Guidelines for the use of epoetin in cancer patients: a much-needed step forward in standardizing anemia treatment

Recently, clinical practice guidelines for the use of epoetin alfa in cancer patients were published.¹  Although based on high-quality evidence, the rapid pace of research in anemia management requires that such guidelines be reviewed and updated regularly. This letter reviews new data, specifically on anemia-related quality of life (QOL) and optimal hemoglobin (Hgb) management, which are relevant to, and may serve to augment, the guidelines.

Although the guidelines endorse epoetin alfa's ability to improve hematologic outcomes, they do not support a relationship between epoetin alfa treatment and QOL improvements, primarily due to methodologic concerns regarding critical studies; however, there is new evidence to consider. An a priori, planned, multivariate analysis of QOL data from Littlewood et al,²  accounting for possible confounding variables including disease progression, still indicated significant (P < .05) improvements in QOL for all 5 cancer-specific scales.³  A more conservative analysis by Fairclough et al,⁴  using joint-mixed effects modeling to account for nonrandom missing data, produced significant between-group differences in QOL scores comparable with those previously reported.

There were 2 studies published after the guidelines based on Littlewood et al's data²  that examined the clinical significance of QOL improvements in patients receiving epoetin alfa. Patrick et al used change in Hgb level as an internal standard to determine the minimally important difference in QOL that could be considered clinically meaningful.⁵  Differences in QOL scores between the epoetin alfa and placebo groups exceeded these minimally important differences, supporting their clinical relevance. Cella et al compiled population-based reference QOL data from 1078 persons in the United States via an internet survey.⁶  Comparison of the survey results with the Littlewood et al data²  showed that epoetin alfa treatment overcame 49% to 95% of the QOL deficit seen in anemic cancer patients compared with the population-norm sample. The Patrick et al and Cella et al analyses address the concerns of the guidelines and provide additional support for the beneficial effects of epoetin alfa on QOL in anemic cancer patients.

Selecting the optimal Hgb level for intervention is critical for maximizing patient benefits related to epoetin alfa treatment. The guidelines make a conservative recommendation (Hgb ≤ 100 g/L [10 g/dL]) based on published reports from clinical trials meeting strict criteria. However, the guidelines also state that epoetin alfa administration in patients with Hgb levels of 100 to 120 g/L (10-12 g/dL) should be determined by clinical circumstances.

One retrospective analysis⁷  and 2 prospective trials published as abstracts^8,9  provide strong evidence that early intervention with epoetin alfa prevents declines in Hgb level and QOL. A retrospective analysis of the Littlewood et al data²  prospectively stratified by Hgb level (Hgb > 105 g/L [10.5 g/dL] or ≤ 105 g/L [10.5 g/dL]) showed a similar mean increase in Hgb level from baseline for the higher and lower Hgb strata at 4 weeks and at last value; however, the transfusion rate was relatively lower in the higher Hgb stratum (7.1% compared with 28.2% for the ≤ 105 g/L [10.5 g/dL] stratum).⁷  The proportion of responders (patients with Hgb level increase ≥ 20 g/L [2 g/dL]) was also greater in the higher stratum (80.5% vs 68.5% in the ≤ 105 g/L [10.5 g/dL] stratum). With respect to cost effectiveness, fewer patients in the higher (15%) versus the lower (25%) stratum required doubling of their starting dosage.

Interim results of an open-label randomized trial in patients with hematologic malignancies and Hgb levels of 100 g/L (10 g/dL) or more and 120 g/L (12 g/dL) or less show a positive effect of epoetin alfa.⁹  Patients were randomized to either once-weekly epoetin alfa immediately (EPO) or to observation, during chemotherapy, with epoetin alfa offered if Hgb level decreased to less than 90 g/L (9 g/dL) (OBS). From baseline to end of treatment, the EPO group experienced significant increases in Hgb level (P = .007) and improvements in QOL. Furthermore, patients in the EPO group had a significantly greater decrease in clinic visits (P = .002) and days requiring assistance (P < .001), suggesting that treatment of mild anemia (Hgb 100-120 g/L [10-12 g/dL]) may reduce health care resource utilization.

Final results, not yet peer-reviewed, from a double-blind, placebo-controlled clinical trial in breast cancer patients receiving adjuvant or neoadjuvant chemotherapy, support efficacy of early intervention.⁸  Breast cancer patients with mean Hgb levels of 128 g/L (12.8 g/dL) receiving once-weekly epoetin alfa experienced an improvement in Hgb levels (+8 g/L [+0.8 g/dL]) after 16 weeks, and attenuated declines in both QOL and fatigue versus patients receiving placebo. In contrast, patients receiving placebo experienced a more than 20 g/L (2 g/dL) mean decrease in Hgb level after 2 cycles of anthracycline-based chemotherapy.⁸  Therefore, studies in patients with diverse malignancies suggest that epoetin alfa can maintain or improve Hgb level^7-9  and QOL,^8,9  and decrease transfusions⁷  in patients with baseline Hgb level more than 100 g/L (10 g/dL). These results suggest a basis for a stronger recommendation regarding epoetin alfa use in patients with Hgb levels higher than 100 g/L (10 g/dL).

The focus of this letter is to draw attention to developments in 2 critical areas of anemia management: anemia-related QOL and optimal Hgb management. New analyses and data are relevant and may serve to augment the guidelines. As standards of care in anemia management continue to evolve, consideration of emerging data will be an essential part of the review process for clinical practice guidelines.