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Evaluation of the elderly with cancer

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Evaluation of the elderly with cancer Matti Aapro a, Martine Extermann b and Lazzaro Repetto c Institut Multidisciplinaire d'oncologie, Genolier, Switzerland b H. Lee Moffitt Cancer Center, University
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Evaluation of the elderly with cancer Matti Aapro a, Martine Extermann b and Lazzaro Repetto c Institut Multidisciplinaire d'oncologie, Genolier, Switzerland b H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL, USA c Division of Medical Oncology 1,1ST National Institute for Cancer Research, Genoa, Italy Introduction The simultaneous presence of several pathologies is a phenomenon that increases with age. Older patients will often present a high level of comorbidity (Table la and b), [1], but remarkably those cancer patients referred to cancer centres will in general be less affected than other elderly people, as exemplified in results of the Gruppo Italiano di Oncologia Geriatrica (Table 2) looking at various parameters of geriatric evaluation. In the past, such patients have been traditionally excluded from oncological studies. Thus, while 60% of the cancers arise beyond the age of 65, only 20-40% of phase II and HI study patients are in this age range, a large proportion of them being younger than 70 [2]. Oncologists face then a major problem if they want to adapt the results of cooperative studies to the treatment of patients with comorbid diseases. A solution for the future may be to integrate evaluation of comorbidities into oncological studies, in the same way that functional status presently is. As functional status does not appear to correlate closely with either tumour stage or comorbidity [3], comorbidity should be assessed independently. However, contrary to functional status, comorbidity presents the unique challenge of being a multidimensional variable, and diseases influencing mortality may not be the same as diseases influencing function, or tolerance to treatment. Assessment of the patient's disease stage Detection of cancer at an early stage, by screening asymptomatic persons who are at risk for cancer, has the aim of decreasing the number of cancer-related deaths. There are, however, no accepted guidelines for cancer screening in older people, since reduced life expectancy and competing causes of death are considered to worsen the cost/effectiveness ratio of screening tests in the aged [4]. Another reason for advanced stage in most but not all cancers of the elderly is related to late diagnosis and referral by family doctors (General practitioners, GPs). GPs care in most countries for the majority of the population and play a key role in screening asymptomatic subjects, and assessing initial symptoms, then monitoring therapeutic results, including side effects. They may be reluctant to send elderly people for treatment and are often a cause of delay [5]. Once diagnosed with cancer, patients are submitted to staging procedures which should be the same at any age. Unfortunately there is ample evidence that elderly patients are incorrectly staged and sometimes even a positive histologic proof of malignancy is not obtained [6]. Operative risk assessment This point has been recently reviewed extensively [7]. Operating even the very elderly for orthopaedic or cardiovascular diseases is accepted as a routine measure, but there is continued reluctance to recommend aggressive interventions for surgically curable malignancies. Remarkably, studies show that reluctance to advise or to accept an operation is often unrelated to the presence of co-existing debilitating conditions or impaired functional status. Operative mortality has been reduced considerably as the consequence of improvements in anaesthetic and surgical techniques, the availability of new drugs and optimised postoperative care. Obviously, careful evaluation of kidney, liver and cardiac functions are essential and will lead to adapted drug doses and specific types of anaesthesia. While emergency surgery remains a major cause of perioperative death in the elderly, elective operations are a well-controlled procedure, with costs which are similar to those of the younger patients [8]. 223 224 M. Aapro M. Extermann and L. Repetto Table 1 Gruppo Italiano di Oncologia Geriatrica (GIO Ger.) results % Females N % ' 19.5 Tumour sites Total Males N % N (a) 10 most prevalent comorbid conditions among 363 cancer patients Arthrosis-arthritis Hypertension Digestive diseases Cardiac diseases Vascular diseases Genitourinary diseases Other CNS diseases COPD Depression Diabetes Osteoporosis (b) 10 most prevalent comorbid conditions among 292 non-cancer patients Hypertension Arthrosis-arthritis Cardiac diseases Vascular diseases Digestive diseases Osteoporosis Diabetes COPD Depression Metabolic diseases Table 2 Cancer patients referred to a cancer centre and age-matched elderly patients: differences in various parameters Variables Cancer patients (N = 363) Non-cancer patients (N = 292) N % N % M/F rate Comorbid condition 0-1 Performance status 0-1 ADL independent 1ADL independent GDS normal MMS normal 168/ / ADL = activities of daily life; 1ADL = instrumental activities of daily life; GDS = geriatric depression scale; MMS = mini-mental status Fitness for radiation therapy In spite of a general belief that tolerance to radical radiotherapy might be compromised in older patients, the majority of patients treated by radiation oncologists are old and these treatments are usually conducted without major problems [9]. Survival between the different age groups of patients treated with radiotherapy for head and neck or pelvic malignancies is similar and as for surgery, there is no reason to modify the therapeutic approach on the basis of age alone. There is a need for assessing separately the effects of age and of comorbidity on radiotherapy tolerance, as the true effect of age on tolerance is obscured by the presence of associated pathological conditions. A potential problem for the elderly patient treated with radiotherapy is the daily transportation to a radiotherapy centre and also the conditions necessary for treatment such as immobilisation or adopting a supine position for prolonged periods. Patient transportation often depends on partner, family, or community support, and immobilisation may be difficult for many elderly peopie. Evaluation of the elderly with cancer 225 Fitness for chemotherapy Recent studies have documented that elderly people who are carefully screened for any possible disease that could potentially modify bodily functions have less function loss than reported traditionally. However, an apparent excellent general condition can mask a significant loss of organ function. It is also documented that disease or stress can alter dramatically the delicate balance between existing functional reserves and normal physiological functioning. Of particular importance for the discussion of appropriate use of drugs in cancer therapy are changes in renal and hepatic function, as well as modifications of lean body mass and bone marrow reserves. Renal function One should always calculate the actual creatinine clearance in a particular patient using, for example, the formula of Cockroft and Gault [10] which has been shown to be more reliable in elderly people than an evaluation based on standard 24-hour urine collections. Liver function Hepatic function can be modified in several manners by ageing: decreased blood flow, decreased albumin production and decreased cytochrome P450 function [11]. Decreased liver blood flow will result in decreased liver clearance for those drugs which are intensively extracted by the liver. Drugs with a lower extraction ratio are more affected by variations in protein binding, and their liver metabolism increases dramatically with minor changes in the protein-bound drug fraction. The balance of these two elements in elderly people is stated to result in a relative steady state and may not have major implications for the use of cytotoxic agents. Much more important are changes in liver metabolic function, which need to be distinguished between phase I and phase II reactions. Phase I reactions involve drug metabolism through hydroxylation, dealkylation and reduction and involve mainly the cytochrome P450 isoenzymes. Phase II reactions include conjugation (glucuronidation, sulfation), acetylation and methylation. Phase I reactions are possibly modified with advanced age, although this is controversial, while phase II reactions are not. However, concomitant use of several drugs by elderly people may lead to possibly clinically significant changes in cytochrome P450 function. A typical example of such changes is the induction of cytochrome P450 by phenobarbital and sex steroids, and its inhibition by cimetidine. Phase I reaction modifications can unpredictably affect cytotoxic agents like the oxazaphosphorines (cyclophosphamide, ifosfamide) which are activated and also deactivated by this mechanism. Bone marrow reserves Many cytotoxic agents are myelotoxic, and unpredictable myelotoxicity can arise in elderly people, even if doses are adjusted to take into account differences in pharmacokinetics. Such observations are, however, mostly limited to frail (malnourished) patients. Neurotoxicity It is important to consider that many cytotoxic agents (vinca alkaloids, epipodophyllotoxins, taxoids and platinum derivatives) are neurotoxic, and to realise that an elderly person may be considerably handicapped by the loss of peripheral sensitivity. Even more dramatic can be ototoxicity which may lead to clinically significant hearing loss because elderly people have a limited acoustic reserve. Principles of drug dosing There is a correlation between functional status and toxicity of any cancer therapy, and the oncologist will have to weigh several additional factors before deciding to use a determined chemotherapy. Once this choice is made, the doses and schedule of the chemotherapy may need some adaptation to changes in physiological parameters. These have been extensively reviewed and are summarised here [12]. Liver function abnormalities If such abnormalities lead to an increased bilirubin level, several drugs have to have a dose adjustment. This is clearly not different in elderly or younger patients, although in both situations one has to rely on limited amounts of published data. Antimetabolites, epipodophyllotoxins (if renal function is normal), most alkylating agents do not seem to be more toxic in these cases. Doses of anthracyclines and anthraquinones except idarubicin have to be reduced by 50%, if bilirubin is above 1.5 mg/dl, and by 75%, if bilirubin is above 3.0 mg%. Idarubicinol is the active metabolite and idarubicin does not need dose adaptation in case of increased bilirubin values as it has a renal excretion. This means, however, that idarubicinol does need careful adaptation of dose in 226 M. Aapro M. Extermann and L. Repetto case of renal insufficiency, and such guidelines are not yet available. In case of impaired hepatic function vinblastine use needs to follow the same guidelines as are suggested for anthracyclines. Also taxoids should be managed according to the same guidelines as anthracyclines. Docetaxel doses are reduced to 75% of the planned dose if there is a simultaneous abnormality of both alkaline phosphatase and transaminase values, even in the presence of normal bilirubin levels. Renal function abnormalities The Cockroft and Gault formula is readily usable thanks to simple rulers, and has been shown to be a reliable method in patients up to the age of 75 [10]. Oncologists are familiar with dose adaptation of carboplatin [13] and of methotrexate [14]. The hepatic metabolism of taxoids, doxorubicin, epirubicin, and vinca alkaloids in principle permits their use at full dose even if renal function is impaired. Epipodophyllotoxins can probably be used at full dose until a clearance of less than ml/min, if liver function is normal. Bleomycin, carmustine, cisplatin, 2-CDA, camptothecin derivatives, cytarabine, fludarabine, ifosfamide and other agents need to be dose reduced as soon as the creatine clearance is below 60 ml/min, a commonly accepted limit. It is important to note that patients above 70 are not different from younger patients when evaluated for cisplatin-induced nephrotoxicity, and this has also been shown to be true for patients above the age of 80 [15,16]. Thus, if thrombocytopenia is of concern, one can, in patients who can tolerate a careful hyperhydration, use cisplatin instead of carboplatin in elderly patients. Comorbidity and comorbidity index Since different comorbid conditions may have a different impact on prognosis and clinical outcome, an effective measurement of comorbidity should help to establish the benefits and risks rate of treatment in the older patients. The introduction in clinical oncology of a comorbidity index to evaluate the patient's global health and any functional impairment apart from the cancer might have a major impact on clinical management [17]. The Charlson comorbidity scale [18] (Table 3) is a standardised instrument based on 1 year mortality risk. It considers 19 different diseases weighted from 1 to 6 points. This scale is valid in predicting mortality risk over a period of a few weeks to 10 years in conditions that Table 3 Charlson Comorbidity Index Comorbidity Points Myocardial infarct Congestive heart failure Peripheral vascular disease Cerebrovascular disease (except hemiplegia) Dementia Chronic pulmonary disease Connective tissue disease Ulcer disease Mild liver disease Diabetes (without complications) Diabetes with end organ damage 2 Hemiplegia 2 Moderate or severe renal disease 2 2nd solid tumour (non-metastatic) 2 Leukaemia 2 Lymphoma, MM 2 Moderate or severe liver disease 3 2nd metastatic solid tumour 6 AIDS 6 Total points range from breast cancer to spine surgery. It is also correlated with postoperative complications, length of hospital stay and discharge to a nursing home. In this scale, comorbidities were defined in a restrictive way. A large number of diseases are left aside by this scale. As an example, the Charlson scale only considers renal insufficiency when the creatinine concentration is greater than 3 mg/dl, but we know that also with normal serum creatinine levels, older patients may present significant decreases in renal function that warrant dose reductions in chemotherapy. The Cumulative Illness Rating Scale Geriatrics (CIRS-G) [19] (Table 4) classifies comorbidities by organ systems and grades each condition from 0 (no problems) to 4 (several incapacitating or life-threatening conditions). This method analyses comorbidity in a more comprehensive way, is easier to apply on a large setting and requires less time. For these reasons it appears more suitable for randomised trials, as it is more sensitive to individual variation. In a study of Extermann et al. [3,20], both instruments have proven reliable and the interrater correlation was very good. This study also demonstrated that comorbidity and functional status are independent variables in older cancer patients whether we use a restrictive (Charlson) or a comprehensive (CIRS-G) instrument. The striking difference in the sensitivity of the two scales, with the Charlson scale showing 36% of patients as having comorbidities, while the CIRS-G shows 94%, underlines our poor understanding of the Evaluation of the elderly with cancer 227 Table 4 CIRS-G, Cumulative Illness Rating Scale Geriatrics Heart Vascular Hematopoietic Respiratory Eyes, ears, nose and throat and larynx Upper GI Lower GI Liver Renal Genitourinary Musculoskeletal/Integument Neurological Endocrine/metabolic and breast Psychiatric illness Total number of categories endorsed Total score Severity index: (total score/total number of categories) Number of categories at level 3 severity Number of categories at level 4 severity Rating strategy 0 - No problem 1 - Mild or past problem 2 - Moderate problem requiring therapy 3 - Severe or uncontrollable problem 4 - Extremely severe problem or organ failure A manual is available to assist rating Score prognostic value of the measure of comorbidity. Obviously we need confirmation from specifically designed studies before recommending any instrument [20]. Depression Depression is misdiagnosed by oncologists in about half of all cases, usually by missing the diagnosis, especially if affective symptoms such as tears or expression of negative feelings are absent [21]. The Geriatric Depression Scale (GDS) is a widely used tool to evaluate this question. In its short form, it comprises 15 yes or no questions that can be completed by the patient [22]. It performs well in detecting major depression and has shown prognostic validity. It should be remembered, however, that scales are screening tools only and, if positive, should be completed by an evaluation using standard psychiatric criteria (e.g. DSMIV). Mental status Like depression, cognitive disorders are underdiagnosed without screening. The assessment of mental status can be affected by several variables such as education, stress, fatigue. Therefore, the assessment needs to be done in two steps. A short, sensitive screening tool is first used, and when a potential problem is found, an elaborate battery of tests is administered in a specialised consultation. The most commonly used screening tool in a general medical setting is Folstein's Mini Mental Status (MMS) [23]. One fifth of patients screened positive for cognitive disorders in the University of South Florida experience (Martine Extermann, pers. commun.). The MMS has a good ability to discriminate between depression and cognitive disorders. Like the depression scales, these tests are screening tools only. Referral of patients to memory disorder clinics is important as several treatments have become available to slow down the evolution of Alzheimer's disease. This is especially important if these disorders are minor and the cancer has a good prognosis. The Comprehensive Geriatric Assessment (CGA) in clinical oncology A more complete evaluation of the clinical importance of comorbid conditions and functional limitations is provided by the Comprehensive Geriatric Assessment (CGA). CGA, according to the definition of the Consensus Conference sponsored by the Department of Veterans Affairs, NIA (National Institute of Aging) and the Robert Wood Johnson Foundation in 1989, is a multidimensional, interdisciplinary patient evaluation that lead to the identification of patient's problems . The CGA investigates functional, nutritional, psychological, and cognitive status and socio-economical factors which account for the heterogeneity of the older population. It represents a valid tool for recognition of unsuspected comorbid conditions, and physical or emotional dysfunction. CGA is based on standardised interviews and validated scales such as ADL (Activities Daily Living), LADL (Instrumental Activities of Daily Living), biochemistry, GDS, and MMS. The CGA does not require specific instruments and can be applied in unsophisticated medical settings, requires time but expertise in administering interviews is easily acquired and is a low cost procedure. Moreover the CGA allows the collection of homogeneous information among different centres and estimation of life expectancy. 228 M. Aapro M. Extermann and L. Repetto Monfardini et al. [24] have validated a CGA scale, MACE (Multidimensional Assessment of Cancer in the Elderly), in elderly cancer patients. MACE was shown to be reliable and feasible and its use has been proposed in clinical trials. Practical recommendations for evaluation of the elderly A minimum assessment should be conducted (Table 5) comprising anamnesis and physical examination, including psychiatric history, and a formal assessment of orientation in time and space, short term memory (3 items recall), visual and auditive problems. Screening for frailty should be performed (Table 6; adapted and modified from [25]). Special attention should be paid to nutrition and medications, including non-prescription drugs. Before any chemotherapy, calculated creatinine clearance should
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