7
Relation to life expectancy, functional dependence, and tolerance to stress
Relation to life expectancy and tolerance to stress
Relation to life expectancy and dependence
Relation to survival; may indicate motivation to receive treatment
Reversible condition; possible relationship to survival
Risk of drug interactions
Relationship to survival
Functional dependence
It is important to avoid possible misinterpretation of the CGA. First of all, it should not be applied to acute situations. To diagnose functional dependence, the inability to perform ADLs or IADLs should be present as a chronic condition, not just during an acute episode that compels the patient to be bedridden. The same should be said of the so-called geriatric syndromes. Delirium is a geriatric syndrome if it occurs in the presence of a mild upper respiratory or urinary infection or upon administration of drugs that do not cause delirium commonly. Falls are a geriatric syndrome if they are frequent and without apparent causes. Second, a person who is able to compensate for a disability should not be considered dependent in ADLs (e.g., a paraplegic who is able to use a wheelchair is not dependent in transferring).
Dependence in ADLs, the presence of one or more geriatric syndromes, and severe comorbid conditions generally purport a very limited life expectancy and treatment tolerance and the majority of these individuals may be suitable only for palliative care. In any case, each situation should be evaluated individually and treated accordingly.
Figure 1.1 illustrates the approach recommended to the treatment of older individuals, based on the CGA. Alternative treatments may include chemotherapy at lower doses or alternative forms of chemotherapy that may be effective, albeit not as effective as the standard treatment. It may also include management of reversible conditions that prevent the administration of the most effective therapy (such as malnutrition or inadequate caregiver).
Fig. 1.1 CGA based approach to the treatment of the older cancer patient
Ultimately, the treatment-related decision will be negotiated with the patient and his/her caregiver. The CGA allows the practitioner to provide objective information related to the potential benefits and risks of the treatment, to foster realistic expectations, and to facilitate an informed decision. In a randomized study of patients with metastatic non-small cell lung cancer, this approach has led to the best quality care of these patients, that is, to a more prolonged survival at a decreased cost and with improved patient satisfaction [21]. These results were obtained because full information led to earlier participation in clinical trials, reduced use of third-line chemotherapy and of the intensive care, and better planning for end-of-life care.
Clearly, the management of the older cancer patient with systemic treatment is a team endeavor that involves the cooperation of aging and cancer specialists. While it may appear time and cost intensive, the team approach may eventually prevent the wasting of limited health-care resources, by avoiding futile treatment and its potential complications.
Controversy lingers concerning the best form of CGA and as to whether a full-fledged CGA is necessary in all patients. A number of investigators reported that time-sparing screening instruments, including the vulnerable elderly survey-13 (VES-13) [22], the study of osteoporotic fractures test (SOF) [23], the Groningen index [24], and the G-test [25], are as sensitive as a full CGA for the detection of aging-related abnormalities, while other authors did not confirm these findings [26, 27]. At the very minimum, it is important to assess those elements necessary to predict mortality and chemotherapy-related toxicity including ADLs, IADLs, polymorbidity, and nutritional and cognitive status [18–20]. Whenever the time allows it, the investigation of all domains of the CGA appears desirable.
Pharmacology of Aging
Aging may be associated with a number of pharmacologic changes described in Table 1.2 [28].
Table 1.2
Pharmacologic changes of aging
Pharmacokinetics Absorption Volume of distribution Metabolism Renal excretion Hepatic excretion | The effects of aging on absorption are unknown. It is reasonable to assume a progressive decrease in absorption due to atrophic gastritis, decreased gastric motility, and decreased splanchnic circulation Changes in body composition with increased fat and decreased water content Hepatic metabolism is reduced from progressive loss of liver mass and decreased splanchnic circulation Glomerular filtration rate declines with age in virtually all individuals Biliary excretion seems to remain intact |
Pharmacodynamics Hematopoietic system Mucosa epithelium Heart Peripheral nervous system Central nervous system | Decreased concentration of early hematopoietic progenitors, decreased lymphocytic production; homing abnormality that may reduce the concentration of early progenitors in the marrow Decreased epithelial stem cells and increased proliferation of differentiated cells Reduction in myocardial sarcomeres; increased fibrosis and degenerative processes (amyloid) Increased degenerative processes Atrophy and increase in degenerative processes with decreased circulation |
Pharmacokinetics
Data on drug absorption are wanted. This information is critical, given the rapid development of new oral antineoplastic agents during the past two decades. Data limited to imatinib [29] and oral idarubicin [30] suggest that the absorption of oral agents is unaffected by age. These studies included only elderly in good general conditions and under 85. It is reasonable to expect that bioavailability of an oral drug may decrease in some older individuals due to a combination of factors that include reduced splanchnic circulation, decreased gastrointestinal secretions, and mucosal atrophy [28]. Another issue related to oral drug is adherence to the treatment plans, as many older individuals are taking multiple medications and may find it difficult to remember to take each medication at the appointed time. An additional difficulty includes the presence of swallowing disorders, whose prevalence increases with age.
The decreased body total water content is associated with decreased volume of distribution and increased levels of water-soluble drugs in the circulation that may purport increased toxicity. The volume of distribution of hydrosoluble agents may also be determined in part by the concentration of plasmatic proteins and of hemoglobin, to which these drugs may be bound [31].
Renal excretion and hepatic metabolism of drugs are universally decreased with age. While the decline in glomerular filtration rate may be easily accounted for by calculating the creatinine clearance, a clinical test of hepatic metabolism is still wanted.
Pharmacodynamics
As already mentioned, a number of age-related changes in target organs may be associated with increased hematopoietic, mucosal, cardiac, and neurological toxicity. The risk of chemotherapy-induced neutropenia, of neutropenic infections, and of lethal neutropenic infections increases with the age of the patients [32]. Data on the incidence of chemotherapy-induced anemia and thrombocytopenia in older individuals are wanted, but it is clear that the prevalence of anemia and the risk of anemia-related medical complications increase with the age of the patients [31]. In about 50 % of cases, anemia in older individuals is reversible and should be aggressively managed with the double goal to improve the patient’s quality of life and energy levels and to prevent chemotherapy-related complications that are more frequent in the presence of anemia.
Mucositis, especially when it is associated to diarrhea and with dysphagia, may represent a cause of rapid fluid depletion and should be administered very aggressively.
Peripheral neuropathy is a common complication of platinum derivatives, alkaloids, and epothilones and it may be disabling for older individuals.
Cardiotoxicity is a complication of treatment with anthracyclines and anthracenediones and of the monoclonal antibody trastuzumab [33]. The risk of this complication increases with age. The cardiotoxicity from trastuzumab is reversible in the majority of cases upon drug withdrawal.
The information related to the toxicity of new targeted agents in older individuals is limited [34]. In general, these agents are better tolerated than cytotoxic chemotherapy, but even for them, the risk of complications seems to increase with age. In addition to the cardiotoxicity of trastuzumab [33] already mentioned, the risk of hypertension and bleeding with bevacizumab, of severe dermatitis with tyrosine kinase inhibitors (TKI) and anti-EGFR antibodies, and of fluid retention with imatinib is of special concern. In most cases, it is not clear whether the increased risk of toxicity is due to altered pharmacokinetics or pharmacodynamics (increased susceptibility of target tissues to treatment complications). In the case of imatinib, this issue has been studied in details and the increased toxicity was associated with an increased AUC of the drug in older individuals.
Late Complications of Cancer Treatment
Cancer chemotherapy may accelerate the aging process [35]. Almost 40 % of individuals treated for cancer during their childhood develop signs of frailty in their 30s versus 10 % of non-cancer controls. In 33 adult women with early-stage breast cancer [36], adjuvant chemotherapy has been associated with increased expression of aging markers (p16(INK4a) and ARF) in the tissues and increased concentration of inflammatory cytokines in the blood and these changes persisted for at least 1 year. These findings suggest that cytotoxic chemotherapy may accelerate the development of functional dependence in older individuals.
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