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Recombinant Human Erythropoietin in Cancer-Related Anemia

Recombinant Human Erythropoietin in Cancer-Related Anemia

ABSTRACT: The clinical development of recombinant human erythropoietin (rHuEPO) has had a remarkable impact on the clinical practice of oncology. A decade ago, randomized, placebo-controlled trials in anemic cancer patients demonstrated that rHuEPO resulted in an improvement in hemoglobin and hematocrit, a reduction in transfusion requirements, and improvement in quality-of-life (QOL) end points. Based on these trials, recombinant erythropoietin was approved for the treatment of anemia in patients with nonmyeloid malignancies in whom the anemia was caused by the effect of chemotherapy. The clinical indication was to decrease the need for transfusion in patients for whom anemia was not due to other reversible causes. Despite this broad indication, the incorporation of rHuEPO in clinical practice was limited because of a variety of factors, including physician perception that mild-to-moderate anemia in the cancer patient was generally asymptomatic and did not warrant intervention. Subsequently, three large open-label, prospective trials of recombinant erythropoietin were performed in the community setting in anemic cancer chemotherapy patients. All three trials replicated the results of the original randomized study, but with a much larger database of more than 7,000 patients. Importantly, these trials were able to define the major impact of hemoglobin level on quality of life. Patients on these trials who improved their hemoglobin > 2 g/dL or achieved a hemoglobin ³ 12 g/dL had the greatest improvement in symptoms of energy, activities of daily living, and overall quality of life. Furthermore, a once-per-week dosing schedule was found to be comparable to three-times-weekly administration of rHuEPO. A European randomized, placebo-controlled trial confirmed these QOL results, and a meta-analysis of other randomized clinical trials firmly supports the role of erythropoietin therapy in improving hemoglobin levels and reducing transfusion requirements. Based on this aggregate of data, the use of erythropoietin in the treatment of mild-to-moderate anemia has become a standard of care. These studies have also expanded our understanding of the problem of fatigue and the study of interventions that can improve quality of life for cancer patients. [ONCOLOGY 16(Suppl 10):41-53, 2002]

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 increase in the plasma.[1] 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.[2] 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[3] 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.[4]

Erythropoietin Therapy in Cancer Chemotherapy Patients

Pathophysiology

Studies of recombinant erythropoietin demonstrated that the
anemia experienced by the cancer chemotherapy patient is multifactorial—partially
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.

Initial Randomized Trials

The initial randomized, placebo-controlled clinical trials in cancer-related
anemia were performed in three separate populations, as outlined in Table
1
.[5] 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-based chemotherapy or non-cisplatin-based chemotherapy—based
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.[6]

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.

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