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Originally published as JCO Early Release 10.1200/JCO.2006.08.8153 on February 20 2007 © 2007 American Society of Clinical Oncology.
Erythropoietin: High Profile, High Scrutiny
Department of Medicine and Duke Comprehensive Cancer Center, Duke University, Durham, NC Recombinant human erythropoietin has enjoyed a high profile status throughout its history in medicine. The isolation and purification of erythropoietin and the subsequent cloning of the human protein, followed by clinical trials demonstrating the reversal of anemia in renal dialysis patients in the 1980s ushered in the era of biotechnology.1 In the 1990s, randomized clinical trials demonstrated that recombinant human erythropoietin was also effective in treatment of anemia in cancer patients receiving chemotherapy.2 Subsequent open label trials described the impact of erythropoietic therapy in patients with anemia related to cancer chemotherapy.3-5 While these trials lacked a control group, the results were very high profile because of the thousands of patients treated. These data correlated the relationship, not only between rising hemoglobin and reduction in transfusion requirement, but also in defining the relationships between anemia, fatigue, and quality of life measures.6 These results were further validated in a subsequent randomized placebo-controlled study.7 These open label trials also were fundamental to defining the incremental improvement in quality of life measures with increasing hemoglobin levels in cancer chemotherapy patients, with an optimum hemoglobin level of 12 g/dL.8 Based on these data and extensive supporting evidence from other clinical trials, this target hemoglobin of 12 g/dL has been considered the optimal end point in the treatment of cancer-related anemia by guidelines committees including the National Comprehensive Cancer Network.9 In addition to the clinical trials of erythropoietin alfa, similar benefits have been established with erythropoietin beta, as well as darbepoietin alfa.10 The availability of multiple erythropoietic agents has increased not only the number of clinical studies, but also the high visibility of these agents, in the clinical practice of oncology, in health economics, and in the media, from direct to consumer advertising to Wall Street. But being high profile comes with a price. This is true in politics, sports, and it is certainly true in medicine and the pharmaceutical industry. The high profile person, product, or service touches many lives and therefore attracts a higher level of scrutiny. While the basis of that scrutiny may vary between politics and sports, in medicine we have an obligation to be sure our therapies are as safe and effective as possible. We have learned that pharmacovigilence does not end, but rather begins, with clinical trial results and US Food and Drug Administration approval. We have to be constantly alert to new information. As one measure of scrutiny of erythropoietic therapy, there have been three other editorials involving erythropoietin use in cancer patients, published in the Journal of Clinical Oncology (JCO) in the past 2 years. In the first editorial,11 Drs Steensma and Loprinzi have an excellent discussion of the issues raised by the Breast Cancer Erythropoietin Survival Trial (BEST) study.12 This trial randomized mainly nonanemic women with metastatic breast cancer to receive epoetin alfa versus placebo and demonstrated a negative impact on survival largely confined to the first 4 months of the trial. The editorial nicely summarizes the shortfalls of the trial, not the least of which is that the patients were being treated to a higher than standard hemoglobin level. However, they appropriately strike a cautionary note and explore mechanistic possibilities that have spurred additional preclinical and clinical investigation. In a second editorial, the same authors review epoetin alfa and darbepoetin alfa.13 This editorial reviews the clinical trial results14 as well as the broader implications of this high profile study on clinical practice and with payers such as the Center for Medicare & Medicaid Services (Department of Health and Human Services, Baltimore, MD). In addition to dose and scheduling issues, the editorial addresses the need for further clinical investigation in areas such as the role of iron supplementation and in development of new erythropoietic agents that may activate the erythropoietin receptor differently or work through hypoxia-inducible factor and/or other pathways. The most recent editorial by Drs Lai and Grandis was entitled, "Understanding the Presence and Function of Erythropoietin Receptors on Cancer Cells."15 This editorial accompanied an article by Dr Henke,16 which explored the possible relationship between erythropoietin receptors in patients with head and neck cancer and their poor survival in a randomized placebo-controlled trial of epoetin beta in the treatment of patients with head and neck cancer receiving radiotherapy. In this trial, like the BEST trial, patients were being treated to above standard hemoglobin levels. In the accompanying editorial, the authors review the potential importance of erythropoietin and erythropoietin receptor signaling in healthy as well as cancer cells. The complex biology of the signaling process, the variation in in vitro models, as well as the importance of determining, not simply the presence, but the function of epo-receptors will be another critical part of ongoing preclinical and clinical investigation. This brings us to the study by Wright and colleagues in this issue of the JCO.17 These investigators designed a multicenter randomized, double-blind, placebo-controlled trial to evaluate the impact of epoetin alfa on the primary end point of quality of life in patients with non–small-cell lung cancer and disease-related anemia. Patients receiving high-dose thoracic radiation or platinum-based chemotherapy were excluded, with the intent to focus on patients whose anemia was not related to systemic treatment. As a result, only 23% of patients had received prior systemic treatment and no patients on study went on to receive further systemic therapy during the trial. The planned sample size was 300 patients. Treatment included placebo versus epoetin alfa at 40,000 units weekly for 12 weeks, allowing patients to be treated to a hemoglobin level as high as 14 g/dL before withholding study drug. Due to reports of thrombotic events in other epoetin trials, an unplanned safety analysis occurred after the first 70 patients. This revealed a significant difference in the median survival in favor of the patients on the placebo arm of the trial (hazard ratio, 1.84; P =.04) prompting the steering committee to close the study. These 70 patients formed the basis for this report. Given the small sample size, there were no major imbalances detected between the two groups. However, for those of us in the lung cancer community used to overanalyzing the equivalent of a randomized phase II trial, 54% of the placebo group had an Eastern Cooperative Oncology Group performance status of 0 to 1 compared with 42% of epoetin alfa group. There was also a slight imbalance in the mean baseline quality of life score by Functional Assessment of Cancer Therapy–Anemia (FACT-An), 37.8 in the placebo group and 31.5 in the epoetin alfa group. As in the BEST study, the survival differences occurred early with most of the deaths seen in the first 3 to 4 months of the study. The survival curves come close together at weeks 24 to 28, followed by more deaths in the epoetin alfa group compared with the placebo group between weeks 24 and 36. By week 60, one patient was alive in the epoetin alfa arm and three were alive in the placebo group. The overwhelming cause of death in both groups was progressive lung cancer with other deaths due to comorbid illness. The incidence of thrombotic events, which was the initial reason for the unplanned safety analysis, was low in both groups. Hemoglobin levels in the epoetin-treated group significantly improved, from baseline to week 12. No significant differences were seen in terms of quality of life end points, which were complicated by the small sample size and the possible baseline imbalance in the FACT-An score. In the discussion, the authors explain the difficulties associated with the decision to suspend the trial. While the confidence intervals were wide, they identified no other clear factor, other than treatment group, contributing to the poor survival and decided to close the study based on safety concerns. With "safety first" as the mantra of clinical investigation, this was certainly an appropriate decision. But, how about the decision to publish these results? If this unplanned safety analysis had shown the opposite outcome with better survival in the epoetin alfa arm, the study would not have been closed due to safety concerns. Enrollment would have continued to try to identify whether this early observation was real. If the investigators had decided to close it, claiming victory for epoetin alfa, we all know the likelihood of publication would have been low. So is this fair? The answer is yes. Remember, high profile, high scrutiny. Along with the Henke and BEST trials, this represents a third study suggesting a negative impact of erythropoietin use in patients with cancer-related anemia. Like the other two studies, the confidence around the conclusions is complicated by trial limitations. In the current study by Wright, the most serious concern is the small sample size and high short-term mortality in a population with advanced lung cancer no longer receiving active therapy. It is always important to put results of any one trial, or several trials, in the context of a larger base of evidence. In larger randomized trials of lung cancer patients receiving chemotherapy, early versus late intervention with epoetin alfa18 and placebo-controlled trials of darbepoetin19 did not identify any survival decrement with the use of erythropoietin therapy. The most recent Cochrane analysis included a systematic review of 57 trials and 9,353 cancer patients enrolled on randomized controlled trials of epoetin alfa, epoetin beta, or darbepoetin alfa and was recently updated to include trials from 1985 to 2005.9 Erythropoietic agents significantly reduced the risk for red blood transfusion (relative risk [RR] = 0.64; 95% CI, 0.60 to 0.84) and improved hematologic response (RR = 3.43; 95% CI, 3.07 to 3.84). The meta-analysis also confirmed that treatment with epoetin or darbepoetin increases the risk of thromboembolic events (RR = 1.67; 95% CI, 1.35 to 2.06). However, in the current study by Wright,17 as well as in the previous trials,11,15 the survival decrement in the epoetin group could not be clearly linked to excess thromboembolic events. The etiology of thromboembolic events in patients receiving erythropoietic therapy has not been well studied, partially due to the complexity of the increased thromboembolic event rates in cancer patients in general and cancer chemotherapy patients in particular. Clearly, this needs to be a focus both for preclinical, as well as prospective observational and interventional clinical trials to better understand if and how this risk can be modified. In terms of survival, the first Cochrane analysis reported inconclusive evidence that erythropoietin may improve overall survival (hazard ratio, 0.81; 95% CI, 0.67 to 0.99).20 That meta-analysis only included trials up through December 2001 compared with the more recent analysis that includes trials up to April 30, 2005, including the BEST and Henke studies among others. The latter analysis has a hazard ratio of 1.08 (95% CI, 0.99 to 1.18), with the authors conclusion of uncertainty as to "whether and how epoetin or darbepoetin effects overall survival."10 Future updates of the Cochrane meta-analysis of erythropoietic therapy will undoubtedly include the results of Wright and colleagues, as well as other ongoing and completed studies. That would include a randomized double-blind placebo-controlled trial of epoetin alfa in treatment of patients with small-cell lung cancer, published in the JCO in late 2005,21 which did not prompt an editorial. This study was also closed prematurely, not because of safety concerns, but rather low accrual related to the three times per week epoetin alfa/placebo administration. It was an instructive study in that it was conducted before current safety concerns about high hemoglobin levels. Baseline hemoglobin values were 12.8 and 13 g/dL in the two groups at the time of initiation of treatment. The primary end point for this study of overall tumor response was not significantly different at 72% for the epoetin alfa group and 67% for placebo. Hemoglobin was maintained in the prechemotherapy range in the epoetin alfa group and decreased in the placebo group. Median overall survival was 10.5 and 10.4 months, with the overall mortality at 91.7% and 87.8% for the two groups, suggesting no negative impact on survival despite treatment with epoetin alfa, outside the current guidelines. Due to the safety concerns of the Henke and BEST trials, the sponsors appropriately curtailed ongoing or planned trials of comparable design. In contrast, these same trials could have helped increase our understanding of this issue. Fortunately, there still are several ongoing trials with darbepoetin that are primarily addressing a survival end point, some of which have companion tissue collection and hopefully will address a number of clinical and biologic questions.22,23 Of note, in the interim analyses of these trials, none of them have been closed early for safety concerns. However, a randomized double-blind placebo-controlled study of darbepoetin in patients with anemia related to cancer (rather than cancer chemotherapy) was reported in The Cancer Letter.24 The study was unable to meet the primary end point of a significant reduction in transfusion in this population. Furthermore, there was an excess mortality in the darbepoetin-treated group. Survival was not a major end point, but was part of the safety analysis. Median survival follow-up was 4.3 months at the time of analysis. Detailed analysis and further follow-up will certainly be the subject of a future report. The study brings forth common themes; the study was evaluating erythropoietin treatment outside standard guidelines, safety concerns have been raised, and further scrutiny is needed. Along with the editorialists who preceded me on this topic, I would draw the reader's attention to the importance of following practice guidelines in the management of patients with cancer-related anemia, with respect to the target hemoglobin level of 12 g/dL.9 Meanwhile, preclinical and clinical investigation has been enhanced by this controversy, which should help us in our common goal to use this high profile/high scrutiny paradigm to achieve the highest benefit possible for our patients. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: Jeffrey Crawford, Amgen Stock: N/A Honoraria: N/A Research Funds: Jeffrey Crawford, Amgen; Ortho-Biotech Testimony: N/A Other: N/A NOTES published online ahead of print at www.jco.org on February 20, 2007 REFERENCES 1. Eschbach JW, Ergrie JC, Downing MR, et al: Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. N Engl J Med 316:73-78, 1987[Abstract] 2. Henry DH, Abels RI: Recombinant human erythropoietin in the treatment of cancer and chemotherapy-induced anemia: Results of double-blind and open-label follow-up studies. Semin Oncol 21:21-28, 1994 (suppl 3)[Medline] 3. Glaspy J, Bukowski R, Steinberg D, et al: Impact of therapy with epoetin alfa on clinical outcomes in patients with non-myeloid malignancies during cancer chemotherapy in community oncology practice. J Clin Oncol 15:1218-1234, 1997 4. Demetri GD, Kris M, Wade J, et al: 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. J Clin Oncol 16:3412-3425, 1998[Abstract] 5. 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 19:2875-2882, 2001 6. Cella D: Factors influencing quality of life in cancer patients: Anemia and fatigue. Semin Oncol 25:43-46, 1998[Medline] 7. Littlewood TJ, Bajett 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 8. 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 94:888-895, 2002 9. National Comprehensive Cancer Network: version 2. 2006, www.nccn.org. 10. Bohlius J, Wilson J, Seidenfeld J, et al: Recombinant human erythropoietins and cancer patients: Updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst 98:708-714, 2006 11. Steensma DP, Loprinzi CL: Erythropoietin use in cancer patients: A matter of life and death? J Clin Oncol 23:5865-5868, 2005 12. 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 23:5960-5972, 2005 13. Steensma D, Loprinzi C: Epoetin alfa and darbepoetin alfa go head to head. J Clin Oncol 24:2233-2236, 2006 14. Glaspy J, Vadhan-Raj S, Patel R, et al: Randomized comparison of every 2 weeks darbepoetin alfa and weekly epoetin alfa for the treatment of chemotherapy-induced anemia: The 20030125 Study Group Trial. J Clin Oncol 24:2290-2297, 2006 15. Lai SY, Grandis JR: Understanding the presence and function of erythropoietin receptors on cancer cells. J Clin Oncol 24:4675-4676, 2006 16. Henke M, Mattern D, Pepe M, et al: Do erythropoietin receptors on cancer cells explain unexpected clinical findings? J Clin Oncol 24:4708-4713, 2006 17. Wright JR, Yee CU, Julian JA, et al: A randomized, double-blind, placebo-controlled trial of erythropoietin to treat patients with non-small cell lung cancer and disease related anemia. J Clin Oncol 25:1027-1032, 2007 18. Crawford J, Francisco R, Perry M, et al: A randomized trial comparing immediate versus delayed treatment of anemia with once-weekly epoetin alfa in patients with non-small cell lung cancer scheduled to receive first-line chemotherapy. J Thorac Oncol 3:210-220, 2007 19. 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 20. Bohlius J, Langensiepen S, Schwarzer G, et al: Recombinant human erythropoietin and overall survival in cancer patients: Results of a comprehensive meta-analysis. J Natl Cancer Inst 97:489-498, 2005 21. Grote T, Allen A, Castillo R, et al: Efficacy and safety analysis of epoetin alfa in patients with small-cell lung cancer: A randomized, double-blind, placebo-controlled trial. J Clin Oncol 23:9377-9386, 2005 22. Glaspy JA: Cancer patient survival and erythropoietin. J Natl Compr Canc Netw 3:796-804, 2005[Medline] 23. Crawford J: Erythropoiesis-stimulating protein support and survival. Oncology 20:39-43, 2006 (suppl 6) 24. Goldberg P: Study finds more deaths on Aranesp arm in cancer anemia study, no benefit seen [newsletter]. The Cancer Letter 33:1, 2007 Related Article
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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