First published online April 26, 2007
Stem Cells
Vol. 25 No.
8
August 2007, pp.
2094
-2097
doi:10.1634/stemcells.2007-0229; www.StemCells.com
© 2007 AlphaMed Press
OPEN ACCESS ARTICLE
TRANSLATIONAL AND CLINICAL RESEARCH |
Erythropoietin in Cancer: Presumption of Innocence?
C. Anthony Blau
Department of Medicine/Hematology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA
Correspondence: C. Anthony Blau, M.D., Mailstop 357710, K260 Health Sciences Building, Department of Medicine/Hematology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98195, USA Telephone: 206-685-6873; Fax: 206-543-3560; e-mail: tblau{at}u.washington.edu
Received March 28, 2007;
accepted for publication April 24, 2007.
First published online in STEM CELLS EXPRESS April 26, 2007.
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ABSTRACT
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Erythropoietin emerged as the biggest drug in oncology despite never having demonstrated a survival benefit in patients with cancer. Two phase III clinical trials reported more than 3 years ago that erythropoietin adversely affected cancer survival rates, due mainly to tumor progression. Despite changes to the product label for erythropoietins in 2004, clinical practice remained unchanged until recent weeks when, following reports of three new phase III studies and a phase II trial, a "black box warning" for erythropoietin products was issued by the Food and Drug Administration (FDA). Whether erythropoietin products can be considered safe when used for FDA-approved indications is currently at issue; however, addressing this question will be difficult until the mechanisms of erythropoietin-stimulated tumor progression are understood. A thorough evaluation of materials from clinical trials already completed may shed new light on how erythropoietin promotes cancer progression. Until these issues are resolved, oncologists should inform their patients of erythropoietin's potential adverse impact on cancer progression and survival.
Disclosure of potential conflicts of interest is found at the end of this article.
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BURDEN OF PROOF
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In deliberations of guilt or innocence, courts recognize a spectrum across which the degree of certainty can vary. "Probable cause," the standard required for a search warrant, indicates that a "fair probability" exists that evidence of a crime will be found. "Preponderance of evidence," used in most civil cases, requires greater than 50% certainty. "Beyond a reasonable doubt," the standard applied in most criminal cases, indicates that proof exists to the extent that no "reasonable doubt" exists in the mind of a reasonable person (http://en.wikipedia.org/wiki/burden_of_proof). Intuitively, clinicians apply similar standards in deciding how to incorporate new information into the care of their patients, and in few areas of medicine have recent changes been more dramatic than in oncology.
Increasingly, cancers are curable because of therapies that passed through gauntlets of scrutiny. Food and drug administration (FDA)-approved anti-cancer drugs have proven their mettle in phase III clinical trials of patients with advanced cancer, and the most successful among these also confer a survival benefit in the adjuvant setting, where cancer often lurks below the threshold of detection. Complementing therapies that attack cancer are those that address the side effects of cancer and its treatment. This latter category contains hematopoietic growth factors, including various approved forms of erythropoietin.
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ERYTHROPOIETIN FOR CANCER-RELATED ANEMIA
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Erythropoietin received FDA approval for anemia due to renal failure in 1989 and expanded approval for anemia due to cancer chemotherapy in 1993. Erythropoietin alfa (Procrit, Johnson & Johnson, New Brunswick, NJ, http://www.jnj.com; and Epogen, Amgen, Thousand Oaks, CA, http://www.amgen.com), approved in the USA, and erythropoietin beta (NeoRecorman, Roche Diagnostics, Basel, Switzerland, http://www.roche-applied-science.com), approved in Europe, share the same amino acid sequence but differ in carbohydrate content. Darbepoetin alfa (Aranesp, Amgen) differs from recombinant human erythropoietin in that it contains additional N-linked oligosaccharide chains that are accommodated by substitutions at five positions along the 165-amino-acid backbone and which do not alter the tertiary structure. The additional carbohydrates confer a three-fold longer terminal half-life and a five-fold lower affinity for erythropoietin receptors relative to erythropoietin alfa [1]. For purposes of this discussion these variants are referred to collectively as "erythropoietin."
Clinical trials established erythropoietin's ability to increase hemoglobin levels and reduce transfusion requirements [2, 3], but because it was developed as a supportive measure erythropoietin's approval was not contingent upon demonstrating a survival benefit. Nonetheless its use became widespread, both in advanced malignancy and in the adjuvant setting, and erythropoietin emerged as the biggest drug in oncology, with an estimated $11.9 billion in worldwide sales (for all applications) in 2006 [4].
That erythropoietin might confer a survival benefit seemed plausible. A meta-analysis of 60 relevant studies found that anemia increased the relative risk for death by 19% in lung cancer, 75% in head and neck cancer, 47% in prostate cancer, and 67% in lymphoma and was associated with an overall estimated increased risk for death of 65% [5]. Paradoxically, in 2003, two phase III trials, both designed to demonstrate this most hoped for benefit, showed a statistically significant, erythropoietin-associated worsening of survival. The first trial, in 351 patients with head and neck cancer (Henke et al. [6]), and the second, in 939 patients with metastatic breast cancer (the Breast Cancer Erythropoietin Survival Trial-BEST [7]), were the largest studies ever conducted to address this issue. Both were pharmaceutical company-sponsored, multicenter, randomized, double blind, placebo-controlled trials, powered to detect a survival benefit from erythropoietin. Although both studies found increased cardiovascular and thromboembolic events in erythropoietin-treated patients (a well-characterized risk of erythropoietin treatment), the bulk of increased deaths came from an unexpected source: accelerated cancer progression. Whether this effect could be completely attributed to erythropoietin remained to be substantiated.
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FOUR NEW TRIALS DEMONSTRATE AN ADVERSE EFFECT OF ERYTHROPOIETIN ON CANCER SURVIVAL
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Although the Henke et al. and BEST studies ignited intense controversy surrounding their validity and generalizability [8–15], the landscape changed dramatically, beginning at the end of January 2007, when three new phase III trials and a phase II trial all reported statistically significant adverse effects of erythropoietin treatment on cancer survival. Due to the very recent availability of this information only one of these trials, a phase III trial in 70 patients with non-small-cell lung cancer, has been published in the peer-reviewed literature [16]. That study, originally designed to measure erythropoietin's effect on quality of life, was terminated early when an interim analysis showed a statistically significant worsening of survival in the erythropoietin-treated patients, and the excess deaths again appeared to be attributable to tumor progression. The remaining three trials include a phase III trial in which Darbepoietin was tested in 989 patients with various advanced cancers not treated with chemotherapy or radiation [17], a second phase III trial of Darbepoetin in 522 patients with head and neck cancer receiving radiation [18], and a phase II comparison of Darbepoetin versus various dosages of the Roche erythropoietin analog CERA ("continuous erythropoietin receptor activator" or Mincera) [19]. Standing as an important exception to this trend are the results of the most recently announced phase III trial, in which a 24-week course of Darbepoetin was tested in 600 previously untreated patients with extensive-stage small-cell lung cancer, and no significant difference in risk for death or progression-free survival was observed [20].
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AN EVOLVING RESPONSE
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On March 10, 2007 the FDA issued a "black box" warning for nonapproved uses of erythropoietin in cancer, and on May 10, 2007 the Oncologic Drugs Advisory Committee will meet to consider whether the approved indication, for chemotherapy-induced anemia with hemoglobin levels targeted to a range of 10–12 g/dl, should be changed. Since erythropoietin for this approved indication was presumed safe, all of the aforementioned phase III studies examined other settings, where favorable outcomes might have helped to broaden erythropoietin's approved indications. Four of the phase III trials sought to maintain hemoglobin levels above 12 g/dl [6, 7, 16, 18], whereas the fifth unpublished trial fell within the FDA-approved hemoglobin range but excluded patients receiving chemotherapy [17]. Thus the essential question is whether the phase III results in nonapproved settings can be generalized to the current FDA-approved indication, for which the vast majority of erythropoietin usage in cancer is estimated to occur [21]. Phrased differently, is erythropoietin safe when used in accordance with FDA-approved indications? One line of reasoning contends that this question can only be addressed by additional phase III trials for each clinical context where erythropoietin is currently FDA-approved. However if answers to the question of erythropoietin's safety depend on phase III trials yet to be performed, the intervening inaction might expose hundreds of thousands of patients to an increased risk for cancer-associated death. A sole reliance on this approach presumes erythropoietin's innocence, a reversal of the standard paradigm by which drugs obtain FDA approval. Ultimately, the route toward regaining confidence in erythropoietin's safety in cancer must be paved on an understanding of how erythropoietin can, at least in some circumstances, stimulate tumor progression.
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HOW MIGHT ERYTHROPOIETIN STIMULATE TUMOR PROGRESSION?
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Possibly relevant to the unexpected clinical findings are reports that many tumors express erythropoietin receptors [22, 23]. Erythropoietin stimulation of tumor cell lines can induce signal transduction [22, 24, 25], but generally has little or no effect on cell proliferation or cell survival following cytotoxic exposure [26–28]. Tumor samples taken from patients also appear to frequently express the erythropoietin receptor [22, 29–31], although most of these studies are clouded by use of an antibody (C20) that lacks specificity for the erythropoietin receptor [32, 33]. In addition to direct effects on tumor cells, erythropoietin might stimulate tumor progression through effects on angiogenesis [22] or alternatively, by inducing the elaboration of one or more surrogate factors that in turn induce tumor progression [34].
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ASCERTAINING ERYTHROPOIETIN'S ROLE IN CANCER
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Arguably equal in importance to a new round of phase III studies is a more thorough examination of information still extractable from the clinical trials that have already been performed. A key question is whether a subset of patients at risk for erythropoietin-induced tumor progression can be identified, with the prospect that erythropoietin use outside this population might prove to be beneficial. As noted above, the most likely candidate marker of erythropoietin responsiveness is expression of the erythropoietin receptor.
A recent report correlated the outcomes of 154 patients from the Henke study with the erythropoietin receptor status of their tumors [31]. Although this study used the aforementioned C20 antibody, tumors were nevertheless scored and agreed upon by two independent pathologists blinded to treatment assignment, and results showed that erythropoietin was specifically harmful in the two thirds of patients with erythropoietin receptor-positive tumors. To the contrary, erythropoietin treatment appeared possibly beneficial in the remaining patients with receptor-negative tumors. If validated, these findings would markedly advance the rational use of erythropoietin in patients with cancer. In view of the lack of suitable antibodies, quantitative reverse transcriptase polymerase chain reaction provides an alternative and reproducible means for measuring various mRNA transcript levels in paraffin-embedded clinical tumors samples [35, 36], including erythropoietin receptor transcripts ([18] and our unpublished results). The availability of clinical tumor specimens from patients enrolled in the aforementioned phase III trials would provide the ability to determine whether erythropoietin-induced tumor progression is restricted to patients with erythropoietin receptor-positive tumors, or whether other molecular markers yet to be identified predict an adverse response to erythropoietin. Obstacles to this approach include the lack of prospective tumor storage for these trials, requiring the tracking and retrieval of tumor specimens from dozens or even hundreds of different sites, and the fact that trial participants were not consented for study of their tumors. The former issue presents a formidable but likely surmountable logistical obstacle, whereas the latter issue is addressable via federal regulations that permit a minimal risk waiver of informed consent if the research involves no more than minimal risk to the subjects, if the research will not effect the rights or welfare of the subjects, and if obtaining informed consent is impracticable [37].
The fundamental paradox that erythropoietin may stimulate cancer progression even though it reverses an adverse prognostic factor (anemia), might be reconciled if elevated levels of endogenous erythropoietin are also harmful in cancer. In other words, perhaps one reason that anemia is harmful in cancer is due to the reciprocal rise in endogenous erythropoietin levels that accompanies anemia. Although this conjecture is supported by a recent retrospective report in patients with lung cancer [38], the question might be more definitively addressed by exhuming data gathered in the Henke trial (and held by Roche), since baseline erythropoietin levels were performed in all patients at the time of study entry [6]. By examining patients enrolled into the placebo arm of that study, one could determine whether elevated levels of endogenous erythropoietin correlate with a worsening of survival and whether this in turn correlates with tumor erythropoietin receptor expression. Other phase III trials of erythropoietin in patients with cancer (designed to measure endpoints other than survival) [39, 40] also incorporated baseline erythropoietin levels into their studies, and a similar reexamination of these data also appears worthwhile.
Further insights might also be obtained by examining cancer endpoints in other phase III trials. For example, in recent phase III studies comparing different target hemoglobin levels in patients with anemia due to renal failure, it would be of interest to note whether higher doses of erythropoietin were associated with an increase in deaths due to malignancy [41, 42]. The prediction is not that erythropoietin increases the incidence of cancer, but rather that the initiation of erythropoietin treatment might induce a spike in the clinical detection and progression of previously occult cancers, analogous to the manner in which hormonal manipulations can induce "flares" of breast cancer and prostate cancer [43, 44].
What Standard of Evidence?
In the absence of definitive clinical studies, how confident can we be that erythropoietin is safe for the FDA-approved indication of chemotherapy-induced anemia, initiating treatment when the hemoglobin drops below 10 g/dl, and adjusting to maintain hemoglobin levels below 12 g/dl? Perhaps, as in jurisprudence, the requisite level of certainty should depend on circumstances. Battles to cure cancer are won or lost in the adjuvant setting. It is in this context that patients stand to lose the most by exposure to an agent that has the theoretical potential to stimulate cancer progression. In other circumstances the demonstrated and important benefits of erythropoietin might be judged to outweigh the risk of accelerated tumor progression.
Recommendations
Although a harmful effect of erythropoietin in patients with cancer for the current FDA-approved indications has not been established beyond a reasonable doubt, the evidence accumulated to date does seem to have met an important, albeit less stringent, evidentiary standard. A lesser standard may be appropriate in the adjuvant setting, where patients have the most to lose. Although additional phase III clinical trials are necessary, highly relevant data may still be culled from a careful reexamination of trials already performed. New phase III studies should routinely incorporate consents to study patient tumor samples and should measure endogenous erythropoietin levels. In view of the current uncertainties, patients should be involved in the risk-benefit decisions that accompany this well-established but incompletely understood therapy.
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DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
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C.A.B. is named as an inventor on one filed and one issued patent related to the regulation of blood cell production and is a co-founder of and owns stock in CellNexus, L.L.C.
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ACKNOWLEDGMENTS
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I thank Chris P. Miller and Erica Jonlin for very helpful discussions. This work was supported by an NCI Cancer Center Consortium Grant awarded to the Fred Hutchinson Cancer Research Center.
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Abstract
Burden of Proof