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Annals of Oncology 18 (Supplement 1): i49–i53, 2007

doi:10.1093/annonc/mdl451chapter 9

Management of elderly patients with hematological

neoplasms

O. Mora & E. ZuccaIOSI, Oncology Institute of Southern Switzerland, Medical Oncology Department, Ospedale San Giovanni, Bellinzona, Switzerland

introduction

Persons >65 years represent the fastest growing segment of thepopulation in Western countries. Estimates for the EuropeanUnion suggest by 2015 a 22% increase in people older than 65

years and 50% increase in those older than 80 years.Cancer incidence in general increases with age and more than

half of all new cancers occur in patients 65 years of age or older.

The incidence of cancer in the population >65 years is >10 timeshigher than in the population <65 years and more than half of all cancer-related deaths occur in elderly patients.Appropriately, the problem of cancer in the elderly has beendefined as an ‘oncological time bomb’.

Hematological neoplasms do not escape this age-relatedincrease in tumor incidence, which holds true for non-Hodgkin’s lymphomas, multiple myeloma and all leukemiasubtypes, with the exception of acute lymphoblasticleukemia (ALL).

In addition, the prognosis of most hematological tumorsworsens with age (e.g. acute myelogenous leukemia, large-cellnon-Hodgkin’s lymphoma). Nevertheless, these tumors are

often potentially curable and this poses specific problems to thephysicians dealing with elderly people.

Nowadays, older persons in most European and NorthAmerican countries enjoy good health for a longer period thanpreviously realized, and many factors that may compromisefitness in the elderly (e.g. chronic diseases, poor vision, hearingloss and depression) can be easily addressed and often modified.Therefore, a long period of worsening illness and disability is no longer necessarily part of normal aging. With theincreasing number of otherwise healthy older patients with(hematological) cancer, the chronological age cannot anymorebe a criterion for justifying or denying access to a potentially curative but toxic therapy. Any preliminary clinical evaluationof elderly patients with cancer should also be aimed todistinguish the frail patients from the otherwise healthy ones.

While cancer diagnosis is likely to decrease life expectancy inthe majority of younger patients, the same consideration may not be true in older people. Life expectancy (the averagenumbers of remaining years of life) in elderly cancer patients isa function of age, disability and co-morbidity, along with thecancer type and stage (Table 1).

Therapeutic decision making involves a delicate balanceamong all these factors, evaluation of treatment-relatedcomplications and the overall effects of cancer and cancer

treatment on the patients expected survival and quality of life.Therefore, the treatment choice must be tailored to thecondition of the individual patient. The following questionsshould be addressed before any treatment decision: whetherthe patient is likely to die ‘with’ tumor or ‘because of’ it,whether the patient is expected to suffer severe cancer-relatedmorbidity, and whether the patient is likely to tolerate a curative

treatment and its complications.In fact, age in itself should not be a barrier to full-dose cancertreatment. However, the proportion of elderly patients enrolledin registration trials decreases with age: 38% for patients olderthan 65 years, 20% for those older than 70 years and 10% forthose >75 years. This underrepresentation in studies is mostlikely reflected in undertreatment in clinical practice. This may be a very relevant issue when dealing with tumors that can becured.

geriatric assessment in cancer patients

assessment of aging

Chronological age is a well-established prognostic factor forlymphomas and leukemias, and can be the easiest and mostreproducible way to estimate the ‘extent of aging’, but this is notalways appropriate because life expectancy depends on theindividual’s general health. Although it is impossible forphysicians to predict the exact life expectancy of an individualpatient, it is nevertheless possible to make reasonable estimatesof whether a patient is likely to live substantially longer orshorter than an average person in his/her age cohort (Table 1).

assessment of disability

Measures of ‘performance status’ (PS) [the Karnofsky and

Eastern Cooperative Oncology Group (ECOG) scales] areusually designed for use in patients with cancer but are notspecific to the elderly.

The ECOG PS is a simple functional score that ratesfunctional status from 0 (normal activity) to 4 (bedridden) andit has proven to be a powerful independent prognostic predictorin cancer patients. Impairment of PS in elderly patients is likely not to be uniquely cancer related.

Geriatricians have developed a variety of scoring systems suchas the ‘Barthel index’, ‘the activities of daily living scale’ (ADL)and ‘the instrumental activities of daily living scale’ (IADL) for

ª 2007 European Society for Medical Oncology



the functional evaluation of their patients but these tools arenot specific for cancer.

The Barthel index and the ADL scale evaluate the basicfunctional activities. Using ADL, six functions are measured:incontinence, bathing, dressing, toileting, transferring, andfeeding. The instrument has three descriptions for eachfunction: independent, assisted, and dependent functioning.

The IADL scale measures more elaborate functions. The scaleconsists of nine items: ability to use the telephone, shopping,food preparation, housekeeping, handyman work, laundry,mode of transportation, responsibility for own medications, andability to handle finances. Responses to each item range fromindependent to moderately independent to dependent.

assessment of co-morbidity

Co-morbidity is one of the most visible differences between younger and older individuals and may interfere with diagnosisand treatment of cancer even if it is often difficult to distinguishthe results of concomitant illness conditions from the disability from cancer and cancer treatment side-effects. Furthermore,cancer treatment can worsen co-morbidity.

There is no clear consensus about the number and types of conditions that should be included in co-morbidity assessment,and the most commonly used index in geriatric medicine (i.e.the Charlson index, which includes 19 selected conditions) canbe difficult to use in an oncohematological setting. Nevertheless,proper attention should be paid to the most frequent co-morbiddiseases and to those that can become life threatening ordifficult to control (e.g. arrhythmias and congestive heartfailure, chronic obstructive pulmonary disease, insulin-dependent diabetes, chronic liver disease, renal insufficiency,gastrointestinal problems, osteoporosis). In addition to theconcurrent presence of chronic conditions, older individuals

may carry common ‘geriatric syndromes’ such as those relatedto dementia, incontinence, malnutrition, depression, imbalanceand gait disorders.

comprehensive geriatric assessment

This type of assessment derives from the idea that olderindividuals may represent as unique a cohort of patients as dochildren, for whom an entire discipline (pediatrics) exists.

Comprehensive geriatric assessment (CGA) has been definedas ‘a multidisciplinary evaluation in which the multiple

problems of older persons are uncovered, described, andexplained, if possible, and in which the resources and strengthsof the person are catalogued, need for services assessed, anda coordinated care plan developed to focus interventions on theperson’s problems’.

It is aimed to evaluate together the socioeconomic condition,the functional and nutritional status, the co-morbidity with thepresence or absence of geriatric syndromes, and the need of

medications.CGA can provide a common language for classifying the

physiologic age of older cancer patients. It may providea common basis in outcome research. It may be used as a basisfor the choice of cancer treatment in specific clinical situations.

Because most oncologists have limited time and littleexperience with the geriatric assessment and geriatricians may not be readily available, not all patients should or could undergoan extensive geriatric assessment. It should anyway be kept inmind that a proper geriatric assessment could be importantespecially to recognize the frail patient and to direct treatment-related decisions. Therefore, some type of screening isrecommended and should be aimed at evaluating mental status

and emotional status, PS and daily activities (ADL and IADL),home environment, social support, co-morbidity, nutritionstatus, and polypharmacy. However, it is difficult to providea simple general schema.

how to identify the frail patient

Identification of older frail patients with a critical reduction infunctional reserve that makes them unsuitable for the standardforms of aggressive treatment of either severe [such asdaunorubicin and cytarabine in acute myeloid leukemia(AML)] or limited toxicity (such as R-CHOP for large-celllymphomas) is critical in hematological oncology.

Several definitions of frailty have been formulated, all on thebasis of the main concept that frailty implies a critical reductionin functional reserve with limited ability to withstand eventhe most ordinary stresses.

Frailty is common in the last span of human life precedingdeath but it is not synonymous with imminent death. In fact, theaverage life expectancy of the frail patient is 2 years. A practicaldefinition of the frail elderly patient can be provided by thepresence of

• dependence in one or more activities of daily living (bathing,dressing, toileting, continence, mobility, and feeding)

• or three or more co-morbid conditions• or one or more geriatric syndromes.

It is not clear whether any age level should be considereda criterion of frailty but it is advisable to consider age >85 if not a frailty indicator itself at least as a warning to look forthe above listed signs of frailty.

changes of pharmacology parameters

in the elderly

Physiologic modifications of body function are known tooccur with age and may interfere with cancer treatment. The

Table 1 Life expectancy in the elderly in western countries according to

age and sex

Age (year) Median life expectancy (50th percentile)

Women Men

65 19 15

70 16 12

75 12 9

80 9 785 6 5

90 4 3

95 3 2

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decreasing renal excretion of drugs is the most predictablechange: the glomerular filtration rate declines consistently with age by 1 ml/min/year from the age of 40 years. Thehepatic function is also modified in older patients withdecrease in liver size, blood flow, albumin production, andcytochrome P450 function. These changes have importantimpact on the pharmacokinetic processes of absorption,distribution, metabolism, and excretion and the

pharmacodynamic properties of administered drugs. They can lead to opposite and potentially harmful consequences,such as excessive drug concentrations and unacceptabletoxicity or suboptimal drug concentration and ineffectivetreatment.

Moreover, an increased intake of concomitant medications inthe elderly may result in drug–drug interactions by competitionfor serum albumin-binding sites or the cytochrome P450enzymes.

There are several pharmacological parameters that can betaken into account when treating elderly patients withanticancer drugs: oral absorption, volume distribution, body composition (decline in body water and increase in body fat),

serum albumin, hemoglobin level, liver metabolism, renalexcretion, biliary excretion, and drug interactions.However, despite the increased susceptibility of the elderly

to these changes, doses of anticancer drugs are rarely adaptedon the basis of the pharmacokinetics and pharmacodynamics,with the exception of changes secondary to altered renalfunction.

Additionally, older patients appear to be at special risk forsevere and prolonged myelodepression and mucositis, atincreased risk for chemotherapy-associated cardiomyopathy aswell as for central and peripheral neuropathy.

Some threats may be prevented or reduced. For example,myelosuppression can be very severe; however, the use of growth factors [granulocyte colony-stimulating factor (G-CSF)]

in fact can allow administration of curative chemotherapy dosesin many elderly patients. Particular attention should be given toanemia, which causes fatigue that may ultimately precipitatefunctional dependence, especially in those elderly patients whoare already dependent in their instrumental activity of daily living.

treatment of hematological neoplasms

in the elderly

defining the aim of cancer therapy in

the elderly patient

The frail person needs individualized treatment plans and is nota candidate for aggressive life-prolonging cancer treatment butcan be a candidate for aggressive symptom palliation. Common

symptoms of hematological neoplasms include pain, especially bone pain, anemia, fatigue, and bleeding. Anti-neoplastictreatment is very often pivotal to symptom palliation and thebest supportive care may involve cytotoxic chemotherapy.Hence, it is very important to define the aim of thechemotherapy before commencing treatment in elderly cancerpatients.

In frail patients, or patients with considerable co-morbidity,supportive care only is often the best action even when tumorsare potentially curable and the goal is the quality of life. In thisgroup, the toxicity of cancer treatment is generally notacceptable and strong efforts should be made to avoid it.

In the curative setting, it is important to try to maintain dose

intensity because there is a steep dose–response curve, and asmall decrease in dose intensity can lead to a significantdecrease in cure rates. In this situation, some toxicity isacceptable but it must be very carefully managed.

The aforesaid considerations should be always taken intoaccount and Table 2 summarizes some practical tips but thespecific problems posed by each hematological neoplasm shouldnot be overlooked.

acute leukemias in the elderly

Age is a main prognostic factor in both ALL and AML. ALL israre in elderly people but the majority of patients with AML are60 years of age or older and the number of patients is increasing.

While many younger adults with AML can be cured, theoutcome of elderly people remains unsatisfactory, with10% of survival rates at 5 years. High-dose chemotherapy is notbeneficial in elderly patients with AML and the patients >60

years of age have significantly lower remission rates (50% versus75%) than the younger patients as well as a three times higher

Table 2 Some practical suggestions for the management of the older patients with hematological neoplasms

Careful selection of patients suitable for curative therapy

Some geriatric assessment is strongly advisable for all patients >65 years to identify the frail patients unfit for aggressive regimens

Treat co-morbidity aggressively

Manage in advance any conditions that may interfere with cancer chemotherapy (e.g. polypharmacy, risk of malnutrition, absence of reliable care giver)Pharmacological interventions

Adjust dose of chemotherapy to the renal function, to the nadir count, and to other complications

Maintain good hemoglobin levels (>10 g/dl) when needed with the use of erythropoietin

Use G-CSF prophylaxis in patients aged 70 years and older receiving chemotherapy of moderate toxicity (e.g. CHOP)

Consider use of prophylactic antibiotics in patients who may be neutropenic for a week or longer

Consider less toxic alternatives to doxorubicin when equal effectiveness has been demonstrated

In frail patients, consider reducing the initial dose of anticancer agents (especially those that are metabolized in the liver)

Clinical interventions

Treat mucositis aggressively and correct promptly fluid and electrolyte imbalances

Perform neurological examination at each clinic visit to early detect neuropathy

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risk of treatment-related death (30% versus 10%). In thisscenario, intensive chemotherapy with curative aim can be thetreatment of choice only for those patients <80 with goodprognostic features (i.e. favorable karyotype, no antecedentmyelodysplasia, no major co-morbid conditions, and good PS)who are well motivated to take the risk of toxic treatment. Theother patients will probably benefit more from palliativehematological treatment aimed at the best possible quality of

life. Similar considerations can be applied to the few elderly patients with ALL.

myelodysplastic syndromes

Myelodysplastic syndromes (MDSs) comprise a group of hematological neoplasms, manifesting as cytopenias that occuralmost exclusively in the elderly population. Anemia,neutropenia, and thrombocytopenia may occur either alone orin combination and there is, by definition, no underlyingsystemic illness to account for them.

The possibility of cure is restricted to a tiny minority of youngpatients, with compatible donors, for whom allogeneic stem-celltransplantation is the treatment of choice. In general, however,

intensive treatment is considered ineffective andcontraindicated in MDS patients. Low-dose chemotherapy may help controlling the peripheral leucocytosis (subcutaneouscytarabine, oral etoposide, 6-mercaptopurine, and 6-thioguanine can all be effective) but does not alter the long-termoutcome. Supportive care, therefore, with blood productscombined with broad-spectrum antibiotics remains thecornerstone of therapy for elderly patients. Recently, thecombination of G-CSF and erythropoietin has been shown toimprove anemia and neutropenia in some patients.

chronic myeloid leukemia in older people

The age of the majority of patients diagnosed with chronicmyeloid leukemia (CML) is 65 years or older and, because of age-related additional medical problems, until recently mostelderly patients were considered to have in general a poorprognosis.

This is no longer true after the introduction of themolecularly targeted therapy with imatinib mesylate. Patientsaged 60 or older appear to benefit from treatment with imatinibas much as younger patients and increased age does notanymore appear to be necessarily an indicator of unfavorableprognosis of CML.

treatment of aggressive lymphomas in

the elderly

Most non-Hodgkin’s lymphoma subtypes display a peak of incidence in the age group >60. The most common aggressivesubtype is diffuse large B-cell lymphoma. Age has beenrecognized as a major risk factor for the overall survival of diffuse large-cell lymphoma patients, and several factors may contribute to the age-related worsening of outcome (differenttumor biology, age-related immunodeficiency, age-specific co-morbidity, limited ability to tolerate intensive chemotherapy,and socioeconomic factors).

Several studies report increased toxicity of cytotoxic drugs inelderly patients: cardiotoxicity of anthracyclines; hematologicaltoxicity of adriamycin, methotrexate, etoposide, andvinblastine; and pulmonary toxicity of bleomycin andmucositis.

Nevertheless, in recent years large randomized clinical trialshave demonstrated that intense treatment with a curative intentcan be successfully given even in the very elderly, provided that

the proper supportive care is given, especially G-CSFadministration to prevent infections and to allow administration of full-dose therapy without delays between thechemotherapy courses. These studies have shown thatcombining chemotherapy and anti-CD20 monoclonalantibodies seems to be the main optional strategy, and oldernon-frail patients can be treated with the same intensiveapproaches that were usually reserved for younger patients. Thismay result in response, event-free survival, and overall survivalrates similar to those observed in their younger counterparts.Many elderly patients—if not frail—can get successful salvagetreatment at relapse, too. Autologous transplantation of peripheral blood stem cells is the treatment of choice and the

procedure is nowadays usually offered up to 65 years of age.

indolent lymphomas and CLL

These entities afflict almost exclusively adults, particularly themiddle-aged and elderly. Both the incidence and the associatedmortality rates have increased over the past 20 years in elderly persons. An age >70 years has a negative impact on outcome,but the contribution of concomitant diseases herein is very important. Indeed, these diseases have most often a very indolent course and the median survival exceeds 10 years inmost reported series. In spite of the recently reported survivalimprovements, achieved with the addition of the anti-CD20monoclonal antibodies to the therapeutic armamentarium

against low-grade lymphomas, or with timely peripheral bloodstem-cell transplantation, none of the currently availabletreatment regimens have yet been shown able to alter the naturalhistory of these diseases in elderly people.

Neither single-alkylating agent chemotherapy nor aggressivecombination regimens, even when combined with monoclonalantibodies, can cure advanced-stage low-grade non-Hodgkin’slymphomas and CLL. An initial policy of watchful waiting inasymptomatic patients is often appropriate, especially inpatients older than age 70 years since aggressive therapy will notimprove survival.

The decision to start therapy is on the basis of the stage of thedisease, the occurrence of disease-associated symptoms,including B symptoms, recurring infections, autoimmuneanemia or thrombocytopenia, pancytopenia associated withbone marrow infiltration, bulky disease causing discomfort,impairment of organ function, and hypersplenism.

Hodgkin’s lymphoma

In western countries, the incidence of Hodgkin’s lymphoma(HL) shows a bimodal age distribution with a main peak in theearly adulthood and a second peak around the sixth decade.With improved prognosis of HL, interest increasingly focuses onhigh-risk groups such as elderly patients. In general, elderly

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patients with HL have a less favorable prognosis than do younger ones.

In a retrospective analysis of the German Hodgkin’s Study Group, elderly patients more often had mixed-cellularity subtype, ‘‘B’’ symptoms, elevated erythrocyte sedimentationrate, and poorer PS. Acute toxicity during chemotherapy wasgenerally higher in elderly patients, especially severe leucopeniaresulting in higher rates of severe infections. Significantly, fewer

elderly patients received the intended full chemotherapy doseand the survival analysis showed a significantly poorer survival.Higher mortality during treatment as well as lower doseintensity, often due to decreased tolerance to treatment and co-morbid conditions, contributes to the poor outcome. Co-morbidity is often a prognostic factor more important than ageitself. Nevertheless, most elderly patients can be cured if aftercomprehensive assessment before treatment; proper attention isthen paid to the choice of a chemotherapy regimen witha favorable toxicity profile, to the careful monitoring of toxicity,and to the prompt administration of adequate supportive care.

multiple myeloma

Multiple myeloma is predominantly a disease of the elderly witha median age at diagnosis of 65 years and its incidence appears

increasing with age, and age >65 years has been identified as anadverse prognostic factor.

Therapy should be delayed in multiple myeloma until thepatient is symptomatic, while patients with smolderingmyeloma and MGUS should not be treated. An increasingM-protein in the serum or urine, development of anemia,hypercalcemia, renal insufficiency, and/or the development of lytic lesions are common indications for treatment.

Increasing evidence indicates that the approach to treatmentin multiple myeloma in the elderly with good PS and a lack of severe co-morbidities should follow the same guidelines appliedto younger individuals. Reviews of treatment outcomesfollowing transplantation in myeloma have concluded that agealone (<70 years) is not a prognostic variable and should notexclude a patient from consideration for high-dose therapy.

In frail patients with relevant co-morbidities, oralchemotherapy with single alkylating agent, melphalan, is oftenfeasible in the majority of patients. The last decade has seen thedevelopment and use of a number of novel effective drugs formyeloma such as thalidomide that is very active in combinationwith dexamethasone and bortezomib. They may be safely used

in most elderly patients, provided that proper attention is paidto their non-hematological toxicity.

Annals of Oncology chapter 9

Volume 18 | Supplement 1 | January 2007 doi:10.1093/annonc/mdl451 | i53

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