Erythropoietin has long been known to be the major regulator of erythropoiesis. In studies more than three decades ago, Finch demonstrated that as hemoglobin levels fall below 12 g/dL, endogenous levels of erythropoietin(Drug information on erythropoietin) increase in the plasma. In patients with chronic renal failure and low levels of endogenous erythropoietin, replacement therapy with recombinant human erythropoietin (rHuEPO [Epogen, Procrit]) resulted in normalization of hemoglobin levels. Despite the significant impact erythropoietin therapy had on the renal dialysis patient population, this was felt to be a unique situation related to the lack of erythropoietin production in the setting of renal failure. For anemia due to other causes, it was assumed that recombinant erythropoietin would not be effective, because it was assumed that endogenous erythropoietin responses would occur. However, cancer population studies by Miller and colleagues demonstrated that the endogenous erythropoietin response is blunted in the face of cancer-related anemia. Subsequent studies have suggested that this lack of appropriate erythropoietin response in the setting of cancer may be due to inflammatory cytokines that may also play a role in suppressing erythropoiesis as well as in erythropoietin production.
Studies of recombinant erythropoietin demonstrated that the anemia experienced by the cancer chemotherapy patient is multifactorialpartially attributable to the bone marrow suppression of the cancer chemotherapy, partly related to the blunted erythropoietin response and to the suppressive effects of cancer and cytokines on erythropoiesis. Although it was expected that higher doses of erythropoietin would be required, it was remarkable that anemia was ameliorated in most patients with erythropoietin alone, despite this complex multifaceted pathophysiology.
The initial randomized, placebo-controlled clinical trials in cancer-related anemia were performed in three separate populations, as outlined in Table 1. One group of patients with cancer-related anemia not associated with chemotherapy received recombinant human erythropoietin at 100 U/kg SC three times weekly vs placebo for an 8-week period. The other two groups of patients with chemotherapy-related anemia received rHuEPO at 150 U/kg SC three times weekly for a 12-week period vs placebo. These two groups were divided into patients receiving cisplatin(Drug information on cisplatin)-based chemotherapy or non-cisplatin-based chemotherapybased on the assumption that cisplatin might be more likely to cause anemia than non-cisplatin-based regimens because of its renal effects. Subsequent trials demonstrated that, in the absence of renal failure, non-cisplatin-containing regimens are equally likely to cause anemia as cisplatin-based therapy and that most myelosuppressive chemotherapy regimens cause similar levels of anemia.
The dose of erythropoietin chosen for the nonchemotherapy group was based on the assumption that a lower dose would be effective in the absence of chemotherapy. While this theory has been proved true, the shorter time-course of therapy did not allow for the differences between the placebo and erythropoietin group to become evident. Therefore, the US Food and Drug Administration (FDA) limited the initial approval of rHuEPO to patients with non-myeloid malignancies whose anemia was caused by chemotherapy.
The primary efficacy criteria in these registration studies were intended to evaluate the change in hematocrit from baseline to final value; to quantify the number of units of transfusions; and to assess patient perception of quality of life (QOL) as measured by the self-administered linear analog scale for the domains of energy, activity, and overall quality of life. The average age of patients in these trials was 61 to 62 years, and their median hematocrit was 28% to 29%. More than 45% of patients had received transfusions in the 2 to 3 months before the study. As expected, patients generally had inappropriately low endogenous erythropoietin levels, with most levels below 100 mU/mL. The results of these trials are shown in Tables 2 and 3, and Figure 1.
The nonchemotherapy patients treated for 8 weeks with rHuEPO had a significant improvement in hematocrit (+2.8%) compared with the placebo group (-0.1%). However, the cisplatin and noncisplatin patients (treated for 12 weeks) had an even greater difference, with an improvement of 6% to 6.9% compared with 1.1% to 1.3% for the placebo group. The impact of these changes in hematocrit on transfusion requirements can be seen in Table 3.
For the nonchemotherapy group, 26% of both the erythropoietin-treated patients and the placebo patients required transfusions. By contrast, in the combined chemotherapy group, 45.5% of the placebo patients required transfusion vs 27.8% of the erythropoietin-treated patients in the second and third months of the study.
These studies demonstrate that the first month of therapy was required to begin to reverse the anemia of treatment and therefore differences in transfusion requirements were not seen until the second and third months. This finding also demonstrates why the nonchemotherapy group was unable to show a transfusion benefit after only 8 weeks of therapy.
Figure 1 outlines the changes in QOL measures for self-rated scores of energy level, daily activities, and overall QOL measures from baseline to final evaluation for the erythropoietin-treated vs placebo patients. Utilizing the linear analog scale, patients rate these items on a 100-mm scale. The changes noted by patients displayed greater improvement in quality of life for the erythropoietin-treated patients compared with those receiving placebo for energy level, daily activities, and overall quality of life; only the overall quality of life was shown to be significantly improved for the erythropoietin therapy group (P < .05).
This trial also provided an opportunity to carefully assess potential adverse events of recombinant erythropoietin compared with placebo. The reporting of adverse events in both groups was quite similar and reflected the adverse events commonly seen in cancer patients receiving chemotherapy, with only the incidence of diarrhea and edema higher in the rHuEPO group (P < .05). There was a reduction in fatigue from 20% in the placebo group to 15% in the erythropoietin-treated group. Furthermore, there was a statistically significant decrease in dyspnea from 15% in the placebo group to 8% in the erythropoietin group (P < .03). Unlike the renal dialysis population, seizures and hypertension were uncommon in both groups, and not more frequent in the erythropoietin-treated patients, suggesting that these complications may be unique to renal dialysis.
FDA Approval Guidelines
Based on the results of these placebo-controlled, randomized clinical trials, the FDA approved rHuEPO for the treatment of anemia in patients with nonmyeloid malignancies whose anemia was caused by the effects of chemotherapy. The FDA guidelines further clarified that erythropoietin therapy was indicated to decrease the need for transfusions in patients who will receive concomitant chemotherapy for a minimum of 2 months. It was also emphasized that erythropoietin was not indicated in the setting of treatment of anemia caused by other etiologies, such as iron or folate deficiency, hemolysis, or gastrointestinal bleeding.
Because the QOL data from these initial registration trials were not as robust as the hematocrit and transfusion data, the use of erythropoietin to improve quality of life was not included as an FDA indication. However, the observation that overall quality of life was improved in the erythropoietin-treated patients led to some of the largest clinical trials ever performed in cancer patients to better define this relationship.