Management of Chemotherapy-Induced Neutropenia in the Older Cancer Patient

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]

Age and Risk of Myelotoxicity

According to six retrospective studies (Table 1), the risk of myelotoxicity did not increase with the patients' age.[18-23] These findings demonstrate that chemotherapy may be safely administered to some persons over 70, but do not answer the question of whether age is a risk factor for chemotherapy-related myelotoxicity. The population involved in the studies was highly selected according to the exacting eligibility criteria of clinical trials. Virtually no patient was older than 80. In addition, further review of the experience of the Eastern Cooperative Oncology Group revealed that the toxicity of methotrexate, nitrosourea, and doxorubicin was increased in persons 70 and over.[18]

Several other studies showed an increased incidence of myelotoxicity with the age of the patients. In the trials of the Southwest Oncology Group[24] and the Breast Cancer International Research Group (BCIRG)[25] the incidence of myelotoxicity increased after age 65. In addition, due to myelotoxicity, approximately 40% of older women treated by the BCIRG received a total dose of chemotherapy less than two-thirds of the planned dose.[25]

Among 500 unselected large-cell lymphoma patients in the community treated with CHOP/CNOP (cyclophosphamide, mitoxantrone [Novantrone], vincristine [Oncovin], prednisone), the incidence of neutropenic infection was 38% for patients 65 and older and 18% for the younger ones.[11,26] The duration of hospitalization for neutropenic infection was 4 days (25%) longer for older patients.[11] Prolonged hospitalization is a cause of deconditioning and functional dependence.

In a review of patients treated for large-cell lymphoma or breast cancer, age was an independent risk factor for reduction of the dose of chemotherapy below 85% of the planned dose intensity; in 60% of cases neutropenia was the cause of this reduction.[8,9] In a meta-analysis of all randomized controlled studies of filgrastim and lenograstim, failure to use prophylactic growth factors was associated with increased risk of neutropenic infections and neutropenic infection-related mortality.[10] The risk of both increased with the age of the patients.

In seven prospective studies of large-cell lymphoma patients aged 65 or 70 and older treated with CHOP-like regimens, the risk of neutropenia was as high as 90% and the risk of neutropenic infections as high as 50% (Table 2).[27-33] A consistent finding in these studies was that approximately two-thirds of neutropenic infections and of infection-related mortality occurred after the first and second courses of chemotherapy.[8-10,27-33]

Age is associated with increased risk of infection-related mortality during treatment induction in patients with acute myeloid leukemia. This may be ascribed to the nature of the disease, and the fact that after age 60 it is more likely to involve the pluripotent hemopoietic stem cell. Consequently the ability to recover a normal bone marrow after chemotherapy-induced aplasia may be hampered.[34] The risk of neutropenic infections after consolidation with high doses of cytarabine also increases with age.[34]

According to a recent study, age is also a risk factor for chemotherapy-induced thrombocytopenia.[35] While there are no firm data on chemotherapy-induced anemia, it is clear that the incidence and prevalence of anemia increase with age.[15] Anemia has two detrimental effects in older cancer patients. First, it enhances the risk of functional dependence; and second it enhances the risk of chemotherapy-induced toxicity.[15]

In conclusion, the risk of neutropenia, neutropenic infections, and infectious deaths increases with age. Neutropenia in older patients is a risk factor for mortality and for delivery of inadequate chemotherapy doses.

Prevention of Neutropenic Infections in Older Cancer Patients

In this section we will examine two issues: the most effective way of preventing neutropenic infections in older patients and the timing of the use of hemopoietic growth factors.

Approaches to the Prevention
of Neutropenic Infections

Seemingly, neutropenic infections may be prevented with three approaches that can be used alone or in combination. These include reduction of the chemotherapy doses, prophylactic use of antibiotics, and prophylactic use of myeloid growth factors.

Dose reduction may defeat the purpose of chemotherapy itself, at least in the case of curable malignancies. When the CHOP regimen for large-cell lymphoma was originally devised, individuals aged 65 and older received a 25% reduction in the dose of chemotherapy and experienced a 40% reduction in the complete response rate.[2] When older individuals were treated with the same dose as younger individuals, in violation of protocol, the response rate was similar to that of younger individuals . An analysis of the outcome of adjuvant CMF (cyclophosphamide, methotrexate, fluorouracil [5-FU]) in breast cancer 20 years later revealed that only patients who had received at least 85% of the total planned dose of chemotherapy experienced a reduction in breast cancer-related deaths.[3] Furthermore, recent clinical trials in large-cell lymphoma and adjuvant treatment of breast cancer indicated that a dose-dense approach may be associated with better outcome. Consequently dose reduction and dose delay do not appear advisable, at least in the case of curable neoplasms.

Prophylactic use of quinolones and trimethoprim has reduced the risk of sepsis from gram-negative intestinal bacteria in patients with prolonged neutropenia, including those receiving induction treatment for acute myeloid leukemia or hemopoietic stem-cell transplant.[38,39] The benefit of this approach in patients with solid tumors or large-cell lymphoma has not been conclusively demonstrated. The only randomized controlled study addressing this issue had low incidence of neutropenic fever in the control group and used controversial criteria to define infections.[40] A recent study from Timmer-Bonte et al revealed that the combination of antibiotics and growth factors was more effective than antibiotics alone in preventing neutropenic infections in patients receiving chemotherapy for lung cancer.[41] An additional concern related to prophylactic antibiotics is the emergence of antibiotic resistance, which in one study was as high as 60%.[39]

In at least four randomized controlled studies prophylactic growth factors reduced the incidence of neutropenia and neutropenic infections in patients aged 65 and older by approximately 50%.[27,32,33,42] In three of these studies patients with large-cell lymphoma treated with a CHOP-like regimen were randomized to receive filgrastim or no growth factors. In the fourth study patients with solid tumors and lymphoma, receiving different forms of treatment, were randomized to receive pegfilgrastim (Neulasta) or no prophylaxis after the first course of treatment. After the second course of treatment investigators were free to institute prophylactic pegfilgrastim; 50% of them elected to do so.

In conclusion, the only approach conclusively demonstrated to reduce the risk of neutropenia and neutropenic infections in older patients receiving cytotoxic chemotherapy involves the prophylactic use of filgrastim or pegfilgrastim. The role of oral antibiotics is not established, at least in solid tumors and large-cell lymphoma.

Timing of the Administration
of Growth Factors

Since the advent of myelopoietic growth factors it has been debated whether these agents should be initiated after the first course of cytotoxic chemotherapy or at a later time, ie, after a patient had experienced a neutropenic infection or a chemotherapy delay due to neutropenia. This issue was addressed in two recently concluded randomized controlled studies in which patients were randomized to receive prophylactic pegfilgrastim with the first course of treatment or at a later time.[42,43] One study involved only patients 65 and over.[42] In both studies, the immediate use of pegfilgrastim resulted in a reduction of the total number of neutropenic infections as well as of neutropenia related events such as delay of chemotherapy administration or reduction in the doses of the drugs.

This approach is supported by other considerations as well, including the fact that most of chemotherapy-related infections occur after the first and second courses of treatment, and the fact that neutropenia is associated with a compromise in quality of life even in the absence of overt infections. This approach does not seem to increase the cost of treatment and may even reduce it. A cost analysis of the use of growth factors demonstrated that these compounds were cost-effective when the risk of neutropenic infection was around 18%.[44] In older individuals this threshold should be lower, as neutropenic infections are associated with increased duration and cost of hospitalization.

Other Provisions to Reduce the Risk of Neutropenic Infection in Older Individuals

A number of other provisions may help prevent neutropenic infections in older individuals.[45] These include the following:

• Implementing an individualized approach to older patients. Patients with poor performance status, those with functional dependence, such as dependence in the activities of daily living or instrumental activities of daily living, and those with severe comorbidities are at increased risk of neutropenia and neutropenic infections. In these patients it may be prudent to reduce the initial dose of chemotherapy or to forgo the chemotherapy altogether if the patient's life expectancy is so limited that he or she is unlikely to suffer the complications of cancer

• Correction of conditions that may enhance the risk of chemotherapy-related toxicity, which include underlying diseases such as poorly controlled hypertension or diabetes, malnutrition, and inadequate social support

• Adjustment of the first dose of chemotherapy to the glomerular filtration rate, as this declines almost universally with aging.

• Maintenance of hemoglobin levels at 12 g/dL and over, as the risk of myelotoxicity as well as the risk of functional dependence are increased in the presence of anemia.

Conclusions

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 chemotherapy-induced neutropenia is essential for both the safety and adequacy of chemotherapy. 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.

Based on the considerations exposed in this article, the National Cancer Center Network has issued a number of guidelines for the safe management of older persons with cytotoxic chemotherapy[45] (Table 3). Prophylactic use of filgrastim or pegfilgrastim in patients 65 and older receiving chemotherapy with a dose intensity comparable to CHOP has been endorsed also by the guidelines of the American Society of Clinical Oncology[46] and the European Organisation for Research and Treatment of Cancer.[47]

Disclosures:

The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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