Myelosuppression and Its Consequences in Elderly Patients With Cancer

It has long been recognized that cancer is primarily a disease of the elderly. Approximately 60% of all newly diagnosed malignancies are in persons aged 65 years or older, as are 70% of all deaths due to cancer.[1-3] With few exceptions, those malignancies with the highest incidences-such as lung, breast, and colon cancer- mainly affect elderly persons.[4] As life expectancy in the United States increases and the population ages, a substantial increase in the number of persons with cancer is expected. In fact, the number of persons with cancer is expected to double in the next 50 years, from 1.3 million in 2000 to 2.6 million in 2050.[2] As in younger patients, chemotherapy is the mainstay of treatment in patients 65 years of age and older, and the benefits of treatment include extended survival, maintenance of and improvement in quality of life, and palliation of symptoms.[5] The elderly are more susceptible to certain toxicities of chemotherapy, however; in particular, myelosuppression and lifethreatening neutropenia are more common in elderly patients, emphasizing the need for prophylactic intervention.[ 6] Chemotherapy-Induced Neutropenia in the Elderly The role of age in patients' susceptibility to the neutropenic complications of chemotherapy has been extensively explored. Clinical and experimental studies have suggested an age-related decline in the number of hematopoietic stem cells, as well as of the ability of the bone marrow to react to hematopoietic stress, such as hemorrhage or infection.[7] These findings may in part explain the higher rates of myelosuppression after chemotherapy in the elderly. Studies of the clinical impact of myelosuppression in the elderly have consistently found a higher incidence of severe neutropenia and its complications in older patients. In a study of adjuvant chemotherapy for breast cancer with cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar), methotrexate(Drug information on methotrexate), and fluorouracil(Drug information on fluorouracil), the rates of grade 3 hematotoxic effects were significantly higher in older patients than in younger patients (9.2% vs 4.5%; P < .001).[8] Another study in early-stage breast cancer found that the incidence and severity of neutropenia were greater and the absolute neutrophil count nadir was deeper in patients older than 65 years.[9] Retrospective analysis of data from a large randomized phase III trial in non- small-cell lung cancer found a significantly higher incidence of leukopenia in men 70 years of age or older.[10] A retrospective study of practice patterns in non-Hodgkin's lymphoma reported that the incidence of febrile neutropenia was 34% in patients aged 65 years or older and 21% in younger patients.[ 11] Not only are neutropenic complications more frequent in the elderly, they are also often more severe, leading to higher rates of hospitalization, longer hospital stays, and higher mortality. The study of practice patterns mentioned above found that the rate of hospitalization for febrile neutropenia in patients aged 65 years or older was nearly double that in younger patients (28% vs 16%) and the duration of the hospitalization was 30% longer.[11] A study of CHOP (cyclophosphamide, doxorubicin(Drug information on doxorubicin) HCl, vincristine [Oncovin], prednisone) chemotherapy for non-Hodgkin's lymphoma reported that the mean length of stay in hospitalizations for febrile neutropenia was 9.8 days in elderly patients and 7.0 days in younger patients.[12] In a study of chemotherapy for metastatic breast cancer the incidence of life-threatening febrile neutropenia in elderly patients was twice that in younger patients, and the only treatment- related septic deaths were in the elderly patients.[13] In fact, Kuderer et al, after analyzing data from more than 41,000 adult patients with cancer hospitalized for febrile neutropenia, found that age 65 years or older was associated with more than three times higher mortality (6.68% vs 2.00%).[14] Because of their greater susceptibility to myelosuppression, elderly patients are often given lower doses of chemotherapy-these dose reductions are often planned, beginning with the first chemotherapy cycle. A survey of practice patterns in 2,911 patients with non-Hodgkin's lymphoma reported that treatment with chemotherapy was more likely to begin with a planned average relative dose intensity of 80% or less in older patients than in younger patients (28% vs 12%, P < .001).[15] Another survey of practice patterns, in more than 20,000 patients treated with adjuvant chemotherapy for breast cancer, found that two-thirds of patients 65 or older were treated with a dose intensity of less than 85%.[16] Bias against elderly patients may also be manifested in other ways (Table 1). For example, despite the higher incidence of cancer in older patients, they are substantially underrepresented in clinical trials of chemotherapy.[17] Clinical trial protocols frequently exclude patients older than a specified age, owing in part to concerns about the potential for greater toxicity. A review of trials conducted by the Southwest Oncology Group in various malignancies found that only 25% of 16,396 study subjects were 65 or older, even though such patients accounted for 63% of the population with cancer when those studies were conducted.[18] Physician bias may also play a role in excluding elderly patients from clinical trials. A case-matched study in younger and older women with breast cancer found that older women were less likely to be recruited for and enrolled in clinical trials even though they met the eligibility criteria.[19] Elderly patients are also more likely to be treated with less aggressive, and possibly less effective, regimens than younger patients. A number of studies have investigated alternative, non- doxorubicin-containing regimens in elderly patients with non-Hodgkin's lymphoma, and these regimens are associated with poorer clinical outcomes.[ 20-22] A study in patients with aggressive lymphoma found that elderly patients were less likely to be treated with intent for a cure and were less likely to survive for 5 years or longer.[25] A review of treatment practices in non-small-cell lung cancer in the United Kingdom found that diagnosis and treatment were consistently less aggressive in older patients.[26] Published guidelines recommend that elderly patients be treated with chemotherapy, but sometimes they are not. Patients aged 75 years or older with ovarian cancer were found to be significantly less likely than younger patients to be treated with chemotherapy (58.2% vs 86.1%, P = .001).[23] Mahoney et al found that elderly patients with stage III colon cancer were less likely to be treated with chemotherapy after surgery than were younger patients.[24] Such undertreatment may be a primary cause of the poorer outcomes in elderly patients.[27] Indeed, the use of substandard chemotherapy doses and regimens has been shown to contribute to lower overall survival in patients with chemosensitive tumors in several large studies with long followups.[ 20,21,28-32] Otherwise-healthy elderly patients obtain benefits comparable to those obtained by younger patients when they are treated with chemotherapy of similar dose intensity.[1] This has been seen in numerous malignancies, including non-Hodgkin's lymphoma,[ 20] acute myelogenous leukemia,[ 33] early-stage breast cancer,[34] non-small-cell lung cancer,[10,35] and colon cancer[36] (Table 2). Fit elderly patients should therefore be treated as aggressively and with the same curative intent as younger patients. The greater susceptibility to myelosuppression in older patients, however, means that supportive care with colony-stimulating factor (CSF) and erythropoietic agents must be considered. Pharmacologic studies have shown that, despite the decline in hematopoietic reserves with older age, CSF administration is effective in elderly patients. It has been shown to produce the same dose-related increases in peak neutrophil counts in both young and elderly healthy volunteers.[37] Colony-stimulating factor has also been shown to increase the neutrophil counts by the same degree in young and elderly patients with various malignancies treated with myelosuppressive chemotherapy.[38] Managing neutropenia in elderly patients with prophylactic CSF has been assessed in a number of randomized placebo-controlled studies.[ 22,35,36,39-42] In four of these trials, in elderly patients with non- Hodgkin's lymphoma,[22,39-41] CSF started in the first cycle reduced the incidence of grades 3 and 4 neutropenia and of neutropenic infection by 32% to 82% and 32% to 100%, respectively; P < .01 for both.[43] Early CSF use is also associated with shorter hospitalizations for febrile neutropenia in elderly patients with breast cancer,[13] non-Hodgkin's lymphoma,[40] and acute myelogenous leukemia.[33,44,45] In addition, use of CSF in later cycles in patients treated with adjuvant chemotherapy for breast cancer has been shown to increase the proportion of patients in whom the dose intensity of the chemotherapy is maintained above the 85% threshold.[42,46] The use of CSF early in the course of chemotherapy and throughout all cycles makes it possible to deliver standard full-dose, as well as dose-dense, chemotherapy in older patients, with outcomes comparable to those in younger patients.[47-49] Risk Models for Neutropenia Colony-stimulating factor use in the first cycle of chemotherapy is effective in reducing both the incidence and the severity of neutropenia, as well as related complications, but its routine use in all patients treated with chemotherapy is not considered necessary or cost-effective. As discussed by Lyman in this supplement, efforts are under way to determine the characteristics of patients that place them at greater risk for neutropenia and associated complications.[50] The risk models that have been developed so far have found a number of risk factors for chemotherapy-induced neutropenia and neutropenic complications. Advanced age appears to be a general risk factor for chemotherapy-induced neutropenia and its complications in a number of clinical settings. A review of published risk models in which multivariate analysis had been performed analyzed a total of 18 models, including three that had been validated in separate populations.[6] Advanced age was reported to be an independent, significant risk factor in eight of the models and had been validated in at least two of them. In a separate review of the literature on risk factors for chemotherapy-induced neutropenia, nine studies considered the relation between advanced age and the risk of severe neutropenia, eight of which found that older patients were at greater risk and seven of which found that the relation was statistically significant.[51] Because advanced age has been established as a strong risk factor for neutropenic complications, many studies that have evaluated neutropenic events in this patient population have focused on the timing of complications, it being an important consideration in scheduling and coordinating preventive measures, such as prophylactic CSF. It appears that neutropenic complications-including mortality-commonly occur in the early cycles of chemotherapy in older patients. A retrospective analysis of data from 267 consecutive elderly patients with aggressive non-Hodgkin's lymphoma treated with CHOP found that 13% of the patients died of treatment- related causes, with 63% of the deaths occurring in the first cycle of chemotherapy.[52] Eighty-three percent of these deaths were attributed to infection, and 66% of them were in patients with severe neutropenia (Figure 1). A randomized trial that assessed chemotherapy-induced toxicities in 453 elderly patients with non- Hodgkin's lymphoma reported that, depending on the regimen used, 55% to 72% of the neutropenic events occurred in cycle 1 of the chemotherapy.[ 21] In another study, in 577 patients with non-Hodgkin's lymphoma treated with CHOP, 62% of the initial episodes of febrile neutropenia in elderly patients occurred in cycle 1 (Figure 2).[53] A retrospective analysis of data from two clinical trials in patients with metastatic breast cancer treated with doxorubicin and docetaxel(Drug information on docetaxel) (Taxotere) reported that 75% of all febrile neutropenic events occurred in cycle 1.[54] In summary, there is strong evidence that age itself is a general risk factor for severe neutropenia and that neutropenic complications are most likely in cycles 1 and 2 of chemotherapy. Advanced age may also be associated with other patient characteristics that affect that risk. Thus, a more accurate predictor of neutropenia may be the patient's physiologic, rather than chronologic, age. Nevertheless, the fact that advanced age is a significant risk factor-and in the absence of other risk factors to determine which elderly patients are at greatest risk-argues for the use of CSF started in the first cycle of chemotherapy in elderly patients. Such a strategy appears to be most effective in minimizing neutropenic complications and in facilitating the delivery of full-dose chemotherapy. The current guidelines of the American Society of Clinical Oncology (ASCO) for the use of CSF recommend its use in the first cycle of chemotherapy in certain populations of patients who are at higher risk for neutropenic complications. The "special circumstances" in these guidelines include poor performance status, advanced cancer, previous radiation therapy, extensive previous chemotherapy, history of febrile neutropenia, existing neutropenia, and conditions that increase the risks of serious infection.[55] Advanced age has consistently been found in several risk models to be an independent risk factor for severe neutropenia. In additon, the risk for neutropenia appears to be greatest in the earliest cycles of chemotherapy and withholding CSF in older patients until after an event has occurred may place them at an unacceptably high risk for serious infection and death. And, finally, data on elderly patients with various malignancies show that they benefit from chemotherapy as much as younger patients when it is administered at the standard recommended doses; early CSF use helps make this possible. Elderly patients who are treated with moderately aggressive chemotherapy should therefore be considered a special population in whom primary prophylaxis with CSF is warranted. Such an approach has been advocated by an advisory panel of the National Comprehensive Cancer Network (NCCN); the rationale is the greater risk of chemotherapy-induced neutropenia and its complications in elderly patients and the ability of G-CSF (granulocyte colony-stimulating factor) to reduce this risk (Table 3). Specifically, the NCCN guidelines for the management of elderly patients with cancer recommend the routine use of CSF in patients 70 years of age or older who are treated with CHOP or a regimen with similar dose intensity, and in patients 60 or older who are treated with induction or consolidation chemotherapy for acute myelogenous leukemia.[5] Conclusion The elderly are the single largest proportion of patients with cancer, and the majority of cancer-related deaths occur in this population. Elderly patients obtain comparable benefit from standard doses of chemotherapy as younger patients, but they are more susceptible to the myelotoxic effects of chemotherapy-in particular lifethreatening neutropenia-which often occur early. Investigation of clinical risk factors has consistently found that advanced age is a risk factor for neutropenic complications. When prophylactic CSF is administered early in the course of therapy and continued in all chemotherapy cycles it reduces the incidence and severity of neutropenia and associated complications, hence making it possible to use standard doses of chemotherapy. Such use should be routinely considered in elderly patients treated with moderately toxic chemotherapy regimens.