Unraveling the Mystery of Erythropoietin-Stimulating Agents in Cancer Promotion Kelly A

Review

Unraveling the Mystery of Erythropoietin-Stimulating Agents in Cancer Promotion Kelly A. May and Fadlo R. Khuri

Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia

Abstract Patients, undergoing active treatment with radiotherapy, were randomized in a double-blind manner to receive either epoetin Erythropoietin-stimulating agents (ESA) are approved for use beta or placebo. Study drug was initiated at a hemoglobin in treating chemotherapy-induced anemia in patients with concentration of <12 g/dL in women and <13 g/dL in men and nonmyeloid malignancies. However, recent clinical trials have continued until target hemoglobins of z14 g/dL in women and shown evidence of inferior overall survival and/or locore- z15 g/dL in men were reached. Patients treated on the epoetin gional control of tumors in patients receiving ESAs. Given beta arm showed worse locoregional progression, and shorter these concerning data, current studies are focused on elucidat- locoregional progression-free survival and overall survival com- ing the biological mechanisms by which ESAs may contribute pared with those receiving radiotherapy and placebo. to cancer promotion. Evidence suggests that ESAs activate The multicenter, double-blind, randomized, placebo-controlled several signaling pathways that are important in altering Breast Cancer Erythropoietin Survival Trial by Leyland-Jones and tumor behavior and response to treatment. Although further colleagues (3) sought to maintain normal hemoglobin levels in 939 research is needed to more precisely elucidate these mecha- women with metastatic breast cancer undergoing first-line nisms, caution should be exercised in the use of ESAs beyond chemotherapy. With a target hemoglobin level of 12 to 14 g/dL, their approved indication in cancer patients. [Cancer Res 2008; study drug was allowed once hemoglobin reached V13 g/dL. 68(11):4013–17] Following evidence of higher mortality in the Epo arm, the study drug was discontinued and additional data were collected. Patients Introduction treated with Epo had an increased incidence of disease progression Erythropoietin (Epo)-stimulating agents (ESA) are the most and thromboembolic events, and more adverse prognostic factors commonly used growth factors in clinical practice. ESAs are known at baseline. Overall, the authors concluded that these differences to stimulate erythroid cell lines and reverse anemia. In contrast to could not account for the survival differences seen (4). the initial studies that led to their Food and Drug Administration Wright and colleagues (5) conducted a trial to measure changes (FDA) approval for chemotherapy-induced anemia, recent clinical in Functional Assessment of Cancer Therapy-Anemia scores in 300 trials targeting restoration of hemoglobin to normal and even non–small cell lung cancer patients with disease-related anemia supraphysiologic levels have shown worse outcomes for cancer being treated with Epo. Epoetin alfa or placebo was initiated for patients receiving ESAs compared with placebo. Given these hemoglobin levels V12 g/dL. Adjustments were made to the study troubling data, current studies are focused on elucidating the drug if the hemoglobin reached >14 g/dL. Given rising concerns for biological mechanisms of action of ESAs that may underlie these Epo-associated risks during the time of the trial, an unplanned differences in study outcomes. interim safety analysis was conducted. The trial was suspended after 70 patients had been randomized after a significantly Clinical Data improved overall survival was seen in patients receiving placebo. Additionally, Overgaard and colleagues (6) reported the prelim- Epo was approved for use in alleviating chemotherapy-induced inary results of the DAHANCA 10 study conducted by the Danish anemia in patients with nonmyeloid malignancies in 1993 fol- Head and Neck Cancer Group. This open-label study randomized lowed by darbepoetin in 2002. The clinical trials on which ESAs 522 patients with locally advanced head and neck cancer were given FDA approval focused mainly on increased hemoglobin undergoing curative radiotherapy to receive darbepoetin alfa or levels, decreased transfusion requirements, and reduction in red cell transfusion. Administration of darbepoetin alfa continued transfusion-associated risks. Interestingly, improvements in quality unless hemoglobin levels exceeded 15.5 g/dL. Following evidence of life have never been definitively shown in ESA clinical trials. of poorer locoregional control, shorter disease-free survival, and a These early trials were not designed or powered to detect statis- trend toward shorter overall survival in the darbepoetin group, tically significant differences in overall survival. However, a meta- the trial was terminated. analysis suggested a favorable trend in survival outcome (1). This Two other studies that have been independently analyzed by the led to trials using ESAs that were aimed at enhancing survival. FDA (7) also suggest shorter survival times in patients treated with The first of these, the ENHANCE study (2) published in 2003 by darbepoetin alfa compared with control. The first multicenter, Henke and colleagues, enrolled 351 patients with anemia who randomized trial compared the use of darbepoetin alfa with had squamous cell cancer of the oral cavity, pharynx, or larynx. placebo in 989 patients with nonmyeloid malignancies that were not undergoing active anticancer therapy. Study drug was held if the hemoglobin value reached >13 g/dL. The second multicenter, Requests for reprints: Fadlo R. Khuri, Department of Hematology and Medical double-blind, placebo-controlled trial randomized 344 patients Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA with lymphoproliferative malignancies undergoing chemotherapy 30322. Phone: 404-778-4250; E-mail: [email protected]. I2008 American Association for Cancer Research. to receive darbepoetin alfa or placebo until hemoglobin levels doi:10.1158/0008-5472.CAN-07-3324 exceeded 15 g/dL in men or 14 g/dL in women. www.aacrjournals.org 4013 Cancer Res 2008; 68: (11).June 1, 2008

More recently, two additional studies have released results Cell surface expression and correct functional folding necessary indicating adverse outcomes in patients treated with ESAs. Amgen for EpoR signaling is induced by Janus-activated kinase 2 (JAK2), announced preliminary conclusions of the PREPARE (8) trial, a known transducer of important cancer cell signaling. Once acti- which randomized 733 breast cancer patients undergoing neo- vated by ligand, EpoR forms a homodimer that activates a multi- adjuvant chemotherapy to darbepoetin alfa or placebo in an tude of pathways, including activation of JAK2 by phosphorylation open-label fashion. Hemoglobin was to be maintained between (18). JAK2 is mutated in myeloproliferative disorders, particularly 12.5 and 13 g/dL. A planned interim analysis revealed higher polycythemia vera, causing constitutive proliferation of erythroid progression and death rates on the treatment arm. Lastly, cells despite the absence of Epo (25). Could a similar mechanism be the National Cancer Institute Gynecologic Oncology Group (9) at play in human cancers? studied patients with cervical carcinoma undergoing concur- In fact, in cell lines from squamous cell carcinoma of the head rent chemoradiotherapy. Patients were randomized to receive and neck, Epo promotes tumor cell invasion (13, 18). This Epo- either epoetin alfa once their hemoglobin was <12 g/dL or simple stimulated invasion can be blocked by a JAK inhibitor and in a cell blood transfusions for hemoglobin <10 g/dL. The study was line with signal transducer and activator of transcription (STAT) 5A discontinued after 109 of a planned 460 patients were enrolled due mutation (13). This highlights the importance of the JAK-STAT to concerns of higher thromboembolic rates. The final statistical signaling pathway in cancer progression, transducing the Epo- analysis did not confirm increased thromboembolic rates; however, mediated signal and thereby enhancing invasion. progression-free and overall survival were found to favor placebo- Increased tumor survival is also modulated in part by treated patients. suppression of apoptosis despite genetic damage, irradiation, or Together, these eight randomized trials show decreased overall other stimuli. Epo induces nuclear translocation of nuclear factor- survival or locoregional control of tumors in patients receiving nB (NF-nB) through stimulation of EpoR. This activation of NF-nB ESAs, in contrast to the initial meta-analysis (see Table 1). An has been proposed to induce antiapoptotic gene transcription (26). updated Cochrane Review was performed to include data from Protein kinase B (AKT), activated via the phosphoinositide 3-kinase these recent trials. Bohlius and colleagues (10) reported lower (PI3K) signaling pathway, has also been implicated in increasing transfusion rates, increased risk of thromboembolic events, and a tumor cell survival. Epo increased the levels of activated AKT and suggestion of decreased survival in ESA-treated cancer patients. one of its downstream targets, mammalian target of rapamycin In response to these data, the American Society of Clinical (mTOR), in a dose-dependent manner in human melanoma cells Oncology and the American Society of Hematology recommended (19). mTOR is known to affect cell proliferation and angiogenesis, the use of ESAs in patients with nonmyeloid malignancies receiv- whereas AKT can protect cells from death despite the presence of ing chemotherapy only after hemoglobin levels fall to 10 g/dL. apoptotic stimuli. The increased viability of cells on Epo treatment Both societies challenged the clinical relevance of these studies, was diminished by the addition of a PI3K inhibitor (19). pointing out that ESAs were administered in unapproved sett- The Epo-EpoR interaction has also been shown to increase ings, among patient populations not receiving chemotherapy migration of a breast cancer cell line through activation of or by targeting higher than approved hemoglobin levels. It has extracellular signal-regulated kinase (ERK)/mitogen-activated pro- previously been shown that high target hemoglobin levels and tein kinase. Higher Epo and ERK levels were induced by hypoxic rapid increases in hemoglobin are associated with worse out- conditions, which were associated with substantially increased comes (11). It remains unproven whether high target hemoglobin migration. The effect was mitigated by the presence of either concentrations are the only factor contributing to the adverse soluble EpoR or anti-Epo antibodies (20). Therefore, increased Epo, outcomes seen. especially within a hypoxic state, may potentiate the formation of metastases. Ironically, this contradicts the rationale behind several of the recent clinical trials that sought to reverse tissue Possible Mechanisms of Tumor Promotion hypoxia by improving cellular oxygen-carrying capacity by driving Given these concerns, the mechanisms of action of ESAs, hemoglobin to supraphysiologic levels. particularly their effects on nonerythroid cells, have recently come Strengthening the plausibility of the in vivo relevance of these under investigation. Many common tumor types, including lung mechanisms, it has been shown that patients with non–small cell (12), squamous head and neck (13), breast (14), colon (15), gastric lung cancers that concurrently express Epo and EpoR have worse (16), and uterine (17) cancers, have been shown to express Epo disease-specific survival than those who do not (12). A retrospec- receptor (EpoR). EpoR is classified as a type 1 cytokine receptor tive analysis also found worse locoregional progression-free with a single transmembrane domain with three identifiable forms: survival of patients with head and neck squamous cell cancers full length, truncated, and soluble. Its exact physiologic roles in that expressed EpoR when exogenous Epo compared with placebo nonerythroid cell lines remain unclear. It is hypothesized that was administered (27). In addition, patients who continue to smoke Epo and EpoR are synthesized by tumor cells and stimulation in an during therapy have worse overall outcomes. In this chronic autocrine/paracrine fashion affects cancer cell growth and survival hypoxic state, with dysregulation of hypoxia-inducible factor-1a, (12, 18–20). With prominent expression of EpoR on tumor cell elevated systemic levels of Epo can be detected. surfaces, endogenous production of Epo can result in downstream Intratumoral hypoxia may play a key regulatory role in the Epo- signaling cascades. Signaling pathways activated by EpoR stimu- EpoR autocrine/paracrine loop, as both Epo and EpoR are up- lation result in increased migration (20), invasion (13, 18), proli- regulated in hypoxic tumor cell lines (19, 20). Investigators may feration (21), angiogenesis (17), and inhibition of apoptosis (22, 23). have expected alleviation of anemia by systemic Epo to increase Activation or up-regulation of EpoR in malignant tissues does not delivery of chemotherapy or reduce global hypoxia, thus improving seem to confer these actions because Sinclair and colleagues (24) patient outcomes. However, this has never been shown in clinical have shown that gene transcript levels of EpoR are similar among studies. Improved systemic perfusion may not translate into normal and tumor tissues. improved intratumoral blood flow, as tumors often have aberrant

Cancer Res 2008; 68: (11).June 1, 2008 4014 www.aacrjournals.org

Table 1. ESA trials resulting in adverse cancer patient outcome

Study Population Active ESA Hemoglobin Early Outcomes anticancer Rx? range termination?

Henke et al. (2) Locally advanced Y Epoetin h, Female: N Worse locoregional head and neck 300 IU/kg, 12–14 g/dL progression (HR, 1.69; carcinoma (n = 351) 3Â/wk P = 0.007) Male: Shorter locoregional PFS 13–15 g/dL (aRR, 1.62; P = 0.0008) Shorter OS (HR for death, 1.39; P = 0.02) Leyland-Jones Metastatic breast Y Epoetin a, 12–14 g/dL N 12-mo OS, 70% vs 76% et al. (3) carcinoma (n = 939) 40,000 units/wk (HR for death, 1.37; P = 0.01) Wright et al. (5) Non–small cell lung N Epoetin a, 12–14 g/dL Y Median survival, 63 vs carcinoma (n = 70) 40,000 units/wk 129 d (HR for death, 1.84; P = 0.04) Overgaard et al. (6) Locally advanced Y Darbepoetin a, 14–15.5 g/dL Y Worse locoregional head and neck 150 Ag/wk progression (HR, 1.44; carcinoma (n = 522) P = 0.02) Shorter DFS (HR, 1.49; P = 0.004) Anemia of Cancer Trial Nonmyeloid malignancy N Darbepoetin a, 12–13 g/dL N Shorter OS (HR for (20010103; ref. 7) (n = 989) 6.75 Ag/kg/4 wk death, 1.30; P = 0.008) Lymphoproliferative Lymphoproliferative Y Darbepoetin a, Female: N Shorter OS (HR for Malignancy Study malignancy (n = 344) 2.25 Ag/kg/wk 13–14 g/dL death, 1.37; P = 0.037) (20000161; ref. 7) Male: 13–15 g/dL PREPARE Locally advanced breast Y Darbepoetin a, 12.5–13 g/dL N Increased locoregional (Amgen; ref. 8) carcinoma (n = 733) 4.5 Ag/kg/2 wk progression (88/356 vs 70/377 events) Increased death rate (50/356 vs 37/377 events) Thomas et al. (9) Cervical carcinoma Y Epoetin a, 13–14 g/dL Y Lower 3-y PFS (n = 109) 40,000 units/wk (58% vs 65%; P = NR) Lower 3-y OS (61% vs 75%; P = NR)

Abbreviations: HR, hazard ratio; PFS, progression-free survival; aRR, adjusted relative risk; OS, overall survival; DFS, disease-free survival; NR, not reported.

vasculature, which may obey different physiologic principles than remains the fact that commercially available antibodies used to normal vasculature. identify EpoR are nonspecific in their detection, overlapping Epo functions as a proangiogenic cytokine during its regulation of with heat shock protein-70 (HSP-70) among other proteins. High physiologic angiogenesis, as shown in the uterus (17). The role Epo- expression of HSP-70 in tumors has been linked to poor prog- EpoR signaling plays in tumor angiogenesis is not fully established. nosis, aggressive disease, including formation of metastases, and Ribatti and colleagues (16, 28, 29) correlated Epo-EpoR expression resistance to chemoradiotherapy (34). in tumor and vascular endothelial cells with the extent of tumor There have also been conflicting data regarding the chemo- angiogenesis and grade of malignancy for several tumor types. radiosensitivity of cancer cells when cultured with exogenous Epo. Higher histologic stages and grades of tumors have higher expres- Cervical carcinoma cells showed a dose-dependent, Epo-mediated sion levels of Epo and EpoR, which in turn correlates with higher improved survival with decreased apoptosis during treatment with degree of tumor angiogenesis measured by microvessel density. cisplatin and Epo (22). Another study of malignant glioma and Clinically relevant mechanisms remain a matter of debate, as cervical carcinoma cells revealed increased resistance to cisplatin some experiments have shown that suprapharmacologic doses of and radiation in response to Epo (35). Increased survival of Epo are required for activation to take place and that transcrip- melanoma cells when treated with dacarbazine or cisplatin was tional levels of EpoR are not elevated within tumor cells (30). It also shown to be induced by Epo (36). In contrast, renal carcinoma has also been reported that exogenous Epo does not alter the cells cultured with Epo undergo increased apoptosis when exposed proliferation or growth of many EpoR-expressing tumor cell lines to daunorubicin or vinblastine (37). Squamous cell and colorectal (31–33). A major area of concern and limitation of current studies carcinoma xenografts show increased sensitivity to 5-fluorouracil www.aacrjournals.org 4015 Cancer Res 2008; 68: (11).June 1, 2008

Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2008 American Association for Cancer Research. Cancer Research despite the presence of Epo and do not exhibit increased mechanism plays a dominant role or how the multiple pathways proliferative effects (38). Cell line experiments likely do not interact. Intratumoral effects fashioned in an autocrine/paracrine adequately represent the complex milieu of Epo biology, resulting loop may compete with the systemic effects of ESAs. Continued in some discrepancies among in vitro and in vivo experiments. research is therefore crucial. To date, there are no published sur- Overall, it seems that the specific tumor microenvironment is vival data from patients with nonmyeloid malignancies under- critical for determining response to chemoradiotherapy. It may going chemotherapy concurrently with ESA treatment to maintain well be that we meaningfully alter this microenvironment by the hemoglobin in the recommended range of 10 to 12 g/dL. In the use of exogenous ESAs. interim, physicians will need to be more evidence based in their Observed differences in these experiments may be explained in prescribing practices and should exercise caution in the use of part by examining the tissue-protective effects of Epo seen in ESAs, taking into account each patient’s case (41). Most would normal cerebral and myocardial cells. Joyeux-Faure (39) reported agree that decreasing transfusions by alleviating anemia is the Epo-mediated protection against cellular damage caused by only definitively proven benefit of these agents, which may not ischemia, free radicals, or cytotoxic agents. The nonhematopoietic outweigh the possible untoward effects. Recently, the American signaling pathways involved may be regulated by alternate forms of Society of Clinical Oncology and the American Society of Hema- Epo, such as desialylated or carbamylated forms, which confer little tology have updated clinical practice guidelines (42) to reflect our or no erythropoietic response. Alternate regulation of cellular current knowledge regarding both the potential beneficial aspects responses driven by Epo also depends on the dimerization partner of ESAs and their possible risks. or subtype of the activated EpoR. Although a homodimerized In conclusion, Epo-EpoR signaling plays an important role in form of EpoR stimulates erythropoiesis, its heterodimeriza- complex cancer biology that is as yet poorly understood. Although tion with the h-common receptor (shared by other growth factors not entirely elucidated, our knowledge of the biological mecha- and interleukins) confers tissue-protective effects (40). The role nisms by which ESAs activate several survival pathways important of the h-common receptor has yet to be studied in nonmye- for tumor behavior and response to treatment is sufficient to man- loid malignancy. date caution in their use beyond their strict indication in cancer patients. Summary Taken together, increasing evidence suggests multiple mecha- Acknowledgments nisms of ESA-mediated action, possibly explaining the differences Received 11/30/2007; revised 2/7/2008; accepted 2/26/2008. in study outcomes. It remains to be determined whether one We thank Dr. Anthea Hammond for assistance with editing of the manuscript.

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