Skip Navigation

This Article
Right arrow Abstract Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (17)
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Sekine, I
Right arrow Articles by Saijo, N
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sekine, I
Right arrow Articles by Saijo, N
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Japanese Journal of Clinical Oncology Pages 463-473

Cancer Chemotherapy in the Elderly
Introduction
Age and Pharmacokinetics of Antineoplastic Agents
   Absorption
   Distribution
   Metabolism
   Excretion
Pharmacodynamics and Aging
   Toxicity of Chemotherapy
   Efficacy of Chemotherapy
Limitation of this Review and Future Directions
Acknowledgment
References
Cancer Chemotherapy in the Elderly

Cancer Chemotherapy in the Elderly

Ikuo Sekine1, Haruhiko Fukuda2, Hideo Kunitoh1 and Nagahiro Saijo1

1Medical Oncology Division, National Cancer Center Hospital, Tokyo and 2Cancer Information and Epidemiology Division, National Cancer Center Research Institute, Tokyo, Japan

As the geriatric population is growing, it is increasingly important to be familiar with chemotherapy for the elderly. Age-related changes in pharmacokinetics are documented for doxorubicin, etoposide, ifosfamide, daunorubicin, mitomycin, cisplatin and methotrexate. The hematological toxicity of most standard-dose chemotherapy is not affected by age in patients with normal organic functions and good performance status, although increased toxicity with aging is suggested in the use of actinomycin-D, etoposide, vinblastin, methotrexate, methyl-CCNU, doxorubicin and mitomycin, and in dose-intensive chemotherapy. Among non-hematological toxicities, only doxorubicin-induced cardiomyopathy and bleomycin-induced pulmonary toxicity are demonstrated to be accelerated in the elderly. There is no evidence that advanced age decreases the efficacy of chemotherapy for tumors, except for Hodgkin's disease and acute leukemia. These results suggest that advanced chronological age alone is not always associated with severe toxicity and poor prognosis, and that many elderly patients with cancer will benefit from chemotherapy. To answer questions regarding the optimal chemotherapy regimen, dose and intensity in this population, the influence of age should be analyzed in a multivariate approach in future studies.

Key words: pharmacokinetics - pharmacodynamics - toxicity - aging

INTRODUCTION

Since the incidence of cancer increases with age, cancer therapy for the elderly is one of the major issues in medical oncology as the geriatric population is growing. There has been a general tendency among physicians to consider that aged people always have poor tolerance to chemotherapy and, in consequence, many elderly patients with cancer have been undertreated for fear of excessive toxicity (1-4). However, there is little evidence from clinical studies that they should be treated with lower dosages of antineoplastic agents than younger patients. This review deals with a large variety of conflicting opinions concerning the benefit and toxicity of cytotoxic drugs in the elderly, based on associations between age and both pharmacokinetics (PK) and pharmacodynamics (PD), as well as normal changes in aging organs that are targets of antineoplastic agents.

AGE AND PHARMACOKINETICS OF ANTINEOPLASTIC AGENTS

Pharmacologic effects, both therapeutic and toxic, are functions of the intensity and duration of exposure to a drug (5). Drug exposure is affected by the processes of drug absorption, distribution, metabolism and excretion. It is well known that these processes are influenced by physiological changes of organs with aging (Table 1) (6,7), but there are only a limited number of human studies on PK of antineoplastic agents in the elderly (Table 2).

Absorption

Changes in the function of the gastrointestinal tract in old age include impaired acid secretion, and decreased absorptive surface, splanchnic blood flow and gastrointestinal motility (7,20-22). However, absorption of most antineoplastic agents administered orally does not seem to change with age (23,24). Possible exceptions are procarbazine, methotrexate and leucovorin, but no PK data on these drugs are available (23,24).

Table 1. Age-related physiologic changes affecting pharmacokinetics
Absorption Increased gastric pH, decreased absorptive surface, decreased splanchnic blood flow, decreased gastrointestinal motility
Distribution Decreased cardiac output, decreased total body water, decreased lean body mass, increased body fat, decreased serum albumin, increased alpha-acid glycoprotein
Metabolism Decreased hepatic mass, decreased hepatic blood flow, decreased activity of metabolic enzyme
Excretion Decreased renal blood flow, decreased glomerular filtration rate, decreased tubular secretion
Adapted from Montamat et al. (6).

Table 2. Pharmacokinetics of antineoplastic agents in the elderly
Drug Age (yr) No. of patients Dose* Route of
administration		 Alteration of PK in the elderly
Doxorubicin (8) 17-74 37 12.5-50 IV Early clearance [down arrow]
Ifosfamide (9) 40-71 20 1.5 g for 3-5 days DIV Half-life [up arrow], Vd[up arrow]
Etoposide (10) NA 29 50-100 DIV Half-life [up arrow], Vd [up arrow], AUC ->
Daunorubicin (11) 23-74 30 45 for 5 days IV AUC of daunorubicin ->
AUC of daunorubicinol [up arrow]
Daunorubicin (12) 17-74 37 30-45 IV Clearance of daunorubicin ->
Clearance of daunorubicinol ->
Mitomycin-C (13) 26-79 14 8 IV AUC [up arrow]
Cisplatin (14) 41-80 23 80 DIV AUC [up arrow]
Methotrexate (15) 21-97 25 3.6-4.8 mg/body IV Half-life [up arrow]
Methotrexate (16) 28-74 18 150-1500 DIV Clearance [down arrow]
Fluorouracil (17) 25-91 380 365-1224 for 5 days CI Clearance ->
Busulfan (18) 18-65 97 4 mg/kg for 4 days Orally PK ->
Piroxantron (19) 29-72 31 NA NA Clearance ->
Paclitaxel (19) 38-72 16 NA NA Clearance ->
Topotecan (19) 35-77 26 NA NA Clearance ->
Abbreviations: AUC, area under the curve of time versus plasma concentration; CI, continuous infusion; DIV, drip infusion; IV, intravenous bolus administration; NA, not available; PK, pharmacokinetics; Vd, volume of distribution.
*Units are mg/m2 if not specified.

Distribution

The distribution of a drug depends largely on its relative aqueous and lipid solubility, the degree of its binding to plasma proteins and specific tissues, and the total blood flow (25). A decrease in lean body mass and total body water, and an increase in body fat, which are well-documented body compositional alterations in the elderly (26-28), affect the volume of distribution and the elimination half-life of a drug (7,23). The early clearance of doxorubicin declines significantly with age (8). Since early-phase PK of this drug is associated with its tissue binding, this decline can be due to decreased lean body mass in the elderly (29). The volume of distribution and the half-life of ifosfamide (9) and etoposide (10) are increased in elderly patients, probably because these drugs are lipophilic and readily accumulate in lipid-rich tissues. For antineoplastic agents that are highly bound to plasma proteins, such as etoposide, doxorubicin, methotrexate, platinum and taxanes, a decrease in the plasma albumin level would increase the concentration of the unbound fraction of total drug in the plasma, and result in a large volume of distribution because more drug would be free to be distributed to peripheral tissue (23,30). However, the albumin value in the elderly varies, with reports from a 20% decrease (31,32) to almost normal values (33,34). These conflicting results may be attributable to a lack of longitudinal studies and difficulty in excluding subjects with underlying chronic diseases (35).

Metabolism

Liver size decreases by 18-44% between the ages of 20 and 80 years, and hepatic blood flow declines at a rate of 0.3-1.5% per year after the age of 25 (36). In consequence, first-pass metabolism of flow-dependent drugs would be reduced, leading to higher plasma concentrations and reduced systemic clearance of the drugs. The process of hepatic metabolism involves two types of reactions: phase I, consisting of oxidation, reduction and hydrolysis which primarily occur via the cytochrome p450 microsomal system; and phase II, consisting of conjugation reactions. Phase II reactions appear to be unaffected by age, whereas association between age and enzyme activity involving phase I reactions is controversial (37,38). Although studies on cytochrome P450 in human liver biopsy specimens show no significant association between monooxygenase activity and age of patients (39,40), the liver clearance of many non-cytotoxic drugs such as antipyrine is reduced in the elderly (7,41,42). Daunorubicin and its active metabolite daunorubicinol are eliminated mainly from the liver (29). Egorin et al. (11) showed that the area under the curve of time versus plasma concentration (AUC) of daunorubicin did not change with age, but that of daunorubicinol increased by 2-4 times in patients aged >60 years compared to younger patients. However, others reported that plasma clearance of neither compound was affected by age (12). The AUC of mitomycin is also increased with age, probably due to altered hepatic metabolism of the drug (13).

Excretion

Both renal structure and function deteriorate with aging (43,44). Renal weight, renal blood flow, the number of functioning glomeruli and the glomerular filtration rate decline in a linear fashion after the age of 30 years (43,44), and therefore the clearance of drugs which are eliminated mainly from this organ is reduced. The AUC of cisplatin, measured for both ultrafilterable platinum and total plasma platinum, is significantly increased with age (14). The overall elimination half-life of methotrexate is inversely related to creatinine clearance and is prolonged in the elderly (15). The clearance of fluorouracil, busulfan, piroxantron, paclitaxel and topotecan seems unaffected by age (17-19).

PHARMACODYNAMICS AND AGING

Pharmacodynamics describe the relationship between exposure of cells to antineoplastic drugs and their pharmacological effects. In a clinical setting, these effects are manifested as toxicity and tumor response.

Toxicity of Chemotherapy

Elderly patients often have concomitant diseases and/or organ dysfunction. Co-morbidity may influence the severity of chemotherapy-related toxicity, and indication for chemotherapy would be restricted by decreased functional capacity of the organ. In elderly cancer patients without complications, however, there is no agreement as to whether or not age is associated with an increase in various toxicities (24). Their frequency, nature and severity vary with the drug, dose and administration schedule.

Myelotoxicity

Physiological hematopoietic capacity is affected by aging. The bone marrow with hematopoietic function decreases in volume with age and is confined mainly within the spine, pelvis and sternum in the elderly (45). The cellularity in the iliac bone decreases with age, from >80% at under age 10 years to <30% at over age 70 years, as estimated from studies using magnetic resonance imaging (MRI) and histological sections (45-47). The number of hematopoietic progenitor cells per unit volume of bone marrow does not change with age in humans, except for a slight decrease in the erythroid system (48-50), but the number of these cells circulating in the peripheral blood is reduced in the elderly (51,52). Serum levels of hematopoietic growth factors are well maintained in the elderly (53,54), but responses of hematopoietic cells to these factors vary with the report (50-52,55-57). Changes in the marrow microenvironment may also be associated with hematopoietic function of old people (58,59). These results indicate that marrow hematopoietic cells generally continue to function well in the elderly, but that the reserve capacity is reduced because of a decrease in the absolute amount of hematopoietic marrow.

The toxicity of single-agent chemotherapy has been evaluated in phase I and phase II clinical trials of investigational anticancer drugs (Table 3). There is no difference in the incidence of grade 3-4 hematological toxicity between old and younger patients, or in the actual delivered dose and the number of treatment courses, dose reduction, treatment interruption and days of delay (60-63).

Table 3. Toxicity of single-agent chemotherapy in elderly and younger patients
Authors (year) Phase of trial Age of patients No. of patients Grade 3-4 toxicity (%) Comment
Bowen et al. (1993) (60) I <65 434 27  
>65 167 24
Borkowski et al. (1994) (61) I <65 195 32 No difference in delivered dose between the two age groups
>65 54 26
Monfardini et al. (1993) (62) II <60 748 43* No difference in percentages of dose reduction and treatment interruption among all age groups
60-65 246 45*
66-70 169 43*
71-80 103 36*
Giovanazzi Bannon et al. (1994) (63) II <65 401 23* Number of courses was higher in older patients
>65 271 25* No difference in the numbers of dose reduction, interruption, and days of delay
*Hematological toxicity alone.

Table 4. Toxicity and efficacy of combination chemotherapy for solid tumors
Authors (year) Regimen Age of patients No. of patients Grade 3-4 toxicity (%) RR (%) MST (months)
WBC Platelet
Breast cancer
Begg et al. (1980) (65) CMF-AV <60 542 28*   52 -
>60 155 37   49 -
Christman et al. (1992) (66) CAFV, CAV, <50 44 23 4.5 40 17.9
CMFV, 50-69 47 13 0 31 12.8
CAF ± CMF >70 70 31 7.1 29 14.2
Small cell lung cancer
Poplin et al. (1987) (67) CAE <54 51 1020[dagger] 15.6§ 53¶ no diff.
55-59 51 750 15.5 51  
60-64 62 770 15.0 48  
>65 49 330 10.3 57  
Ohnoshi et al. (1992) (68) CEMPr-VAN, <65 117 2000[dagger] 17.2§ 91 14.5
CAV-PE >66 101 1800 16.2 91 12.6
Non-small cell lung cancer
Kubota et al. (1997) (69) VdP <70 53 17[Dagger] 2 31 no diff.
>70 14 14 14 41  
MmVdP, <70 107 19 18 26 no diff.
EP-VdMm >70 29 48 24 45  
Abbreviations: A, adriamycin; C, cyclophosphamide; E, etoposide; F, 5-fluorouracil; M, methotrexate; Mm, mitomycin-C; MST, median survival time; N, nimustine; P, cisplatin; Pr, procarbazine; RR, response rate; V, vincristine; Vd, vindesine; WBC, white blood cell.
*Both leukocytopenia and thrombocytopenia included.
[dagger]Mean nadir white blood cell count (/mm3).
[Dagger]Grade 4 leukocytopenia.
§Mean nadir platelet count (× 104/mm3).
¶Complete response rate.

Hematological toxicity in the elderly who receive combination chemotherapy seems to depend on the drug contained in the regimen and the intensity of the treatment. Using a regression model, Begg et al. (64) calculated the odds ratio (OR) of each cytotoxic drug for grade 3-4 hematological toxicity in elderly patients who were treated with combination chemotherapy. This study combined the results of 95 Eastern Cooperative Oncology Group (ECOG) clinical trials between 1971 and 1984, involving 290 treatment arms and 16 580 patients comprising 8787 patients aged <60 years, 5584 aged 60-69 years and 2209 aged >70 years. They concluded that the incidence of toxicity was not affected by age for most of the agents, but that the following six drugs were significantly associated with a higher risk of severe hematological toxicity for patients at the age of >70 years: actinomycin-D, OR = 4.2; etoposide, OR = 2.6; vinblastin, OR = 2.5; methotrexate, OR = 2.2; methyl-CCNU, OR = 1.5; doxorubicin, OR = 1.4. However, this study included both previously treated and untreated patients, and did not evaluate interaction between drugs or dose-response effects. Clinical trials comparing toxicity between elderly and younger patients with various malignant diseases are summarized in Tables 4 and 5. In general, the degree of hematological toxicity of combination chemotherapy for solid tumors seems not to differ between elderly and younger patients, but is more severe in patients over 70 years old receiving mitomycin-containing chemotherapy (69). For hematological malignancies, most chemotherapy regimens are more toxic for patients of advanced age. The CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisone) for non-Hodgkin's lymphoma, however, is well tolerated regardless of age (74). These results indicate that (i) the hematological toxicity of most standard-dose chemotherapy is not affected by age; (ii) the following drugs seem to be associated with more severe hematological toxicity in the elderly: actinomycin-D, etoposide, vinblastin, methotrexate, methyl-CCNU, doxorubicin and mitomycin; (iii) intensive chemotherapy is more likely to be highly toxic in the elderly, especially in those with hematological malignancies.

Infections

Elderly patients can be predisposed to infection during chemotherapy because of impaired immune function as well as neutropenia (77,78). The marked feature of immunosenescence is a decline in T-cell-mediated immunity, which is primarily attributable to completion of thymic involution by the age of 50 years (79,80). Intrathymic T-cell selection and maturation are impossible, and therefore the supply of new naive T cells from the thymus to the periphery is diminished in the elderly. In consequence, the number of naive T cells decreases, but that of memory T cells increases with aging because antigen-driven conversion of naive to memory cells still continues throughout life (79,81,82). The responsiveness of T cells to antigens and mitogens seems to decline in the elderly, which is explained at least in part by increased rigidity of the plasma membrane, decreased surface expression of co-stimulatory molecules, and altered signal transduction pathways of T cells in the elderly (79,81,83). Production of interleukin (IL)-2 (84,85) and expression of IL-2 receptors (85,86) in T cells decrease with age, leading to impaired clonal expansion of these cells (81). Age-associated alterations are also noted in the production of other cytokines, such as IL-4, IL-6, IL-10, interferon-gamma, tumor necrosis factor-alpha and transforming growth factor-beta (79,81). Impaired humoral immunity in the elderly is mainly caused by dysfunction of T cells that regulate B-cell activation and differentiation (79,81,83). Production and affinity maturation of antibody in response to antigen decline in the elderly (83,87,88). Changes in function of antigen-presenting cells such as macrophages and dendric cells are controversial (89-91).

In spite of age-related dysfunction in the immune system described above, there is little evidence that the incidence of infection during chemotherapy increases with age. Dixon et al. (92) showed that pneumonia occurred in 10% of patients aged <60 years, but in 47% of patients aged >60 years, who received combination chemotherapy for small cell lung cancer, although the incidence of prolonged neutropenia did not differ between the two age groups. Febrile episodes are also more common in elderly patients with this disease (67,68). A higher incidence of severe infection and death as a result of sepsis was observed in elderly patients during treatment of leukemia (93,94). In other malignancies, however, no difference is noted in the occurrence of infection between elderly and younger patients (65,72,73,95).

Table 5. Toxicity and efficacy of combination chemotherapy for hematological malignancies
Authors (year) Regimen Age of patients No. of patients Grade 3-4 toxicity (%) CR (%) MST (months)
WBC    Platelet
Myeloma
Cohen and Bartolucci (1985) (70) BCP <60 79 6.3 7.6 23[dagger] no diff.
60-69 68 8.0 4.4 32  
>70 40 2.5 12 38  
MelP <60 83 4.8 3.6 30[dagger] no diff.
60-69 50 14 2.0 38  
>70 53 7.5 0 26  
Hodgkin's disease
Peterson et al. (1982) (71) MOPrP, MVPP, <40 205 7 6 70 >120
CcOPP, CcVPP, 40-59 107 15 10 66 54
BOPP >60 73 19 17 40 18
Non-Hodgkin lymphoma
Dixon et al. (1986) (72) CHOP, CHOP-Ble, <55 119 17 6.7 62 >52
CHOP-Levamisole 55-64 107 25 3 55 34
>65 51 22 1 37 16
Vose et al. (1988) (73) CHP/BleOP <60 45 7* 76 >36
>60 112 7 61 16
Grogan et al. (1994) (74) CHOP, m-BACOD <65 67 4* 76 no diff.
>65 60 1 65  
Acute leukemia
Kantarjian et al. (1994) (75) VHDex <60 216 3* 82 20
>60 52 12 58 10
Rees et al. (1996) (76) DAT+mAzE, <60 588 12* 73  
DAT+COAP 60-69 251 29 47  
>70 84 33 44  
Abbreviations: A, ara-C; Az, 5-azacytidine; B, carmustine (BCNU); Ble, bleomycin; C, cyclophosphamide; Cc, lomustine (CCNU); CR, complete response rate; D, daunorubicin; Dex, dexamethasone; E, etoposide; H, adriamycin; m, m-AMSA; M, mechlorethamine; mel, nelphalan; MST, median survival time; O, vincristine; P, prednisone; Pr, procarbazine; T, 6TG; V, vinblastine; WBC, white blood cell.
*Percentage of toxic death.
[dagger]Both complete and partial responses are included.

Cardiotoxicity

The heart changes with age in both structure and function (96-99). Moderate left ventricular hypertrophy, increased circumference of the aortic and pulmonary valves, fibrotic thickness and calcification of the valves, and tortuous and focally calcified coronary arteries are found in the aging heart. Loss of myocytes and an increase in matrix connective tissue are observed in the aged myocardium, and these changes are more pronounced in the male heart than in the female heart. There are also atrophy and loss of specialized conduction tissue in the atria and ventricles. Cardiac functions at rest do not change with aging, but chronotropic response to beta-sympathetic stimulation and maximum work capacity of the heart decline significantly in the elderly (96,100). Abnormal findings in electrocardiography (ECG) are observed in 57% of the elderly aged >65 years, and 80% of the abnormality is associated with dysfunction of the conduction system (101). By 24 h ambulatory ECG, paroxysmal atrial tachycardia and ventricular tachycardia were detected in 13 and 4%, respectively, of 98 healthy people aged >60 years (102). In a large population-based study, the incidence of ventricular tachycardia was found to have increased significantly with age, although serious arrhythmias were uncommon (103). Exercise-induced non-sustained ventricular tachycardia was observed in 0.15% of healthy volunteers aged <65 years and 3.75% of those aged >65 years (104). Thus, arrhythmias are common in the elderly even if they complain of no symptoms.

Cardiotoxicity is a major limiting factor in the use of anthracyclines, including doxorubicin and daunorubicin. Doxorubicin-induced cardiotoxicity can be classified into three categories: acute toxicity consisting of supraventricular or ventricular tachycardias, subacute consisting of toxic myocarditis or pericarditis, and chronic consisting of cumulative dilated cardiomyopathy (105). Age, as well as total dose of drug administered, the schedule of administration, pre-existing cardiac disease, and radiotherapy to the mediastinum, are the established risk factors for doxorubicin-induced dilated cardiomyopathy (105-111). Bristow et al. (108) recommended that the total dose of doxorubicin should be limited within 300 mg/m2 for patients >70 years of age. Cardiotoxicity of daunorubicin is equivalent to that of doxorubicin, but few reports are focused on damage to the heart by the drug in the elderly (105,112). For other cytotoxic agents, there is no proven correlation between age and the degree of cardiotoxicity (95,105,106).

Pulmonary toxicity

It is well established that lung function declines in the elderly (113). The vital capacity and forced expiratory volume in the first second decrease, and the residual volume increases with age as a result of the diminished elastic force of the lung. The increased closing volume in the elderly promotes collapse of small conducting airways, non-uniformity of alveolar ventilation and air trapping. Diffusion capacity also decreases with age, and this is associated with uneven distribution of the inspired gas and blood flow within the lung, decreased gas-exchange surface, and resistance to transfer of gas molecules from gas phase to the hemoglobin molecule. In contrast to physiological changes, morphology in the aging lung is not conclusive because it is often difficult to distinguish changes in the lung with age from those due to smoking and other environmental exposures (114). The number of alveoli per unit lung volume decreases and the amount of emphysema increases with age even in non-smokers. Alterations in the amount and nature of elastic and collagen tissues vary with reports, but most of them show no or only subtle changes. These physiological and anatomical changes with age probably compromise the ability to clear pathogens arriving in the lung through the airways, but their effects on the responses of the lung to agents arriving in the lung through the blood stream are unknown.

The incidence of pulmonary toxicity due to antineoplastic agents is variable, partly because of the different diagnostic criteria employed and difficulty in excluding other causes such as infection (115).

Among many anticancer drugs causing pulmonary toxicity, only bleomycin is shown to be associated with increased toxicity in the elderly (115-118). Bleomycin directly injures the pulmonary capillary endothelium and type I pneumocytes, leading to diffuse alveolar damage and interstitial fibrosis (115). Pulmonary toxicity of the drug is manifested by cough, dyspnea and bilateral pulmonary infiltrates on chest X-ray films, with an incidence of approximately 3% of patients receiving a total dose of <450 units of bleomycin (115,116). Established risk factors for the toxicity are age >70 years, cumulative dose >450 units, thoracic radiotherapy and a high inspired concentration of oxygen. Bleomycin pulmonary toxicity occurs in 10-50% of patients with one or more of these factors (115-118). Interstitial pneumonitis accompanying bone marrow transplantation is the other example of chemotherapy-related pulmonary toxicity increasing with age (115,119).

Neurotoxicity

Apart from loss of neurons and degenerative changes such as accumulation of lipofuscin, altered structure and function of the central nervous system in the elderly are not clearly understood (120,121). On MRI scanning of the brain, a diffuse periventricular white matter change is frequently detected in the elderly. This is usually reported as secondary to microvascular leukoencephalopathy, but evidence of an actual pathological correlation is scant (122). The influence of aging on cerebral blood flow is inconsistent among reports, but most show a decline in this parameter with age (122-125). This age-related decrease in blood flow of the brain is enhanced by cerebral arterial sclerosis even in the absence of any ischemic symptoms (124,126). In contrast, metabolism of the brain is well maintained throughout life (122). The function of the blood-brain barrier seems to be affected by age, and therefore the brain's susceptibility to drugs may be increased (127-129).

Basic alterations in aged peripheral nerves, axonal degeneration, secondary demyelination, and subsequent loss of myelinated fibers, are more prominent in thick nerve bundles and their distal part (121). The conduction velocity of peripheral nerves decreases with age (130). With these changes, elderly patients are considered to be at higher risk of peripheral neuropathy.

A common manifestation of central neurotoxicity is white matter changes (131,132). Following high-dose cytarabine therapy, encephalopathy, cerebellar dysfunction and peripheral neuropathy have been observed. Gottlieb et al. (133) claimed that this neurotoxicity is age related, but another study found no association between the neurotoxicity and patient age after adjustments for renal insufficiency (134). Hearing loss associated with cisplatin administration may be affected by age (135). In the treatment of Hodgkin's disease, increased neurotoxicity with age was noted, which is attributable to vincristine (70). However, no difference in neurotoxicity was observed between young and old patients with non-Hodgkin lymphoma who were treated with the CHOP regimen (72), and those with lung cancer who received combination chemotherapy containing vinca alkaloids and cisplatin (68,69). An analysis of patients who received chemotherapy for colorectal cancer, sarcoma, and head and neck cancer also disclosed no difference in neurotoxicity (95).

Nephrotoxicity

There is no evidence of an increased risk of nephrotoxicity in the elderly (136). Cisplatin at a dose of 60-100 mg/m2 can be safely administered to elderly patients (137,138).

Mucositis

For all antineoplastic agents interfering with cell division, the oral mucosa is one of the target tissues most commonly affected. Mucositis is typically observed after the use of methotrexate, 5-fluorouracil, doxorubicin and bleomycin (139,140). The severity of mucositis may be affected by aging, because age-related depletion of mucosal stem cells leads to delayed renewal of epithelial cells in the mucosa (141-143). In clinical trials, however, an increased degree of mucositis is not demonstrated in the elderly.

Efficacy of Chemotherapy

Tumor cell sensitivity to chemotherapy

Little information is available on the chemosensitivity of tumors from ordinary experimental studies on a correlation between the age of animals and tumor growth, or from histopathological studies on the association between the age of patients and both tumor type and differentiation (144,145). Recent advances in cell biology, however, are yielding new findings from which we can understand the PD of tumor cells and aging. Proposed age-related changes in tumor cells are overexpression of p-glycoprotein, a higher concentration of glutathione reductase, increased hypoxia, abnormal protein synthesis with production of abnormal topoisomerase I and II, alteration in intracellular metabolism of drugs, and decreased DNA repair of genotoxic lesions (23,144,146-149). Of these, an association between increased p-glycoprotein expression and a poor complete remission rate has been demonstrated in elderly patients with acute leukemia (150-152).

Results of clinical trials for solid tumors

According to a review of 19 ECOG trials involving 5459 patients (of these, 935 were aged >70 years), in general, there is no meaningful difference in response to chemotherapy and survival between elderly and younger patients with solid tumors (96). However, further discussion is necessary in some fields. Although chemotherapy for metastatic breast cancer in elderly patients produces a response rate and survival comparable to those in younger patients (67,153), adjuvant chemotherapy following surgery does not appear to be beneficial in patients aged >70 years (154). In the treatment of small-cell lung cancer, advanced age is an adverse prognostic factor in some studies (155-157), but not in others (68,69,158,159). Begg et al. (96) reported in 1983 that advanced age was associated with poor tumor response and survival in patients with ovarian cancer. Recent experience, however, revealed that progression-free survival and overall survival of these patients were not affected by age (160).

Results of clinical trials for hematological malignancies

The influence of aging on treatment outcome largely depends on the type of malignancy. There is no difference in the response rate to chemotherapy and survival between elderly and younger patients with myeloma (71), whereas elderly patients with Hodgkin's disease (72,161) have poorer responses and survival than younger patients. Results of treatment for non-Hodgkin lymphoma are controversial (73-75,162-165). Advancing age is associated with suppressed rates of response to chemotherapy and survival in patients with leukemia (76,77,162,166,167), although there are clinical trials providing exceptions (168,169).

LIMITATION OF THIS REVIEW AND FUTURE DIRECTIONS

Because most clinical studies reviewed here are retrospective, we should evaluate these results with caution. Toxicity data would be reliable if each patient were queried specifically as to the occurrence of various possible adverse effects. However, because it is often difficult to predict an uncommon adverse reaction to a drug, toxicity relatively common in elderly patients but rare in younger patients, e.g. central neurotoxicity such as dementia, may be overlooked. Comparison of survival between elderly and younger patients may lead to a biased conclusion, because other prognostic factors are not controlled.

Since elderly patients entered in clinical trials are highly selective, results obtained in these trials cannot fit all elderly patients who need cytotoxic therapy. Oshita et al. (170) prospectively evaluated the feasibility of cisplatin-based chemotherapy in patients aged >75 years with advanced lung cancer who had normal organic functions and ECOG performance status scores of 0-1. Of 34 patients with lung cancer, only 10 (29%) were eligible for this study. The reasons for exclusion were ischemic heart disease in 14, poor performance status in 11, renal dysfunction in 10 and abnormal ECG without ischemia in nine patients, and eight patients had two or more reasons.

The following issues should be studied prospectively in future trials. First, the standard chemotherapy established for non-elderly patients may be effective as well in the elderly with acceptable toxicity. Second, dose modification based on PK would be useful in the treatment of these patients. Gelman and Taylor (171) successfully reduced the toxicity of chemotherapy consisting of cyclophosphamide, methotrexate and 5-fluorouracil in women over age 65 with advanced breast cancer, without a decrease in efficacy, by modifying the initial doses of cyclophoshamide and methotrexate in proportion to pre-treatment creatinine clearance. Third, hematopoietic growth factors may be of great value in the elderly, although they produce only limited benefits in younger patients (172,173). Several randomized studies demonstrated that both mortality associated with neutropenia and survival were significantly improved by using these cytokines in elderly patients with acute leukemia (174,175). Finally, a patient's tolerance to chemotherapy would correlate better with `biological age' than with `chronological age', because the rate of aging is not uniform among all individuals. This measure could be estimated from external appearance, physical strength, physiological function tests and laboratory examinations (176,177). Among important fields of future research is identifying biomarkers which are validated and weighed according to their correlation with the degree of chemotherapy-induced toxicity, mortality and survival.

As the size of the geriatric population grows, it is increasingly important to be familiar with cancer treatment in this group. Advanced chronological age alone is not always a poor prognostic factor, and many elderly patients with cancer will benefit from chemotherapy. To answer many questions regarding the optimal treatment for these patients, the influence of age should be analyzed by a multivariate approach in future studies.

Acknowledgment

This work was supported in part by grants-in-aid for cancer research from the Ministry of Health and Welfare of Japan.

References

1. Berkman B, Rohan B, Sampson S. Myths and biases related to cancer in the elderly. Cancer 1994;74(7 suppl):2004-8. MEDLINE Abstract

2. Samet J, Hunt WC, Key C, Humble CG, Goodwin JS. Choice of cancer therapy varies with age of patients. J Am Med Assoc 1986;255:3385-90.

3. Fentiman IS, Tirelli U, Monfardini S, Schneider M, Festen J, Cognetti, et al. Cancer in the elderly: why so badly treated? Lancet 1990;335:1020-2. MEDLINE Abstract

4. Fentiman IS. Treatment of cancer in the elderly. Br J Cancer 1991;64:993-5. MEDLINE Abstract

5. Greenblatt DJ. Elimination half-life of drugs: value and limitations. Annu Rev Med 1985;36:421-7. MEDLINE Abstract

6. Montamat SC, Cusack BJ, Vestal RE. Management of drug therapy in the elderly. N Engl J Med 1989;321:303-9. MEDLINE Abstract

7. Greenblatt DJ, Sekkers EM, Shader RI. Drug disposition in old age. N Engl J Med 1982;306:1081-8. MEDLINE Abstract

8. Robert J, Hoerni B. Age dependence of the early-phase pharmacokinetics of doxorubicin. Cancer Res 1983;43:4467-9. MEDLINE Abstract

9. Lind MJ, Margison JM, Cerny T, Thatcher N, Wilkinson PM. The effect of age on the pharmacokinetics of ifosfamide. Br J Clin Pharmacol 1990; 30:140-3. MEDLINE Abstract

10. Fujiwara Y, Ohune T, Niitani K, Okusaki K, Sumiyoshi H, Ohashi N, et al. Clinical pharmacological profile of etoposide in the elderly. Proc Am Soc Clin Oncol 1996;15:174.

11. Egorin MJ, Zuhowski EG, Thompson B, Reich L, Lee EJ, Reck K, et al. Age-related alterations in daunorubicin pharmacokinetics. Proc Am Soc Clin Oncol 1987;6:38.

12. Kokenberg E, Sonneveld P, Sizoo W, Hagenbeek A, Löwenberg B. Cellular pharmacokinetics of daunorubicin: Relationships with the response to treatment in patients with acute myeloid leukemia. J Clin Oncol 1988;6: 802-12. MEDLINE Abstract

13. Miya T, Sasaki Y, Karato A, Saijo N. Pharmacokinetic study of mitomycin C with emphasis on the the influence of aging. Jpn J Cancer Res 1992;83: 1382-5. MEDLINE Abstract

14. Yamamoto N, Tamura T, Maeda M, Ando M, Shinkai T, Eguchi K, et al. The influence of ageing on cisplatin pharmacokinetics in lung cancer patients with normal organ function. Cancer Chemother Pharmacol 1996;36:102-6.

15. Kristensen LO, Weismann K, Hutters L. Renal function and the rate of disappearance of methotrexate from serum. Eur J Clin Pharmacol 1975;8:439-44. MEDLINE Abstract

16. Kerr IG, Jolivet J, Collins JM, Drake JC, Chabner BA. Test dose for predicting high-dose methotrexate infusions. Clin Pharmacol Ther 1983;33:44-51. MEDLINE Abstract

17. Milano G, Etienne MC, Thyss C-VA, Frenay JSM, Renee N, Schneider M, et al. Influence of sex and age on fluorouracil clearance. J Clin Oncol 1992;10:1171-5. MEDLINE Abstract

18. Miller CB, Piantadosi S, Vogelsang GB, Marcellus DC, Grochow L, Kennedy MJ, et al. The impact of age on outcome of patients undergoing autologous bone marrow transplant. J Clin Oncol 1996;14:1327-32. MEDLINE Abstract

19. Borkowski JM, Duerr M, Donehower RC, Rowinsky EK, Chen T-L, Ettinger DS, et al. Relation between age and clearance rate of nine investigational anticancer drugs from phase I pharmacokinetic data. Cancer Chemother Pharmacol 1994;33:493-6. MEDLINE Abstract

20. Geokas MC, Haverback BJ. The aging gastrointestinal tract. Am J Surg 1969;117:881-92. MEDLINE Abstract

21. Reinus JF, Brandt LJ. Effects of aging on digestive function, disorders, and diseases. In: Haubrich WS, Schaffner F, Berk JE, editors. Gastroenterology, 5th edn. Philadelphia: WB Saunders 1995;3301-12.

22. Texter EC. The splanchnic circulation and nutrition absorption in the aging patient. In: Texter EC, editor. The Aging Gut. New York: Masson Publishing USA Inc. 1983;13-20.

23. Balducci L, Parker M, Sexton W, Tantranond P. Pharmacology of antineoplastic agents in the elderly patient. Semin Oncol 1989;16:76-84. MEDLINE Abstract

24. Schneider M. Cancer chemotherapy in the elderly. In: Schilsky RL, Milano GA, Ratain MJ, editors. Principles of Antineoplastic Drug Development and Pharmacology. New York: Maecel Dekker Inc. 1996;363-73.

25. Cohen JL. Pharmacokinetic changes in aging. Am J Med 1986;80(suppl. 5A):31-8. MEDLINE Abstract

26. Bruce A, Andersson M, Arvidsson B. Body composition. Prediction of normal body potassium, body water and fat in adults on the basis of body height, body weight and age. Scand J Clin Lab Invest 1980;40:461-73. MEDLINE Abstract

27. Forbes GB, Reina JC. Adult lean body mass declines with age: some longitudinal observations. Metabolism 1970;19:653-63. MEDLINE Abstract

28. Novak LP. Aging, total potassium, fat free mass and cell mass in males and females between the ages of 18 and 85 years. J Gerontol 1972;27:438-43. MEDLINE Abstract

29. Doroshow JH. Anthracyclines and anthracenediones. In: Chapner BA, Longo DL, editors. Cancer Chemotherapy and Biotherapy, 2nd edn. Philadelphia: Lippincott-Raven 1996;409-34.

30. Byrne A, Carney DN. Cancer in the elderly. Curr Problems Cancer 1993;17:149-217.

31. Wallace S, Whiting B, Runcie J. Factor affecting drug binding in plasma of elderly patients. Br J Clin Pharmacol 1976;3:327-30. MEDLINE Abstract

32. Bender A, Post A, Meier J Higson J, Reichard G. Plasma protein binding of drugs as a function of age in adult human subjects. J Pharm Sci 1975;64:1711-13. MEDLINE Abstract

33. Aramaki T, Terada H, Okumura H. Liver dysfunction in the elderly and its management. ICU [amp] CCU 1997;21:189-96 (in Japanese).

34. Reed AH, Cannon DC, Winkelman JW, Bhasin YP, Henry RJ, Pileggi VJ. Estimation of normal ranges from a controlled sample survey. I. Sex- and age-related influence on the SMA 12/60 screening group of tests. Clin Chem 1972;18:57-66. MEDLINE Abstract

35. Kelso T. Laboratory values in the elderly. Emerg Med Clin North Am 1990;8:241-54. MEDLINE Abstract

36. Wynne HA, Cope LH, Mutch E, RawlinsMD, Woodhouse KW, James OFW. The effect of age upon liver volume and apparent liver blood flow in healthy man. Hepatology 1989;9:297-301. MEDLINE Abstract

37. Vestal RE. Aging and determinants of hepatic drug clearance. Hepatology 1989;9:331-4. MEDLINE Abstract

38. Durnas C, Loi C, Cusack BJ. Hepatic drug metabolism and aging. Clin Pharmacokinet 1990;19:359-89. MEDLINE Abstract

39. Brodie MJ, Boobis AR, Bulpitt CJ, Davies DS. Influence of liver disease and environmental factors on hepatic monooxygenase activity in vitro. Eur J Clin Pharmacol 1981;20:39-46. MEDLINE Abstract

40. Woodhouse KW, Mutch E, Williams FM, Rawlins MD, James OF. The effect of age on pathways of drug metabolism in human liver. Age Ageing 1984;13:328-34. MEDLINE Abstract

41. Kitani K. Drugs and the aging liver. Life Chem Rep 1988;6:143-230.

42. Woodhouse KW, James OFW. Hepatic drug metabolism and ageing. Br Med Bull 1990;46:22-35. MEDLINE Abstract

43. Brown WW, Davis BB, Sory LA, Eongsurawat N, Mallone JD, Domoto DT. Aging and the kidney. Arch Intern Med 1986;146:1790-6. MEDLINE Abstract

44. Anderson S, Mrenner BM. Effects of aging on the renal glomerulus. Am J Med 1986;80:435-42. MEDLINE Abstract

45. Custer RP, Ahlfeldt EF. Studies on structure and function of bone marrow. II. Variations in cellularity in various bones with advancing years of life and their relative response to stimuli. J Lab Clin Med 1932;17:960-2.

46. Hartsock RJ. Smith EB, Petty CS. Normal variations with aging on the amount of hematopoietic tissue in bone marrow from the anterior iliac crest. Am J Clin Pathol 1965;43:326-31.

47. Ricci C, Cova M, Kang YS, Yang A, Rahmouni A, Scott WW Jr, et al. Normal age-related patterns of cellular and fatty bone marrow distribution in the axial skeleton: MR imaging study. Radiology 1990;177:83-8. MEDLINE Abstract

48. Lipschitz DA, Udupa KB, Milton KY, Thompson CO. Effect of age on hematopoiesis in man. Blood 1984;63:502-9. MEDLINE Abstract

49. Mori M, Tanaka A, Sato N. Hematopoietic stem cells in elderly people. Mech Ageing Dev 1986;37:41-7. MEDLINE Abstract

50. Chatta GS, Andrews RG, Rodger E, Schrag M, Hammond WP, Dale DC. Hematopoietic progenitors and aging: alterations in granulocytic precursors and responsiveness to recombinant human G-CSF, GM-CSF, and IL-3. J Gerontol 1993;48:M207-12. MEDLINE Abstract

51. Lipschitz DA, Udupa KB. Age and the hematopoietic system. J Am Geriatr Soc 1986;34:448-54. MEDLINE Abstract

52. Chatta GS, Price TH, Allen RC, Dale DC. Effects of in vivo recombinant methionyl human granulocyte colony-stimulating factor on the neutrophil response and peripheral blood colony-forming cells in healthy young and elderly adult volunteers. Blood 1994;84:2923-9. MEDLINE Abstract

53. Kario K, Matsuno T, Nakao K. Serum erythropoietin levels in the elderly. Gerontology 1991;37:345-8. MEDLINE Abstract

54. Kawakami M, Tsutsumi H, Kumakawa T, Abe H, Hirai M, Kurosawa S, et al. Levels of serum G-CSF in patients with infections. Blood 1990;76:1962-4. MEDLINE Abstract

55. Price TH, Chatta GS, Dale DC. Effect of recombinant granulocyte colony-stimulating factor on neutrophil kinetics in normal young and elderly humans. Blood 1996;88:335-40. MEDLINE Abstract

56. Chatta GS, Price TH, Stratton JR, Dale DC. Aging and marrow neutrophil reserves. J Am Geriatr Soc 1994;42:77-81. MEDLINE Abstract

57. Shank W, Balducci L. Recombinant hematopoietic growth factors: comparative hematopoietic response in younger and older subjects. J Am Geriatr Soc 1992;40:151-4. MEDLINE Abstract

58. Lee MA, Segal GM, Bagby GC. The hematopoietic microenvironment in the elderly: defects in IL-1-induced CSF expression in vitro. Exp Hematol 1989;17:952-6. MEDLINE Abstract

59. Lipschitz DA, Udupa KB, Boxer LA. Evidence that microenvironment factors account for the age-related decline in neutrophil function. Blood 1987;70:1131-5. MEDLINE Abstract

60. Bowen KJ, Eckardt J, Clark G, Koeller J, Barker L, Burris HA, et al. The impact of patient age on the outcome of phase I trials. Proc Am Soc Clin Oncol 1993;12:184.

61. Borkowski JM, Duerr M, Donehower RC, Rowinsky EK, Chen T-L, Ettinger DS, et al. Relation between age and clearance rate of nine investigational anticancer drugs from phase I pharmacokinetic data. Cancer Chemother Pharmacol 1994;33:493-6. MEDLINE Abstract

62. Monfardini S, Sorio R, Renard J, Kaye S, van Glabbeke M. Entry of elderly patients in EORTC new drug development studies. Proc Am Soc Clin Oncol 1993;12:132.

63. Giovanazzi-Bannon S, Rademaker A, Lai G, Benson III AB. Treatment tolerance of elderly cancer patients entered onto phase II clinical trials: An Illinois Cancer Center Study. J Clin Oncol 1994;12:2447-52. MEDLINE Abstract

64. Begg CB, Elson PJ, Carbone PP. A study of excess hematologic toxicity in elderly patients treated on cancer chemotherapy protocols. In: Yancik R, Yates JW, editors. Cancer in the Elderly. New York: Springer Publishing Co. 1989;149-63.

65. Begg CB, Cohen JL, Ellerton J. Are the elderly predisposed to toxicity from cancer chemotherapy? Cancer Clin Trial 1980;3:369-74.

66. Christman K, Muss HB, Case LD, Stanley V. Chemotherapy of metastatic breast cancer in the elderly. J Am Med Assoc 1992;268:57-62.

67. Poplin E, Thompson B, Whitacre M, Aisner J. Small cell carcinoma of the lung: Influence of age on treatment outcome. Cancer Treat Rep 1987;71:291-6. MEDLINE Abstract

68. Ohnoshi T, Ueoka H, Hino N, Yonei T, Horiguchi T, Kiura K, et al. Treatment of small cell lung cancer in the elderly: The progress and limitation of chemotherapy. Nippon Kyobu Shikkan Gakkai Zasshi 1992;30:216-23 (in Japanese). MEDLINE Abstract

69. Kubota K, Furuse K, Kawahara M, Kodama N, Ogawara M, Tanaka M, et al. Cisplatin-based combination chemotherapy for elderly patients with non-small cell lung cancer. Cancer Chemother Pharmacol 1997;40:469-74. MEDLINE Abstract

70. Cohen HJ, Bartolucci A. Age and the treatment of multiple myeloma. Southeastern Cancer Study Group experience. Am J Med 1985;79:316-24. MEDLINE Abstract

71. Peterson BA, Pajak TF, Cooper MR, Nissen NI, Glidewell OJ, Holland JF, et al. Effect of age on therapeutic response and survival in advanced Hodgkin's disease. Cancer Treat Rep 1982;66:889-98. MEDLINE Abstract

72. Dixon DO, Neilan B, Hones SE, Lipschitz DA, Miller TP, Grozea PN, 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. MEDLINE Abstract

73. Vose JM, Armitage JO, Weisenburger DD, Bierman PJ, Sorensen S, Hutchins M, et al. The importance of age in survival of patients treated with chemotherapy for aggressive non-Hodgkin's lymphoma. J Clin Oncol 1988;6:1838-44. MEDLINE Abstract

74. Grogan L, Corbally N, Dervan PA, Byrne A, Carney DN. Comparable prognostic factors and survival in elderly patients with aggressive non-Hodgkin's lymphoma treated with standard-dose adriamycin-based regimens. Ann Oncol 1994;5(suppl. 2):S47-51.

75. Kantarjian HM, Brien SO, Smith T, Estey EH, Beran M, Preti A, et al. Acute lymphocytic leukemia in the elderly: characteristics and outcome with the vincristine-adriamycin-dexamethasone (VAD) regimen. Br J Haematol 1994;88:94-100. MEDLINE Abstract

76. ReesJKH, Gray RG, Wheatley K. Dose intensification in acute myeloid leukemia: greater effectiveness at lower cost. Principal report of the Medical Research Council's AML9 study. Br J Haematol 1996;94:89-98.

77. Ben-Yehuda A, Weksler ME. Host resistence and the immune system. Clin Geriatr Med 1992;8:701-23. MEDLINE Abstract

78. Saltzman RI, Peterson PK. Immunodeficiency of the elderly. Rev Infect Dis 1987;9:1127-39.

79. Wick G, Grubeck-Loebenstein B. Primary and secondary alterations of immune reactivity in the elderly: impact of dietary factors and disease. Immunol Rev 1997;160:171-84. MEDLINE Abstract

80. George AJT, Ritter MA. Thymic involution with aging: obsolescence or good housekeeping? Immunol Today 1996;17:267-72.

81. Miller RA. Aging and immune function. Int Rev Cytol 1991;124:187-215. MEDLINE Abstract

82. Franceschi C, Monti D, Barbieri D, Grassilli E, Troiano L, Salvioli S, et al. Immunosenescence in humans: deterioration or remodelling?. Int Rev Immunol 1995;12:57-74. MEDLINE Abstract

83. Miller RA. The aging immune system: primer and prospectus. Science 1996;273:70-4. MEDLINE Abstract

84. Gillis S, Kozak R, Durante M, Weksler ME. Immunological studies of aging. Decreased production of and response to T-cell growth factor by lymphocytes from aged humans. J Clin Invest 1981;67:937-42. MEDLINE Abstract

85. Nagel JE, Chopra RK, Chrest FJ, McCoy MT, Schneider EL, Holbrook NJ, et al. Decreased proliferation, interleukin 2 synthesis, and interleukin 2 receptor expression are accompanied by decreased mRNA expression in phytohemagglutinin-stimulated cells from elderly donors. J Clin Invest 1988;81:1096-102. MEDLINE Abstract

86. Negoro S, Hara H, Miyata S, Saiki O, Tanaka T, Yoshizaki K, et al. Mechanisms of age-related decline in antigen-specific T cell proliferative response: IL-2 receptor expression and recombinant IL-2 induced proliferative response of purified Tac-positive T cells. Mech Ageing Dev 1986;36:223-41. MEDLINE Abstract

87. Yang X, Stedra J, Cerny J. Relative contribution of T and B cells to hypermutation and selection of the antibody repertoire in germinal centers of aged mice. J Exp Med 1996;183:959-70. MEDLINE Abstract

88. Schulze DH, Goidl EA. Age-associated changes in antibody-forming cells (B cells). Proc Soc Exp Biol Med 1991;196:253-9. MEDLINE Abstract

89. Beckman I, Dimopoulos K, Xu XN, Bradley J, Henschke P, Ahern M. T cell activation in the elderly: evidence for specific deficiencies in T cell/accessory cell interactions. Mech Ageing Dev 1990;51:265-76. MEDLINE Abstract

90. Rich EA, Mincek MA, Armitage KB, Duffy EG, Owen DC, Fayen JD, et al. Accessory function and properties of monocytes from healthy elderly humans for T lymphocyte responses to mitogen and antigen. Gerontology 1993;39:93-108. MEDLINE Abstract

91. Fagiolo U, Cossarizza A, Scala E, Fanales-Belasio E, Ortolani C, Cozzi E, et al. Increased cytokine production in mononuclear cells of healthy elderly people. Eur J Immunol 1993;23:2375-8. MEDLINE Abstract

92. Dixon CL, Valdivieso M, Umsawasdi T, Dubois G, Patton D, Chen T, et al. Small cell bronchogenic carcinoma: factors associated with pneumonia during chemotherapy. J Clin Oncol 1984;2:201-6. MEDLINE Abstract

93. Glucksberg H, Cheever MA, Farewell VT, Fefer A, Sale GE, Thomas ED. High-dose combination chemotherapy for acute nonlymphoblastic leukemia in adults. Cancer 1981;48:1073-81. MEDLINE Abstract

94. Yates J, Glidewell O, Wiernik P, Cooper MR, Steinberg D, Dosik H, et al. Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia: a CALGB study. Blood 1982;60:454-62. MEDLINE Abstract

95. Begg CB, Carbone PP. Clinical trials and drug toxicity in the elderly. Cancer 1983;52:1986-92. MEDLINE Abstract

96. Lakatta EG, Gerstenblith G, Weisfeldt ML. The aging heart: structure, function, and disease. In: Braunwald E, editor. Heart Disease, 5th edn. Philadelphia: WB Saunders Co. 1997;1687-703.

97. Olivetti G, Giordano G, Corradi D, Melissari M, Lagrasta C, Gambert SR, et al. Gender differences and aging: effects on the human heart. J Am Coll Cardiol 1995;26:1068-79. MEDLINE Abstract

98. Kitzman DW, Scholz DG, Hagen PT, Ilstrup DM, Edwards WD. Age-related changes in normal human hearts during the first 10 decades of life. Part II (Maturity): A quantitative anatomic study of 765 specimens from subjects 20 to 99 years old. Mayo Clin Proc 1988;63:137-46. MEDLINE Abstract

99. Kitzman DW, Edwards WD. Age-related changes in the anatomy of the normal human heart. J Gerontol 1990;45:M33-9. MEDLINE Abstract

100. Fleg JL, O'Connor F, Gerstenblith G, Becker LC, Clulow J, Schulman SP, et al. Impact of age on the cardiovascular response to dynamic upright exercise in healthy men and women. J Appl Physiol 1995;78:890-900. MEDLINE Abstract

101. Dolgin M. Cardiac arrhythmias in the elderly: selected aspects. Mt Sinai J Med 1985;52:601-9. MEDLINE Abstract

102. Fleg JL, Kennedy HL. Cardiac arrhythmias in a healthy elderly population. Chest 1982;81:302-7. MEDLINE Abstract

103. Manolio TA, Furberg CD, Rautaharju PM, Siscovick D, Newman AB, Borhani NO, et al. Cardiac arrhythmias on 24-h ambulatory electrocardiography in older women and men: the Cardiovascular Health Study. J Am Coll Cardiol 1994;23:916-25. MEDLINE Abstract

104. Fleg JL, Lakatta EG. Prevalence and prognosis of exercise-induced nonsustained ventricular tachycardia in apparently healthy volunteers. Am J Cardiol 1984;54:762-4. MEDLINE Abstract

105. Allen A. The cardiotoxicity of chemotherapeutic drugs. In: Perry MC, editor. The Chemotherapy Source Book. Baltimore: Williams [amp] Wilkins 1992;582-97.

106. Von Hoff DD, Rozencweig M, Piccart M. The cardiotoxicity of anticancer agents. Semin Oncol 1982;9:23-33. MEDLINE Abstract

107. Praga C, Beretta G, Vigo PL, Lenaz GR, Pollini C, Bonadonna G, et al. Adriamycin cardiotoxicity: a survey of 1273 patients. Cancer Treat Rep 1979;63:827-34. MEDLINE Abstract

108. Bristow MR, Mason JW, Billingham ME, Daniels JR. Doxorubicin cardiomyopathy: evaluation by phonocardiography, endomyocardial biopsy, and cardiac catheterization. Ann Intern Med 1978;88:168-75. MEDLINE Abstract

109. Von Hoff DD, Layard MW, Basa P, Davis HL Jr, Von Hoff AL, Rozencweig M, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979;91:710-7. MEDLINE Abstract

110. Bristow MR, Billingham ME, Mason JW, Daniels JR. Clinical spectrum of anthracycline antibiotic cardiotoxicity. Cancer Treat Rep 1978;62:873-9. MEDLINE Abstract

111. Dresdale A, Bonow RO, Wesley R, Palmeri ST, Barr L, Mathison D, et al. Prospective evaluation of doxorubicin-induced cardiomyopathy resulting from postsurgical adjuvant treatment of patients with soft tissue sarcomas. Cancer 1983;52:51-60. MEDLINE Abstract

112. Von Hoff DD, Rozencweig M, Layard M, Slavik M, Muggia FM. Daunomycin-induced cardiotoxicity in children and adults. Am J Med 1977;62:200-8. MEDLINE Abstract

113. Knudson RJ. Physiology of the aging lung. In: Crystal RG, West JB, editors. The Lung. New York: Raven Press 1991;1749-59.

114. Thurlbeck WM. Morphology of the aging lung. In: Crystal RG, West JB, editors. The Lung. New York: Raven Press 1991;1743-8.

115. Kreisman H, Wolkove N. Pulmonary toxicity of antineoplastic therapy. In: Perry MC, editor. The Chemotherapy Source Book. Baltimore: Williams [amp] Wilkins 1992;598-619.

116. Ginsberg SJ, Comis RL. The pulmonary toxicity of antineoplastic agents. Semin Oncol 1982;9:34-51. MEDLINE Abstract

117. Haas CD, Coltman CA Jr, Gottlieb JA, Haut A, Luce JK, Talley RW, et al. Phase II evaluation of bleomycin. A Southwest Oncology Group study. Cancer 1976;38:8-12. MEDLINE Abstract

118. Parvinen LM, Kilkku P, Makinen E, Liukko P, Gronroos M. Factors affecting the pulmonary toxicity of bleomycin. Acta Radiol Oncol 1983;22:417-21. MEDLINE Abstract

119. Fields KK, Elfenbein GJ. Bone marrow transplantation in the older patients. In: Balducci L, Lyman GH, Ershler WB, editors. Geriatric Oncology. Philadelphia: JB Lippincott 1992;190-8.

120. Hof PR, Glannakopoulos P, Bouras C. The neuropathological changes associated with normal brain aging. Histol Histopathol 1996;11:1075-88. MEDLINE Abstract

121. Adams R, Victor M. Principles of Neurology, 3rd edn. New York: McGraw-Hill Book Co. 1985;449-58.

122. Taveras JM, Pile-Spellman J. Degenerative conditions. In: Taveras JM, Pile-Spellman J, editors. Neuroradiology, 3rd edn. Baltimore: Williams [amp] Wilkins 1996;365-87.

123. Meyer JS, Terayama Y, Takashima S. Cerebral circulation in the elderly. Cerebrovasc Brain Metab Rev 1993;5:122-46. MEDLINE Abstract

124. Chehrazi BB, Youmans JR. Cerebral blood flow in clinical neurosurgery. In: Youmans JR, editor. Neurological Surgery, 3rd edn. Philadelphia: WB Saunders Co. 1990;696-740.

125. Rapoport SI. Positron emission tomography in normal aging and Alzheimer disease. Gerontology 1986;32:6-13. MEDLINE Abstract

126. Naritomi H, Meyer JS, Sakai F, Yamaguchi F, Shaw T. Effects of advancing age on regional cerebral blood flow. Studies in normal subjects and subjects with risk factors for atherothrombotic stroke. Arch Neurol 1979;36:410-6. MEDLINE Abstract

127. Shah GN, Mooradian AD. Age-related changes in the blood-brain barrier. Exp Gerontol 1997;32:501-19. MEDLINE Abstract

128. Garton MJ, Keir G, Lakshmi MV, Thompson EJ. Age-related changes in cerebrospinal fluid protein concentrations. J Neurol Sci 1991;104:74-80. MEDLINE Abstract

129. Saija A, Princi P, Imperatore C, De Pasquale R, Costa G. Ageing influences haloperidol-induced changes in the permeability of the blood-brain barrier in the rat. J Pharm Pharmacol 1992;44:450-2. MEDLINE Abstract

130. Arasaki K, Iijima M, Nakanishi T. Normal maximal and minimal motor nerve conduction velocities in adults determined by a collision methods. Muscle Nerve 1991;14:647-53. MEDLINE Abstract

131. Kaplan RS, Wiernick PH. Neurotoxicity of antineoplastic drugs. Semin Oncol 1982;9:102-30.

132. Lee Y-Y, Navert C, Glass JP. Treatment-related white matter changes in cancer patients. Cancer 1986;57:1473-82. MEDLINE Abstract

133. Gottlieb D, Bradstock K, Koutts J, Robertson T, Lee C, Castaldi P. The neurotoxicity of high-dose cytosine arabinoside is age-related. Cancer 1987;60:1439-41. MEDLINE Abstract

134. Damon LE, Mass R, Linker CA. The association between high-dose arabinoside neurotoxicity and renal insufficiency. J Clin Oncol 1989;7:1563-8. MEDLINE Abstract

135. Schaefer SD, Post JD, Close LG, Wright CG. Ototoxicity of low- and moderate-dose cisplatin. Cancer 1985;56:1934-9. MEDLINE Abstract

136. Patterson WP, Reams GP. Renal and electrolyte abnormalities due to chemotherapy. In: Perry MC, editor. The Chemotherapy Source Book. Baltimore: Williams [amp] Wilkins 1992;648-65.

137. Hrushesky WJM, Shimp W, Kennedy BJ. Lack of age-dependent cisplatin nephrotoxicity. Am J Med 1984;76:579-84.

138. Saudes ATL, Otto J, Creisson A, Gaspard MH, Dassonville O, Schneider M. Renal tolerance of cisplatin in patients more than 80 years old. J Clin Oncol 1994;12:2121-5.

139. Peterson DE, Schubert MM. Oral toxicity. In: Perry MC, editor. The Chemotherapy Source Book. Baltimore: Williams [amp] Wilkins 1992;508-30.

140. Dreizen S. Description and incidence of oral complications. NCI Monogr 1990;9:11-15. MEDLINE Abstract

141. Mowry K, Haley JA. Pharmacology and organ toxicity of chemotherapy in older patients. Oncology 1992;6(suppl. 2):62-8.

142. Guggenheimer J, Verbin RS, Appel BN, Schmutz J. Clinicopathologic effects of cancer chemothereutic agents on human buccal mucosa. Oral Surg 1977;44:58-63.

143. Lockhart PB, Sonis ST. Relationship of oral complications to peripheral blood leukocyte and platelet counts in patients receiving cancer chemotherapy. Oral Surg 1979;48:21-8.

144. Ershler WB, Longo DL. Aging and cancer: issues of basic and clinical science. J Natl Cancer Inst 1997;89:1489-97. MEDLINE Abstract

145. Holmes FF. Clinical evidence for a change in tumor aggressiveness with age. Semin Oncol 1989;16:34-40. MEDLINE Abstract

146. Gupta S. P-glycoprotein expression and regulation. Age-related changes and potential effects on drug therapy. Drug Aging 1995;7:19-29.

147. Young SD, Hill RP. Effects of reoxygeneration on cells from hypoxic regions of solid tumors: anticancer drug sensitivity and metastatic potential. J Natl Cancer Inst 1990;82:371-80. MEDLINE Abstract

148. Lee SW, Fukunaga N, Rigney DR, Shin DY, Wei JY. Downregulation of DNA topoisomerase I in old versus young human diploid fibroblasts. Mutat Res 1997;373:179-84. MEDLINE Abstract

149. Weirich-Schwaiger H, Weirich HG, Gruber B, Schweiger M, Hirsch-Kauffmann M. Correlation between senescence and DNA repair in cells from young and old individuals and in premature aging syndromes. Mutat Res 1994;316:37-48. MEDLINE Abstract

150. Leith CP, Kopecky KJ, Godwin J, McConnell T, Slovak ML, Chen IM, et al. Acute myeloid leukemia in the elderly: assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group study. Blood 1997;89:3323-9. MEDLINE Abstract

151. List AF. The role of multidrug resistance and its pharmacological modulation in acute myeloid leukemia. Leukemia 1996;10(suppl. 1):S36-8. MEDLINE Abstract

152. Willman CL. Immunophenotyping and cytogenetics in older adults with acute myeloid leukemia: significance of expression of the multidrug resistance gene-1 (MDR1). Leukemia 1996;10(suppl. 1):S33-5. MEDLINE Abstract

153. Tormey DC, Gelman R, Band PR, Sears M, Rosenthal SN, DeWys W, et al. Comparison of induction chemotherapies for metastatic breast cancer. Cancer 1982;50:1235-44. MEDLINE Abstract

154. Early Breast Cancer Trialists' Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. Lancet 1992;339:71-85.

155. Osterlind K, Andersen PK. Prognostic factors in small cell lung cancer: multivariate model based on 78 patients treated with chemotherapy with or without irradiation. Cancer Res 1986;46:4189-94. MEDLINE Abstract

156. Albain KS, Crowley JJ, LeBlanc M, Livingston RB. Determinants of improved outcome in small-cell lung cancer: an analysis of the 2,580-patient Southwest Oncology Group data base. J Clin Oncol 1990;8:1563-74. MEDLINE Abstract

157. Feld R, Evans WK, Coy P, Hodson I, MacDonald AS, Osoba D, et al. Canadian multicenter randomized trial comparing sequential and alternating administration of two non-cross-resistant chemotherapy combinations in patients with limited small-cell carcinoma of the lung. J Clin Oncol 1987;5:1401-9. MEDLINE Abstract

158. Spiegelman D, Maurer LH, Ware JH, Perry MC, Chahinian AP, Comis R, et al. Prognostic factors in small-cell carcinoma of the lung: an analysis of 1,521 patients. J Clin Oncol 1989;7:344-54. MEDLINE Abstract

159. Souhami RL, Law K. Longevity in small cell lung cancer. A report to the Lung Cancer Subcommittee of the United Kingdom Coordinating Committee for Cancer Research. Br J Cancer 1990;61:584-9. MEDLINE Abstract

160. Swenerton K, Jeffrey J, Stuart G, Roy M, Krepart G, Carmichael J, et al. Cisplatin-cyclophosphamide versus carboplatin-cyclophosphamide in advanced ovarian cancer: a randomized phase III study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1992;10:718-26. MEDLINE Abstract

161. Enbald G, Glimelius B, Sundström C. Treatment outcome in Hodgkin's disease in patients above the age of 60: a population-based study. Ann Oncol 1991;2:297-302.

162. Walsh SJ, Begg CB, Carbone PP. Cancer chemotherapy in the elderly. Semin Oncol 1989;16:66-75. MEDLINE Abstract

163. Coiffier B. What treatment for elderly patients with aggressive lymphoma? Ann Oncol 1994;5:873-5. MEDLINE Abstract

164. Armitage JO, Potter JF. Aggressive chemotherapy for diffuse histiocytic lymphoma in the elderly: increased complications with advancing age. J Am Geriatr Soc 1984;32:269-73. MEDLINE Abstract

165. O'Reilly SE, Connors JM, Macpherson N, Klasa R, Hoskins P. Malignant lymphomas in the elderly. Clin Geriatr Med 1997;13:251-63. MEDLINE Abstract

166. Stasi R, Venditti A, Poeta GD, Aronica G, Dentamaro T, Cecconi M, et al. Intensive treatment of patients age 60 years and older with de novo acute myeloid leukemia. Cancer 1996;77:2476-88. MEDLINE Abstract

167. Burnett AK, Eden OB. The treatment of acute leukemia. Lancet 1997;349:270-5. MEDLINE Abstract

168. Foon KA, Zighelboim J, Yale C, Gale RP. Intensive chemotherapy is the treatment of choice for elderly patients with acute myelogenous leukemia. Blood 1981;58:467-70. MEDLINE Abstract

169. Cassileth PA, Begg CB, Bennett JM, Bozdech M, Kahn SB, Weiler C, et al. A randomized study of the efficacy of consolidation therapy in adult acute nonlymphocytic leukemia. Blood 1984;63:843-7. MEDLINE Abstract

170. Oshita F, Kurata T, Kasai T, Fukuda M, Yamamoto N, Ohe Y, et al. Prospective evaluation of the feasibility of cisplatin-based chemotherapy for elderly lung cancer patients with normal organic functions. Jpn J Cancer Res 1995;86:1198-202. MEDLINE Abstract

171. Gelman RS, Taylor SG IV. Cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy in women more than 65 years old with advanced breast cancer: the elimination of age trends in toxicity by using doses based on creatinine clearance. J Clin Oncol 1984;2:1404-13. MEDLINE Abstract

172. The American Society of Clinical Oncology. American Society of Clinical Oncology recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. J Clin Oncol 1994;2471-508.

173. The American Society of Clinical Oncology. Update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based clinical practice guidelines. J Clin Oncol 1996;14:1957-60.

174. Büchner T, Hiddemann W, Wörmann B, Zühlsdoef M, Rottman R, Innig G, et al. Hematopoietic growth factors in acute myeloid leukemia: supportive and priming effects. Semin Oncol 1997;24:124-31. MEDLINE Abstract

175. Buchner T, Hiddemann W, Koenigsmann M, Zuhlsdorf M, Wormann B, Boeckmann A, et al. Recombinant human granulocyte-macrophage colony-stimulating factor after chemotherapy in patients with acute myeloid leukemia at higher age or after relapse. Blood 1991;78:1190-7. MEDLINE Abstract

176. Uttley M, Crawford MH. Efficacy of a composite biological age score to predict ten-year survival among Kansas and Nebraska Mennonites. Hum Biol 1994;66:121-44. MEDLINE Abstract

177. Nakamura E. A study on the basic nature of human biological aging processes based upon a hierarchical factor solution of the age-related physiological variables. Mech Ageing Dev 1991;60:153-70. MEDLINE Abstract

Received May 13, 1998; accepted May 20, 1998
For reprints and all correspondence: Ikuo Sekine, Medical Oncology Division, National Cancer Center Hospital, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan. E-mail: isekine{at}gan2.ncc.go.jp
Abbreviations: PK, pharmacokinetics; PD, pharmacodynamics; AUC, area under the curve; MRI, magnetic resonance imaging; OR, odds ratio; ECOG, Eastern Cooperative Oncology Group; IL, interleukin; ECG, electrocardiography

This page is run by Oxford University Press, Great Clarendon Street, Oxford OX2 6DP, as part of the OUP Journals
Comments and feedback: www-admin{at}oup.co.uk
Last modification: 20 Aug 1998
Copyright©Japanese Journal of Clinical Oncology, 1998.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Jpn J Clin OncolHome page
T. Shimizu, I. Sekine, M. Sumi, Y. Ito, K. Yamada, H. Nokihara, N. Yamamoto, H. Kunitoh, Y. Ohe, and T. Tamura
Concurrent Chemoradiotherapy for Limited-disease Small Cell Lung Cancer in Elderly Patients Aged 75 Years or Older
Jpn. J. Clin. Oncol., April 10, 2007; (2007) hym005v1.
[Abstract] [Full Text] [PDF]

Home page
 Jpn J Clin OncolHome page
A. Inoue and N. Saijo
Recent Advances in the Chemotherapy of Non-small Cell Lung Cancer
Jpn. J. Clin. Oncol., July 1, 2001; 31(7): 299 - 304.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
A. Seluanov, V. Gorbunova, A. Falcovitz, A. Sigal, M. Milyavsky, I. Zurer, G. Shohat, N. Goldfinger, and V. Rotter
Change of the Death Pathway in Senescent Human Fibroblasts in Response to DNA Damage Is Caused by an Inability To Stabilize p53
Mol. Cell. Biol., March 1, 2001; 21(5): 1552 - 1564.
[Abstract] [Full Text]

This Article
Right arrow Abstract Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (17)
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Sekine, I
Right arrow Articles by Saijo, N
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sekine, I
Right arrow Articles by Saijo, N
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?