Special Treatment Considerations in the Elderly
One substantial obstacle in treating older leukemia patients with induction chemotherapy is the presence of medical comorbidities, which can limit their ability to tolerate traditional chemotherapy regimens used to treat AML (Figure 1). Over 25% of cancer patients over age 75 have six or more comorbidities.[15] The presence and severity of comorbidities has an independent adverse effect on the survival of patients with all types of cancer.[16] This may be due, in part, to the physical burden of the medical condition, the increased risk of toxicity from intensive chemotherapy, or drug interactions between chemotherapeutic agents and drugs used to treat various medical conditions. For example, cardiotoxicity secondary to anthracyclines, which are commonly used to treat acute leukemia, occurs more frequently in elderly patients.
Furthermore, elderly patients are less likely to be offered intensive induction, owing largely to physician or patient concerns of excessive toxicity with standard chemotherapy regimens. In a review of Medicare claims between 1991 and 1996 of all patients older than age 60 diagnosed with AML, only 30% of patients received intensive chemotherapy.[17] For those patients who received induction chemotherapy, median survival was significantly prolonged compared to the entire leukemia group (8 vs 2 months).
However, it is not clear that intensive vs nonintensive options are offered to patients based on functional status or comorbidities alone. In a prospective analysis of elderly patients with AML and advanced MDS, 51% of patients opted for a less aggressive treatment algorithm.[18] Patients receiving intensive chemotherapy tended to be younger than those choosing best supportive care or nonintensive chemotherapy; however, baseline performance status or quality-of-life scores were not significantly different between the two groups. Thus, inferior outcomes may be, in part, attributable to elderly patients receiving low-intensity treatment regimens based on either physician or patient perception of their ability to tolerate cytotoxic agents.
Induction Chemotherapy
Standard induction chemotherapy for AML in adults has traditionally consisted of a combination of cytarabine and an anthracycline, with or without additional cytotoxic agents. Regardless of the induction regimen utilized, elderly patients are less likely than their younger counterparts to achieve complete remission from their leukemia (30%-50% vs 60%-80%, see Table 3).[7,11,19-28] Furthermore, long-term outcomes in this setting remain dismal for elderly patients, who have a median survival of only 6 to 12 months. Alternative strategies have been investigated to improve remission rates, prolong long-term survival, and minimize treatement-related toxicities that lead to increased morbidity and mortality. These strategies include the use of less-intensive chemotherapy regimens, altered dosing or choice of anthracyclines, addition of alternative chemotherapies, maintenance chemotherapy, and the use of growth factors in priming or neutrophil recovery.
Given the suboptimal outcomes using induction chemotherapy in elderly AML patients, several groups have investigated whether standard induction is superior to supportive care or low-dose chemotherapy for patients over age 50 to 65.[29-31] However, only one trial—by the European Organization for Research and Treatment of Cancer (EORTC)—provided prospective, randomized data to suggest that outcomes from induction therapy were superior to palliative care alone, showing median overall survivals of 22 vs 11 weeks, respectively (P = .015).[30] That said, the majority of patients enrolled in this trial were between the ages of 66 and 75, and thus, it remains unclear whether standard induction chemotherapy continues to be beneficial for patients older than age 75.
A retrospective study examined this question by comparing outcomes for patients over age 75 to those between 65 and 74 who received either induction chemotherapy, low-dose palliative chemotherapy, or supportive care alone.[32] For the cohort of patients older than 75 who received a standard anthracycline-based regimen, complete remission and overall survival rates were not significantly different from those achieved by the younger group and were also comparable to historical studies of elderly patients.
Contrary to this finding, a retrospective review of patients older than age 75 treated in Italy between 1987 and 1996 found no benefit in terms of overall survival in patients treated with induction therapy vs low-dose chemotherapy or supportive care.[33] However, for the small number of patients who were able to attain a complete remission, survival was improved. A similar finding was reported by M. D. Anderson, suggesting that patients older than age 80 should not receive standard induction therapy. This is based on a single-institution experience with 30 patients over the age of 80 treated with either an anthracycline alone, an anthracycline plus cytarabine, or fludarabine with cytarabine. The median survival for these patients was a mere 3 to 4 weeks, which compared to a median overall survival of 10 weeks for age-matched controls of a historical cohort who did not receive induction chemotherapy.[34]
Other investigators have suggested that the decision to offer induction chemotherapy should not be based on age alone, but rather on the presence of adverse features predictive of an inferior response to chemotherapy. In a review of over 150 patients with AML over the age of 60 treated with intensive induction chemotherapy, the presence of a complex karyotype was highly predictive of outcome.[35] A median survival of 15 months was attained for patients with a normal karyotype, compared with 4 months for those with a complex karyotype. With a lack of prospective data to guide management of patients over age 75, each patient must be considered individually, with the decision regarding induction chemotherapy based on comorbidities, cytogenetics, and patient preference.
Elderly patients who are considered candidates for standard induction therapy will receive an anthracycline-based regimen, such as daunorubicin at 45 to 60 mg/m2 for 3 days combined with cytarabine at 100 mg/m2 by continuous infusion over 7 days (ie, "7 + 3"). Multiple trials have assessed the utility of combining additional agents, such as thioguanine (Tabloid) or etoposide to the standard anthracycline-based protocol.[19,36] There have been no clear improvements in overall survival when these agents are substituted or combined with cytarabine and an anthracycline.
The optimum choice of anthracycline has also been investigated, and neither mitoxantrone (Novantrone) nor idarubicin has yielded improvements in overall survival for elderly patients when compared to standard doses of daunorubicin.[20] Because of the increased risk of cardiotoxicity with anthracyclines in the elderly, alternative doses of daunorubicin have been explored. A large meta-analysis of over 2,000 patients demonstrated a benefit in terms of complete remission rates and disease-free survival for patients who received a total of at least 90 mg/m2 of daunorubicin.[37] The incidence of early death was identical between the two groups, and thus, there is no definitive benefit associated with reducing the dose of daunorubicin in elderly patients.
Growth Factors
Leukemic blasts in elderly patients with AML are more commonly resistant to standard chemotherapy, as evidenced by inferior remission rates compared to younger cohorts. Growth factor priming in elderly patients with leukemia has been of interest to several groups.[20,38] Both granulocyte colony-stimulating factor (G-CSF [Neupogen]) and granulocyte-macrophage colony-stimulating factor (GM-CSF [Leukine]) have been shown to alter the cell-cycle kinetics of the leukemic blasts, rendering them more susceptible to agents such as cytarabine, which is a cell-cycle dependent cytotoxic drug.[39] In younger patients, the addition of G-CSF to induction chemotherapy with idarubicin and cytarabine followed by amsacrine and cytarabine resulted in significant improvements in disease-free and overall survival.[38] However, a large Eastern Cooperative Oncology Group (ECOG) study revealed no improvements in complete remission or overall survival from GM-CSF priming in elderly AML patients given just prior to induction chemotherapy.[20]
A more common use of growth factors, both in clinical trials and in standard practice, has been in the postchemotherapy stage of treatment. There is generally a 2- to 3-week delay in neutrophil reconstitution following the completion of chemotherapy, and elderly patients in particular are at high risk for severe infection and early death. One complicating factor has been the theoretical concern that growth factor use would stimulate residual leukemia cells to proliferate, thus limiting the effectiveness of induction therapy. Preclinical studies have supported this theory with the finding that G-CSF and GM-CSF can upregulate procaspase protein levels in leukemia cell lines, further promoting cell survival and proliferation.[39] However, several groups have investigated the use of growth factors on various days following the completion of chemotherapy, and there has been no evidence of inferior clinical outcome.[21,36,40-42] With the use of G-CSF or GM-CSF following induction, a 2- to 6-day improvement in neutrophil recovery time can be seen, and in some cases with reduced numbers of severe infections. Only one study to date has reported an improved overall survival with the use of GM-CSF.[41]
Given the current evidence, the use of growth factor support post-induction chemotherapy is unlikely to be harmful and may reduce the number of days the patient remains neutropenic and thus susceptible to severe infections.
