficient size to permit statistical comparisons between older and younger patients are needed. Effects on PK parameters of influences related to impairment of excretory (renal) and metabolic (hepatic) function and drug–drug interaction can affect any age
group, but are more common in elderly patients. It is therefore important to determine whether the PK behavior of a drug is different in elderly patients than in younger adults. Vinorelbine is one of the drugs available in oral and intravenous forms. The Elderly Lung Cancer Vinorelbine Study was the first randomized trial that showed that single-agent vinorelbine prolonged survival and improved quality of life in elderly patients with NSCLC compared with supportive care alone.10 Similar results were noted by Crawford et al when randomization was made between single-agent vinorelbine and 5-fluorouracil/leucovorin in patients with stage IV NSCLC.11 The Multicenter Italian Lung Cancer in the Elderly Study compared vinorelbine versus gemcitabine versus the combination of the 2 agents and found no difference in response or survival among the singleagent and combination arms.12 Increased toxicity, especially myelosuppression, was noted on the combination-therapy arm. Single-agent chemotherapy has therefore been proposed for patients > 70 years of age. Multiple PK studies comparing oral and intravenous vinorelbine have found the oral form to be 40% bioavailable, and thus a bioequivalent area under the concentration–time curve was demonstrated between oral and intravenous recommended dosages.13-15 In the phase II trial in this issue of Clinical Lung Cancer, Puozzo and Gridelli studied PK parameters of oral vinorelbine in an elderly patient population.16 In the analysis of drug safety and efficacy, a population PK model was developed from a PK database of vinorelbine from phase I/II clinical trials and a limited sampling strategy was defined. A population PK approach offers the possibility of gaining integrated information on pharmacokinetics not only from relatively sparse data obtained from study subjects but also from relatively dense data or a combination of both. This has been an interest of the US Food and Drug Administration and the pharmaceutical industry.17 In the study
Clinical Lung Cancer January 2004
243
of Puozzo and Gridelli, there was no statistically significant correlation between age and oral vinorelbine total clearance and PK parameters.16 The authors therefore do not recommend dose reduction for oral vinorelbine in elderly patients based on these PK studies. This study is important for future trials and as a reference to the fact that bioavailability in elderly patients may not be statistically different from that in younger people despite concerns of lower clearance. This may further help oncologists in their rethinking of withholding chemotherapy from fit elderly patient populations. Patient adherence remains a concern with oral chemotherapy. Convenience of administration of oral chemotherapy by physicians is especially relevant in elderly patients with frail veins; however, oral chemotherapy adherence should be optimized and methods of measurement developed. Comprehensive Geriatric Assessment Toxicity-induced loss of independence is a major concern for patients and their families. Physicians must base their decisions in the management of elderly patients with chemotherapy on cellular type and staging of cancer and on overall fitness, comorbidities, functional status, mental status, and family/social support of the patient. Comprehensive geriatric
244
Clinical Lung Cancer January 2004
assessment has been found to be helpful in treatment decision making. The use of chemotherapy in this population requires special consideration because of the frequency of comorbid conditions and concomitant drug therapy and the consequent risk of drug interactions. Formulating guidelines based on renal or hepatic function may have significant potential applicability to elderly patients. Elderly patients should be included in clinical trials, especially phase III trials, in meaningful numbers. This subgroup should be represented sufficiently to permit comparison of their drug responses with those of younger patients. Inclusion of both groups in the same studies has the advantage of allowing direct comparisons of older and younger patients using data collection in similar ways. Such comparison is more difficult when separate studies of older and younger patients are undertaken. However, studies more relevant to elderly patients, such as those of cognitive assessment, can best be accomplished in separate studies 1. Lee-Chiong TL Jr, Matthay RA. Lung cancer in the elderly patient. Clin Chest Med 1993; 14:453-478. 2. Crook A, Duffy A, Girling DJ, et al. Survey on the treatment of non-small cell lung cancer (NSCLC) in England and Wales. Eur Respir J 1997; 10: 1552-1558. 3. Earle CC, Venditti LN, Neumann PJ, et al. Who gets chemotherapy for metastatic lung cancer? Chest 2000; 117:1239-1246. 4. Hutchins LF, Unger JM, Crowley JJ, et al. Underrepresentation of patients 65 years of age or older in cancer-
treatment trials. N Engl J Med 1999; 341:2061-2067. 5. Langer CJ, Manola J, Bernardo P, et al. Cisplatinbased therapy for elderly patients with advanced nonsmall cell lung cancer: J Natl Cancer Inst 2002; 94:173-181. 6. Finkelstein DM, Ettinger DS, Ruckdeschel JC. Longterm survivors in metastatic non-small cell lung cancer: an Eastern Cooperative Oncology Group Study. J Clin Oncol 1986; 4:702-709. 7. Jiroutek M, Johnson D, Blum R, et al. Prognostic factors in advanced non-small cell lung cancer (NSCLC): analysis of Eastern Cooperative Oncology Group (ECOG) trials from 1981-1992. Proc Am Soc Clin Oncol 1998; 17:461a (Abstract #1774). 8. Liu G, Franssen E, Fitch MI, et al. Patient preference for oral versus intravenous palliative chemotherapy. J Clin Oncol 1997; 15:110-115. 9. Partridge AH, Avorn J, Wang PS, et al. Adherence to therapy with oral antineoplastic agents. J Natl Cancer Inst 2002; 94:652-661. 10. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small cell lung cancer. The Elderly Lung Cancer Vinorelbine Italian Study Group. J Natl Cancer Inst 1999; 91:66-72. 11. Crawford J, O’Rourke M, Schiller JH, et al. Randomized trial of vinorelbine compared with fluorouracil plus leucovorin in patients with stage IV non-small cell lung cancer. J Clin Oncol 1996; 14:2774-2784. 12. Gridelli C, Perrone F, Gallo C, et al. Chemotherapy for elderly patients with advanced non-small-cell lung cancer, the Multicenter Italian Lung Cancer in Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst 2003; 95:362-372. 13. Marty M, Fumoleau P, Adenis A, et al. Oral vinorelbine pharmacokinetics and absolute bioavailability study in patients with solid tumors. Ann Oncol 2001; 12:1643-1649. 14. Variol P, Bonneterre J, Marty M, et al. Pharmacokinetic/pharmacodynamic relationships of IV and oral navelbine in phase I patients. Proc Am Soc Clin Oncol 2001; 20:110a (Abstract #435). 15. Puozzo C, Zorza G, Guimbaud R, et al. Metabolism of vinorelbine in human clinical application. Proc Am Soc Cancer Res 2000; 41:280 (Abstract #1781). 16. Puozzo C, Gridelli C. Non–small-cell lung cancer in elderly patients: influence of age on vinorelbine oral pharmacokintics. Clin Lung Cancer 2004; 5:237-242. 17. Peck C, Barr W, Benet L, et al. Opportunities for integration of pharmacokinetics, pharmacodynamics and toxikinetics in rational drug development. Clin Pharmacol Ther 1992; 51:465-473.