Perspective
Weighing the Hazards of Erythropoiesis Stimulation in Patients with Cancer
N Engl J Med 2007; 356:2445-2448June 14, 2007
- Article
On May 10, 2007, the Food and Drug Administration (FDA) convened a meeting of its Oncology Drug Advisory Committee to discuss concerns about risks associated with the erythropoiesis-stimulating agents (ESAs) used to treat anemia caused by chemotherapy. The principal ESAs under scrutiny were epoetin alfa (Procrit, Eprex, and Epogen) and darbepoetin alfa (Aranesp), and the risks — actual or potential — were thromboembolic disease, promotion of tumor growth, and decreased survival. The actual risk of thromboembolic events was shown in two phase 3 clinical trials, reported in the Journal in 2006, that unequivocally showed an increased risk of death or cardiovascular or thromboembolic events among patients with chronic renal failure who were treated with ESAs to drive hemoglobin levels into the normal range (13.5 g per deciliter or higher), as compared with those treated to achieve levels in a subnormal range (10.5 to 11.5 g per deciliter).
In 1993, the FDA approved epoetin alfa for patients with cancer on the basis of pooled data from six randomized, double-blind, placebo-controlled trials that included 131 patients with various types of cancer. The approval focused on the effectiveness of epoetin alfa in reducing the number of transfusions required to treat chemotherapy-induced anemia — not the anemia of cancer. In oncology, ESAs are helpful in supportive care, but the FDA has not approved the use of such agents to alleviate fatigue or weakness or to improve patients' quality of life.
In 2003, concern about a detrimental effect of ESAs in patients with cancer arose with the publication of the results of a multicenter, double-blind trial conducted by Henke et al.1 involving 351 patients with anemia (hemoglobin level, <12 g per deciliter in women or <13 g per deciliter in men) who had cancer of the oral cavity, pharynx, or larynx (see table
Adverse Outcomes Associated with Erythropoiesis-Stimulating Agents (ESA) Treatment in Patients with Cancer.). In this trial, patients were randomly assigned to receive radiotherapy along with either placebo or epoetin beta (Neo-Recormon) at a dose of 300 IU per kilogram of body weight three times weekly, starting 10 to 14 days before radiotherapy and continuing throughout treatment. The epoetin beta group had substantially shorter progression-free survival and overall survival than the placebo group.In another study, the Breast Cancer Erythropoietin Survival Trial (BEST), 939 patients with metastatic breast cancer receiving first-line chemotherapy were randomly assigned to receive either epoetin alfa (Eprex) at a dose of 40,000 IU once weekly or placebo for 12 months.2 Treatment with the study drug was initiated if the hemoglobin level was 13 g per deciliter or lower at baseline or if it decreased to that point. Overall survival at 1 year was lower in the epoetin alfa group. The study was stopped early by an independent data and safety monitoring committee because of higher mortality in the epoetin alfa group at 4 months. As in the study by Henke et al., the first part of the survival curve in the BEST trial showed an increased risk of death from cancer, which is suggestive of enhanced tumor growth.
In May 2004, the results of such studies prompted the FDA to convene an advisory committee to assess the safety of ESAs in patients with cancer. The committee agreed on the need for additional large, randomized trials to determine the safety of ESAs in patients with several types of tumors, including head and neck, breast, and non–small-cell lung cancer. Accrual was to be completed over a period of 3 to 5 years, but as of May 2007, enrollment was poor.
Two trials involving patients with small-cell lung cancer showed that the use of an ESA according to approved guidelines resulted in no apparent reduction in survival, and a meta-analysis showed equivalent overall survival and disease control among patients with cancer when ESAs were used within the recommended dose range. Nevertheless, four recent studies showed evidence of harm associated with the use of ESAs in patients with cancer. One of these trials aimed to randomly assign 300 patients with advanced metastatic non–small-cell lung cancer to receive 12 weekly injections of epoetin alfa or placebo, with a target hemoglobin level of 12 to 14 g per deciliter.3 The trial was stopped early after an unplanned safety analysis involving 70 patients revealed a significant difference in median survival in favor of placebo. In the second study, 522 patients who were scheduled for definitive radiotherapy for head and neck cancer were randomly assigned to receive darbepoetin alfa or red-cell transfusion.4 This trial was terminated early after a futility analysis indicated that there was a detrimental effect on local–regional control (the primary end point) and a trend toward shorter survival in the darbepoetin alfa group. The table includes the results of two other unpublished trials in which the outcome was worse in the darbepoetin alfa group than in the control group.
In March 2007, the results of these six trials led the FDA to advise caution in the use of ESAs. The agency mandated the addition of a black-box warning about the potential for tumor promotion and thromboembolic events, and FDA instructions required ESAs to be withheld from patients whose hemoglobin level exceeded 12 g per deciliter until the level fell below 11 g per deciliter.
Given the recent results, the FDA convened another meeting of the Oncology Drug Advisory Committee to seek guidance in redefining safe guidelines for ESA use in patients with cancer. A clear consensus emerged that product labeling should indicate further restrictions on approved use and that additional trials should be pursued aggressively to clarify whether ESAs are indeed associated with an increased risk of tumor growth. The agency heard recommendations that it consider limiting the use of ESAs in patients with the types of tumors in which clinical trials have demonstrated adverse outcomes, that it define a hemoglobin level at which ESA treatment should be initiated in asymptomatic patients, and that it restrict the duration of use of ESAs in patients with cancer. The advisory committee did not support a recommendation urging modification of the hemoglobin level at which ESA administration should be suspended.
Some meeting participants argued that while awaiting definitive data, oncologists should refrain from using ESAs in patients with squamous-cell cancer of the head and neck for whom curative therapy was intended. Participants also advised caution in the use of ESAs in patients undergoing chemotherapy for breast cancer and non–small-cell lung cancer.
The mechanism underlying the enhanced growth of tumors with higher doses of ESAs remains uncertain. There is good evidence that hypoxic tumors resist chemotherapy and radiotherapy. The biology of tumor hypoxia, with enhanced cell signaling through the Akt–mammalian target of rapamycin (mTOR) axis and subsequent up-regulation of hypoxia-inducible factor 1α, is what inspired the clinical trials in which ESA treatment was combined with radiotherapy, cytotoxic chemotherapy, or both in an attempt to overcome hypoxia-induced resistance. But another possibility is that certain tumor cells have erythropoietin receptors that stimulate cell growth when they are bound by erythropoietin or an erythropoietin-like ligand. Squamous-cell lung cancer, squamous-cell tumors of the head and neck, and breast adenocarcinomas seem to express erythropoietin receptors, but such receptors' role, if any, in tumor growth is unclear. Henke et al. showed that erythropoietin receptors were expressed by two thirds of tumors in their study and that expression of such receptors in erythropoietin-treated patients was associated with shorter survival.5 Conversely, in vitro studies have shown that stimulating erythropoietin receptors in cell lines from head and neck cancer and breast cancer causes the death of cells, though the questionable quality of the reagents used to detect erythropoietin receptors must be considered in interpreting these data.
In the face of media attention to the hyperbolic advertising by the companies that make ESAs and the substantial profits accrued by physicians who use such agents aggressively, the FDA has sought guidance in exercising prudent, evidence-based judgment. In order to maintain the public trust, the agency should act transparently in adopting new guidelines, and medical oncologists should begin using these agents in a compassionate but disciplined fashion, placing patient benefit above all other considerations.
An interview with James Doroshow, director of the Division of Cancer Treatment and Diagnosis at the National Cancer Institute, can be heard at www.nejm.org.
Source Information
Dr. Khuri is a professor and the section head of hematology and medical oncology at the Emory Winship Cancer Institute, Atlanta.
- References
References
1
Henke M ,Laszig R ,Rube C , et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 2003;362:1255-1260
CrossRef | Web of Science | Medline2
Leyland-Jones B ,Semiglazov V ,Pawlicki M , et al. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. J Clin Oncol 2005;23:5960-5972
CrossRef | Web of Science | Medline3
Wright JR ,Ung YC ,Julian JA , et al. Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol 2007;25:1027-1032
CrossRef | Web of Science | Medline4
Goldberg P . Danish researchers post long-awaited Aranesp results -- ever so discreetly. Cancer Lett 2007;33:1-65
Henke M ,Mattern D ,Pepe M , et al. Do erythropoietin receptors on cancer cells explain unexpected clinical findings? J Clin Oncol 2006;24:4708-4713[Erratum, J Clin Oncol 2007;25:1457.]
CrossRef | Web of Science | Medline
- Citing Articles (44)
Citing Articles
1
Camilla Molich Hoff. (2012) Importance of hemoglobin concentration and its modification for the outcome of head and neck cancer patients treated with radiotherapy. Acta Oncologica1-14
CrossRef2
M. Chavez-MacGregor, H. Zhao, M. Kroll, S. Fang, N. Zhang, G. N. Hortobagyi, T. A. Buchholz, Y.- C. Shih, S. H. Giordano. (2011) Risk factors and incidence of thromboembolic events (TEEs) in older men and women with breast cancer. Annals of Oncology 22:11, 2394-2402
CrossRef3
Kathrin Rupertus, Sebastian Senger, Michael D. Menger, Martin K. Schilling, Otto Kollmar. (2011) Darbepoetin-α Promotes Neovascularization and Cell Proliferation in Established Colorectal Liver Metastases. Journal of Surgical Research
CrossRef4
Mariana Chavez-MacGregor, Hui Zhao, Shenying Fang, Tomasz P. Srokowski, Gabriel N. Hortobagyi, Sharon H. Giordano. (2011) Complications associated with erythropoietin-stimulating agents in patients with metastatic breast cancer. Cancer 117:16, 3641-3649
CrossRef5
Peir-Haur Hung, Cheng-Huang Shen, Hung-Bin Tsai, Chih-Yen Hsiao, Pei-Chun Chiang, How-Ran Guo, Kuan-Yu Hung. (2011) Gender effect on renal outcome in patients with urothelial carcinoma. World Journal of Urology 29:4, 511-516
CrossRef6
Pere Gascón, José Almenárez, Ángel Artal, Carlos Camps, José Luis Fírvida, Pilar Garrido, José Luis González Larriba, Joaquín Montalar. (2011) Management of lung cancer-associated anaemia: the Spanish Lung Cancer Anaemia Survey (SLCAS). Clinical and Translational Oncology 13:5, 328-334
CrossRef7
Hans C. Ebbers, Aukje K. Mantel-Teeuwisse, Ellen H.M. Moors, Huub Schellekens, Hubert G. Leufkens. (2011) Todayʼs Challenges in Pharmacovigilance. Drug Safety 34:4, 273-287
CrossRef8
Chunkit Fung, David J. Vaughn. (2011) Complications associated with chemotherapy in testicular cancer management. Nature Reviews Urology 8:4, 213-222
CrossRef9
Semira Sheikh, Tim J Littlewood. (2010) Erythropoiesis-stimulating agents for anemic patients with cancer. Expert Review of Hematology 3:6, 697-704
CrossRef10
Pellegrino Musto, Oreste Villani, Maria Carmen Martorelli, Giuseppe Pietrantuono, Roberto Guariglia, Giovanna Mansueto, Fiorella D’Auria, Vitina Grieco, Gabriella Bianchino, Anna Sparano, Antonia Zonno, Rosa Lerose, Grazia Sanpaolo, Antonietta Falcone. (2010) Response to recombinant erythropoietin alpha, without the adjunct of granulocyte-colony stimulating factor, is associated with a longer survival in patients with transfusion-dependent myelodysplastic syndromes. Leukemia Research 34:8, 981-985
CrossRef11
Kathrin Rupertus, Jens Sperling, Marcus Corsten, Claudia Scheuer, Ruth M. Nickels, Martin K. Schilling, Michael D. Menger, Otto Kollmar. (2010) Darbepoetin-α Enhances Hepatectomy-Associated Stimulation of Colorectal Liver Metastatic Growth. Annals of Surgery 252:1, 131-141
CrossRef12
Joanna Erps, Matti Aapro, Karen MacDonald, Pierre Soubeyran, Matthew Turner, Hans Warrinnier, Tara Albrecht, Ivo Abraham. (2010) Promoting evidence-based management of anemia in cancer patients: concurrent and discriminant validity of RESPOND, a web-based clinical guidance system based on the EORTC guidelines for supportive care in cancer. Supportive Care in Cancer 18:7, 847-858
CrossRef13
Vassiliki Pelekanou, George Notas, Elias Sanidas, Andreas Tsapis, Elias Castanas, Marilena Kampa. (2010) Testosterone membrane-initiated action in breast cancer cells: Interaction with the androgen signaling pathway and EPOR. Molecular Oncology 4:2, 135-149
CrossRef14
N. D. Taylor, J. C. Way, P. A. Silver, P. Cironi. (2010) Anti-glycophorin single-chain Fv fusion to low-affinity mutant erythropoietin improves red blood cell-lineage specificity. Protein Engineering Design and Selection 23:4, 251-260
CrossRef15
Laura García-Estévez, Ignasi Tusquets, Isabel Álvarez, César Rodríguez, Yolanda Fernández, Miguel Ángel Seguí, Jesús García-Mata, Ana Lluch. (2010) Supportive care for patients with early breast cancer. Clinical and Translational Oncology 12:1, 32-42
CrossRef16
D. L. Hershman, D. L. Buono, J. Malin, R. McBride, W. Y. Tsai, A. I. Neugut. (2009) Patterns of Use and Risks Associated With Erythropoiesis-Stimulating Agents Among Medicare Patients With Cancer. JNCI Journal of the National Cancer Institute 101:23, 1633-1641
CrossRef17
Eirini Katodritou, Meletios A. Dimopoulos, Konstantinos Zervas, Evangelos Terpos. (2009) Update on the use of erythropoiesis-stimulating agents (ESAs) for the management of anemia of multiple myeloma and lymphoma. Cancer Treatment Reviews 35:8, 738-743
CrossRef18
Bunn, H. Franklin, . (2009) End Run around Epo. New England Journal of Medicine 361:19, 1901-1903
Full Text19
T.S. Dharmarajan, David Widjaja. (2009) Erythropoiesis-Stimulating Agents in Anemia: Use and Misuse. Journal of the American Medical Directors Association 10:9, 607-616
CrossRef20
A. Shander, M. D. Cappellini, L. T. Goodnough. (2009) Iron overload and toxicity: the hidden risk of multiple blood transfusions. Vox Sanguinis 97:3, 185-197
CrossRef21
Alfonso Quintás-Cardama, Fabio Pires De Souza Santos, Hagop Kantarjian, Susan O'Brien, Stefan Faderl, Ahmed Awais, Gautam Borthakur, Jorge Cortes. (2009) Dynamics and management of cytopenias associated with dasatinib therapy in patients with chronic myeloid leukemia in chronic phase after imatinib failure. Cancer 115:17, 3935-3943
CrossRef22
I. Ray-Coquard, S. Dussart, C. Goillot, D. Mayeur, P. Debourdeau, H. Ghesquieres, T. Bachelot, A. Le Cesne, B. Anglaret, C. Agostini, J.-P. Guastalla, L. Lancry, P. Biron, F. Desseigne, J.-Y. Blay. (2009) A risk model for severe anemia to select cancer patients for primary prophylaxis with epoetin : a prospective randomized controlled trial of the ELYPSE study group. Annals of Oncology 20:6, 1105-1112
CrossRef23
Paolo Pedrazzoli, Giovanni Rosti, Simona Secondino, Salvatore Siena. (2009) Iron supplementation and erythropoiesis-stimulatory agents in the treatment of cancer anemia. Cancer 115:6, 1169-1173
CrossRef24
M. Jädersten, E. Hellström-Lindberg. (2009) Myelodysplastic syndromes: biology and treatment. Journal of Internal Medicine 265:3, 307-328
CrossRef25
H. Link. (2009) Anämie bei Krebs. Der Onkologe 15:2, 129-141
CrossRef26
Ping Fu, Xiaohong Jiang, Murat O. Arcasoy. (2009) Constitutively active erythropoietin receptor expression in breast cancer cells promotes cellular proliferation and migration through a MAP-kinase dependent pathway. Biochemical and Biophysical Research Communications 379:3, 696-701
CrossRef27
Fabio Puglisi, Laura Deroma, Stefania Russo, Giacomo Cartenì, Andrea Sporchia, Giovanni Ucci, Giorgio De Signoribus, Salvatore Del Prete, Aldo Vecchione, Graziella Pinotti, Patrizia Beccaglia. (2009) Effect of age on hemoglobin levels and quality of life following treatment with epoetin alfa in cancer patients. Critical Reviews in Oncology/Hematology 69:2, 175-182
CrossRef28
Martine Margaretha Goedendorp, Marieke FM Gielissen, Constantijn AHHVM Verhagen, Gijs Bleijenberg, Martine Margaretha Goedendorp. 2009. Psychosocial interventions for reducing fatigue during cancer treatment in adults. .
CrossRef29
Domenico Ribatti. (2009) Erythropoietin and cancer, a double-edged sword. Leukemia Research 33:1, 1-4
CrossRef30
Guruprasad Srinivas, Piero Anversa, William H. Frishman. (2009) Cytokines and Myocardial Regeneration. Cardiology in Review 17:1, 1-9
CrossRef31
Nadine Shehata, Irwin Walker, Ralph Meyer, Adam E Haynes, Kevin Imrie, . (2008) The use of erythropoiesis-stimulating agents in patients with non-myeloid hematological malignancies: a systematic review. Annals of Hematology 87:12, 961-973
CrossRef32
Martin H Fenner, Arnold Ganser. (2008) Erythropoietin in cancer-related anemia. Current Opinion in Oncology 20:6, 685-689
CrossRef33
Mario Cazzola, Luca Malcovati. (2008) Prognostic relevance of anemia in myelodysplastic syndromes. American Journal of Hematology 83:10, 761-762
CrossRef34
T. Steinmetz, U. Totzke, U. Söling, M. Groschek, J. Mittermüller, M. Schweigert, H. Tesch, S. Nawka, S. Schmitz, A. Tsamaloukas. (2008) Hemoglobin levels that trigger erythropoiesis-stimulating agent treatment decisions for cancer-associated anemia – examination of practice in Germany. Current Medical Research and Opinion 24:10, 2751-2756
CrossRef35
Eirini Katodritou, Evgenia Verrou, Christina Hadjiaggelidou, Vassiliki Gastari, Konstantinos Laschos, Loukas Kontovinis, Dimitrios Kapetanos, Nikos Constantinou, Evangelos Terpos, Konstantinos Zervas. (2008) Erythropoiesis stimulating agents are associated with reduced survival in patients with multiple myeloma. American Journal of Hematology 83:9, 697-701
CrossRef36
Cecilia T. Costiniuk, Fernando Camacho, Curtis L. Cooper. (2008) Erythropoiesis‐Stimulating Agent Use for Anemia Induced by Interferon‐Ribavirin Treatment in Patients with Hepatitis C Virus Infection Is Not Associated with Increased Rates of Cardiovascular Disease, Thrombosis, Malignancy, or Death. Clinical Infectious Diseases 47:2, 198-202
CrossRef37
Dominique Spaëth. (2008) Epoetin beta once weekly: review of its efficacy and safety in patients with chemotherapy-induced anemia. Expert Review of Anticancer Therapy 8:6, 875-885
CrossRef38
Gillian Thomas, Shamshad Ali, Frank J.P. Hoebers, Kathleen M. Darcy, William H. Rodgers, Malti Patel, Ovardia Abulafia, Joseph A. Lucci, Adrian C. Begg. (2008) Phase III trial to evaluate the efficacy of maintaining hemoglobin levels above 12.0 g/dL with erythropoietin vs above 10.0 g/dL without erythropoietin in anemic patients receiving concurrent radiation and cisplatin for cervical cancer. Gynecologic Oncology 108:2, 317-325
CrossRef39
J. D. Rizzo, M. R. Somerfield, K. L. Hagerty, J. Seidenfeld, J. Bohlius, C. L. Bennett, D. F. Cella, B. Djulbegovic, M. J. Goode, A. A. Jakubowski, M. U. Rarick, D. H. Regan, A. E. Lichtin. (2008) Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update. Blood 111:1, 25-41
CrossRef40
A. Pelegrí. (2007) Impact of erythropoietin treatment on the quality of life of oncologic patients. Clinical and Translational Oncology 9:10, 645-651
CrossRef41
Farrah N Daly, David Schiff. (2007) Supportive management of patients with brain tumors. Expert Review of Neurotherapeutics 7:10, 1327-1336
CrossRef42
Saurabh Aggarwal. (2007) What's fueling the biotech engine?. Nature Biotechnology 25:10, 1097-1104
CrossRef43
(2007) Erythropoietins in Oncology. New England Journal of Medicine 357:12, 1262-1263
Full Text44
Hang Quach, H Miles Prince, Linda Mileshkin. (2007) Treatment Strategies in Elderly Patients with Multiple Myeloma. Drugs & Aging 24:10, 829-850
CrossRef
- Letters
