Advances in the Management of Chemotherapy-Induced Anemia and Its Treatment

Anemia is a frequent but insidious complication of cancer and its cytotoxic chemotherapy, contributing to debilitating fatigue, lethargy, cardiovascular problems, shortness of breath, and reduced cognitive function in individuals who often already have significant morbidity and diminished quality of life (QOL) as a consequence of their malignancy.[1,2] Although the complexities of cancer pathology can make it difficult to delineate the precise contribution of anemia to clinical outcome, associations with reduced treatment effectiveness, increased mortality, increased transfusion requirements, reduced performance and QOL, and increased cost have been observed.[3,4]

Erythropoietic support with recombinant human erythropoietin (rHuEPO; epoetin alfa [Procrit] and epoetin beta) has become the standard of care for chemotherapy-induced anemia, by increasing hemoglobin (Hgb) levels with subsequent reductions in transfusion requirements and improvements in QOL.[5-11] Moreover, the introduction of darbepoetin alfa (Aranesp), a novel erythropoiesis-stimulating protein (ESP) with a longer terminal half-life, has lessened the effect of ESP support on patients without compromising efficacy.[12-17] However, despite widespread recognition that the appropriate management of anemia in patients with cancer is a crucial component of the treatment paradigm,[18-20] it is evident that many patients are not receiving timely intervention.[21,22] The articles in this supplement to ONCOLOGY summarize some of the key issues in the effective management of chemotherapy-induced anemia.

New data are emerging in the field of anemia management in patients with hematologic malignancies. Dr. David J. Straus addresses the utility of epoetin alfa and darbepoetin alfa in improving Hgb levels, with consequent improvements in QOL, fatigue, productivity, and cognitive function, and without adverse effects on clinical outcome. Interestingly, these effects are apparent even in patients with mild anemia, suggesting that physicians should carefully consider treating anemia in patients with Hgb levels between 11 and 12 g/dL. This is reflected in the overview of clinical guidelines for ESP use in chemotherapy-induced anemia provided by Dr. George M. Rodgers and by the review of evidence to support early intervention with ESPs from Dr. Gary H. Lyman. The most recent evidence-based practice guidelines (from the National Comprehensive Cancer Network) suggest a threshold Hgb level of 10 to 11 g/dL for commencing erythropoietic therapy with either epoetin alfa or darbepoetin alfa.[19] These guidelines are based on an approximate 20% to 50% relative risk reduction in transfusion with ESP treatment. However, it appears that a similar magnitude of effect is seen when mild chemotherapy-induced anemia is treated with ESPs, suggesting that the focus of anemia management should possibly switch from correcting decreased Hgb levels to maintaining reasonable target Hgb levels. The impact of early intervention with ESPs on QOL and on the ability to maintain chemotherapy and radiotherapy schedules needs to be carefully weighed against other clinical and economic considerations.

Clinical guidelines for cancer- and chemotherapy-induced anemia also discuss the utility of iron supplementation in patients receiving erythropoietic therapy. Dr. David H. Henry discusses the possibility of augmenting response to ESPs with appropriate iron supplementation, based on several studies that have compared hematopoietic response rates in epoetin alfa-treated patients with iron deficiency receiving oral or intravenous iron or no iron. In addition, guidelines emphasize that one of the primary goals of increasing Hgb levels is to improve QOL and reduce fatigue. This point is reiterated by Dr. David Cella, who highlights the importance of establishing a patient's fatigue level at clinic visits by using appropriate and validated questionnaires to ensure that tangible improvements in QOL are being achieved.

There is constant tension between minimizing the effect of cancer therapy on patients and ensuring the best possible outcome. Recently, data have demonstrated that darbepoetin alfa can be effectively administered once every 3 weeks, which may allow the dosing of ESP therapy to be synchronized with standard chemotherapy cycles. Indeed, as Dr. John Glaspy explains, the hematopoietic and clinical responses observed with darbepoetin alfa given every 3 weeks are indistinguishable from results produced with weekly dosing, and are not compromised by synchronous cytotoxic treatment.

This has exciting implications for improving treatment convenience for patients, the importance of which is highlighted in the review from Dr. Barry Fortner. Reducing the number of clinic visits by synchronizing anemia treatment with existing chemotherapy may translate into considerable time savings for both the patient and caregiver, as well as a reduction in human resource time and costs at the medical clinic.

Finally, the risk-benefit profile of any treatment needs to be carefully considered. Concerns have been raised over a possible association between the use of ESPs and decreased survival, potentially as a consequence of a rapid rise in Hgb levels. Dr. Jeffrey Crawford discusses these concerns, providing evidence suggesting that there may be an improvement in survival with erythropoietic therapy. Five controlled trials of darbepoetin alfa, each with enrollments of between 600 and 1,000 patients, have been initiated to test the effect of treatment on survival, with meta-analysis of the five trials having 80% power to detect a hazard ratio for mortality as small as 1.15.

In summary, simplification of the management of cancer- and chemotherapy-induced anemia is becoming a more achievable goal with refinement of dosing schedules, clearer correlations with clinical outcome, and increasing confidence in safety. The tangible benefits for patients, health-care providers, and payers should become clearer as additional data are gathered and analyzed.

-Gary H. Lyman, MD, MPH, FRCP (EDIN)
-John Glaspy, MD, MPH

Disclosures:

Dr. Lyman has received research support from Amgen and has served on speakers bureaus for Amgen and Ortho Biotech. Dr. Glaspy has received research support from Amgen and Ortho Biotech.

References:

1. Curt GA, Breitbart W, Cella D, et al: Impact of cancer-related fatigue on the lives of patients: New findings from the Fatigue Coalition. Oncologist 5:353-360, 2000.

2. Glaspy J: Anemia and fatigue in cancer patients. Cancer 92:1719-1724, 2000.

3. Knight K, Wade S, Balducci L: Prevalence and outcomes of anemia in cancer: A systematic review of the literature. Am J Med 116(suppl 7A):11S-26S, 2004.

4. Lyman GH, Berndt ER, Kallich JD, et al: The economic burden of anemia in cancer patients receiving chemotherapy. Value Health 8:149-156, 2005.

5. Seidenfeld J, Piper M, Flamm C, et al: Epoetin treatment of anemia associated with cancer therapy: A systematic review and meta-analysis of controlled clinical trials. J Natl Cancer Inst 93:1204-1214, 2001.

6. Glaspy J, Bukowski R, Steinberg D, et al: Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. Procrit Study Group. J Clin Oncol 15:1218-1234, 1997.

7. Demetri GD, Kris M, Wade J: Quality-of-life benefit in chemotherapy patients treated with epoetin alfa is independent of disease response or tumor type: Results from a prospective community oncology study. Procrit Study Group. J Clin Oncol 16:3412-3425, 1998.

8. Gabrilove JL, Cleeland CS, Livingston RB, et al: Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: Improvements in hemoglobin and quality of life are similar to three-times-weekly dosing. J Clin Oncol 19:287-2882, 2001.

9. Crawford J, Cella D, Cleeland CS, et al: Relationship between changes in hemoglobin level and quality of life during chemotherapy in anemic cancer patients receiving epoetin alfa therapy. Cancer 95:888-895, 2002.

10. Littlewood TJ, Bajetta E, Nortier JW, et al: Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: Results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol 19:2865-2874, 2001.

11. Hedenus M, Adriansson M, San Miguel J, et al: Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: A randomized, double-blind, placebo-controlled study. Br J Haematol 122:394-403, 2003.

12. Schwartzberg LS, Yee LK, Senecal FM, et al: A randomized comparison of every-2-week darbepoetin alfa and weekly epoetin alfa for the treatment of chemotherapy-induced anemia in patients with breast, lung, or gynecologic cancer. Oncologist 9:696-707, 2004.

13. Patton J, Reeves T, Wallace J: Effectiveness of darbepoetin alfa versus epoetin alfa in patients with chemotherapy-induced anemia treated in clinical practice. Oncologist 9:451-458, 2004.

14. Kotasek D, Steger G, Faught W, et al: Darbepoetin alfa administered every 3 weeks alleviates anaemia in patients with solid tumours receiving chemotherapy: Results of a double-blind, placebo-controlled, randomised study. Eur J Cancer 39:2026-2034, 2003.

15. Vansteenkiste J, Pirker R, Massuti B, et al: Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst 94:1211-1220, 2002.

16. Vadhan-Raj S, Mirtsching B, Charu V, et al: Assessment of hematologic effects and fatigue in cancer patients with chemotherapy-induced anemia given darbepoetin alfa every two weeks. J SupportOncol 1:131-138, 2003.

17. Berndt E, Kallich J, McDermott A, et al: Reductions in anaemia and fatigue are associated with improvements in productivity in cancer patients receiving chemotherapy. Pharmacoeconomics 23:505-514, 2005.

18. Rizzo JD, Lichtin AE, Woolf SH, et al: Use of epoetin in patients with cancer: Evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol 20:4083-4107, 2002.

19. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Cancer and treatment-related anemia. Version 1.2006. Available at http://www.nccn.org. Accessed on March 03, 2006.

20. Bokemeyer C, Aapro MS, Courdi A, et al: EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer. Eur J Cancer 40:2201-2216, 2004.

21. Ludwig H, Van Belle S, Barrett-Lee P, et al: The European Cancer Anaemia Survey (ECAS): A large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients. Eur J Cancer 40:2293-2306, 2004.

22. Adams JR, Elting LS, Lyman GH, et al: Use of erythropoietin in cancer patients: Assessment of oncologists' practice patterns in the United States and other countries. Am J Med 116:28-34, 2004.