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Management of Chemotherapy-Induced Neutropenia in the Older Cancer Patient

Management of Chemotherapy-Induced Neutropenia in the Older Cancer Patient

ABSTRACT: The chemotherapy of most cancers may be beneficial to older individuals as long as patients are selected on the basis of their life expectancy and functional reserve, conditions that may interfere with the tolerance of chemotherapy are corrected, and adequate doses of chemotherapy are administered. Prevention of neutropenia-related infection may both improve the outcome of cancer and reduce the risk of toxic deaths in older patients. The prophylactic use of myelopoietic growth factors is recommended in individuals aged 65 and older when the risk of chemotherapy-induced neutropenic infection is at least 10% or higher. In this article we explore the management of neutropenia and neutropenic infections in older cancer patients, as well as review the causes and the risk of this complication.

Cancer is a disease of aging. In the year 2000, 12% of the population was 65 and over and accounted for more than 50% of all malignancies; in the year 2030, these figures are expected to be 20% and 70%, respectively.[1] Older individuals may benefit from cytotoxic chemotherapy to the same extent as the younger ones[2-7] provided they receive adequate doses of treatment. Unfortunately, age is an independent risk factor for receiving inadequate dose intensity of chemotherapy; the main reason for this inadequacy is the risk of chemotherapy-related toxicity, especially neutropenic infections.[8,9]

In their analysis of patients in the community treated with adjuvant chemotherapy for breast cancer or with CHOP (cyclosphosphamide, doxorubicin HCl, vincristine [Oncovin], prednisone) for non-Hodgkin's lymphoma, Lyman et al found that as many as 60% of individuals aged 65 and over received suboptimal dose intensity of chemotherapy.[9] A recent meta-analysis of all randomized controlled studies of granulocyte colony-stimulating factor use (G-CSF; filgrastim [Neupogen] and lenograstim [Granocyte]) in the management of lymphoma and solid tumors is of particular concern to our discussion. The authors demonstrated that patients not receiving primary prophylaxis with growth factors experienced a significant increase in neutropenia-related deaths. Most of the deaths occurred in individuals 65 and older.[10]

These reports suggest that prevention of neutropenia-related infection may both improve the outcome of cancer and reduce the risk of toxic deaths in older patients. An additional benefit includes the preservation of function of older cancer patients. In the presence of neutropenic infections, patients 65 and over experienced a more prolonged hospitalization than the younger patients,[11] and hospitalization is a major risk factor for functional decline in the elderly.

In this article we explore the management of neutropenia and neutropenic infections in older cancer patients, as well as review the causes and the risk of this complication.

The Meaning of Aging: Treatment Implications

Aging involves a progressive reduction in the functional reserve of multiple organ systems, due to a condition of chronic and progressive inflammation.[12,13] Reduced functional reserve, increased prevalence of comorbid conditions, and waning social support conspire to reduce the life expectancy of the older person and enhance vulnerability to stress.[1] Thus, with age, the benefits of cancer chemotherapy may be reduced and the risks increased. It is important to highlight that age is highly individualized and poorly reflected by chronologic age. Thus the treatment of the older person with cancer must be based on an evaluation of individual life expectancy and tolerance of stress, as well as of the personal and social resources available to each individual.

Pharmacology of Age

It is reasonable to expect that with age, the pharmacokinetics of cytotoxic chemotherapy may be altered and the risk of some forms of toxicity enhanced.[14] Of the pharmacokinetic parameters illustrated in Figure 1, renal excretion of drugs is almost universally reduced, as age is associated with a progressive decline in glomerular filtration rate. Failure to adjust the doses of drugs to the glomerular filtration rate may be associated with increased risk of therapeutic complications. The volume of distribution of hydrosoluble drugs declines with age due to reduced total body water, reduced concentration of albumin in the serum, and reduced red blood cell mass. This decline may also be associated with increased toxicity due to increased concentration of drugs in the circulation. Of the components of volume of distribution, only the red blood cell mass may be corrected by medical intervention. While the hepatic uptake and metabolism of drugs become progressively more limited with age, the implications of this change have not been completely understood due to the difficulty of studying hepatic pharmacology in the clinical setting.

In addition to pharmacokinetic changes, age may be associated with increased vulnerability of normal organs systems to the toxicity of chemotherapy. Hemopoiesis is of special concern as it is an almost universal target of chemotherapy toxicity. The hemopoietic effects of aging are not completely understood, but age seems to be associated with a reduced ability of the hemopoietic system to respond to hemopoietic stress, including the increased destruction of hemopoietic precursors by chemotherapy. Seemingly, increased circulating levels of inflammatory cytokines hamper the response of hemopoietic progenitors and precursors to hemopoietic growth factors in the aged.[15-17] The proinflammatory state of aging may also hinder the production of growth factors.[17]

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