The current study’s findings suggest that aerobic and strength-resistance training combined with prophylactic EPO therapy benefits patients by reducing the number of RBC and platelet transfusions and the number of attempts at and total number of days of stem cell collection. Hemoglobin levels during the transplantation period were similar for the exercise and usual care groups. However, compared to the exercise group, the usual care group required significantly more RBC transfusions to maintain the same level of hemoglobin, suggesting that exercise had an effect on hemoglobin level. The findings in the current study are, therefore, consistent with others that report the benefit of exercise in raising hemoglobin levels in patients with cancer. The underlying mechanism to explain this benefit is unknown, but the greatest benefit seems to come from exercise in combination with EPO.
Based on the study results, EPO therapy acted with exercise to decrease the number of transfusions among patients receiving high-dose chemotherapy and transplantations as treatment for multiple myeloma. Duration of EPO administration is important in maintaining higher hemoglobin levels during the transplantation period. Patients in the current study who received EPO according to the study algorithm through their first transplantation had higher hemoglobin levels during the transplantation period than patients who were in the study only through stem cell collection. Even with EPO therapy, patients in the current study had an average hemoglobin level of 10.8 g/dl during the transplantation period.
The results also suggest that the investigational use of EPO as prophylactic therapy is beneficial for patients with normal or near-normal hemoglobin levels and patients with anemia. Unless baseline hemoglobin was greater than 15 g/dl, all patients in the study received EPO according to the study algorithm just before receiving chemotherapy. Starting EPO therapy before chemotherapy may help prevent chemotherapy-induced anemia, but several weeks of EPO therapy are needed before the benefit is seen (Ortho Biotech Products, 2005
). Study results may not be applicable to patients with less myelosuppressive treatment regimens.
Erythropoiesis-stimulating agents (ESAs) were approved by the U.S. Food and Drug Administration (FDA) based on their effectiveness in reducing the need for RBC transfusions in patients receiving chemotherapy for cancer. The current approved labeling for ESAs, including an FDA Black Box Warning, recommends using the lowest dose necessary in patients receiving chemotherapy to avoid the need for blood transfusions. The FDA (2007) also advises that hemoglobin not exceed 12 g/dl. Health risks associated with the use of ESAs in the treatment of anemia for use in patients with advanced breast, head and neck, lymphoid, and non-small cell lung cancers include shortened overall survival or time-to-tumor progression and an increased incidence of thrombotic events (e.g., myocardial infarction, stroke, thrombosis) in patients receiving chemotherapy (FDA).
The incidence of DVT (21%) was high among patients in the current study. The risk of DVT is known to be high with cancer (Naess et al., 2007
), with central venous catheters (Monreal et al., 2006
), and with chemotherapy and thalidomide (Zangari et al., 2003
), particularly with doxorubicin and thalidomide (Zangari et al., 2002
). Additional studies are being conducted using medical record reviews to compare the incidence of DVT among patients in the current study with patients who were treated with the same high-dose chemotherapy and autologous PBSCT protocol but did not receive ESA therapy according to the current study’s algorithm.
The Centers for Medicare and Medicaid Services (CMS) recently limited coverage of ESAs to patients receiving chemotherapy with a hemoglobin level below 10 g/dl with symptomatic ischemia and who cannot be transfused, or below 9 g/dl in patients with cardiovascular disease (Purrough et al., 2007
). The American Society of Clinical Oncology (ASCO) expressed concern over CMS’s national coverage that “makes it impossible for physicians to use these agents in a manner consistent with the FDA-approved prescription labeling for these agents,” and, at the request of CMS, ASCO submitted supporting clinical information (Bailes, 2007
, p. 2). The FDA’s response was that FDA-approved labeling and the CMS coverage decision were generally consistent (FDA, 2007
). CMS asked for new evidence to show that patients receiving chemotherapy for cancer require hemoglobin levels to be above 10 g/dl. ESA therapy is superior to transfusion therapy (Schnell, 2007
The current study is limited by the lack of transfusion criteria (i.e., hemoglobin level or other criteria used to determine whether a transfusion is needed). The analysis may have missed specific disease-related influences on hemoglobin levels. Patients with hemoglobin less than 8 g/dl received RBC transfusions according to the transplantation protocol. Some patients with hemoglobin values above 8 g/dl may have received transfusions because of symptoms or other clinical indications. Although randomization should have distributed disease risks equally for the exercise and usual care groups, patients were not randomly assigned to the short- and long-term groups. However, by taking the first eligible patients, similar numbers of patients from the exercise and usual care groups did take part in the long-term study. The hemoglobin level at which anemia requires transfusions is not well established (Bailes, 2007
). Whether patients in the current study received transfusions because of a low hemoglobin level, symptoms, or both is unknown. Regardless of the reason, patients in the usual care group received more transfusions than patients in the exercise group to maintain a similar hemoglobin level.