Treatment with erythropoiesis-stimulating agents in chronic kidney disease patients with cancer

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1 mini review & 2014 International Society of Nephrology Treatment with erythropoiesis-stimulating agents in chronic kidney disease patients with cancer Azzour D. Hazzan 1, Hitesh H. Shah 1, Susana Hong 1, Vipulbhai Sakhiya 1, Rimda Wanchoo 1 and Steven Fishbane 1 1 Division of Kidney Diseases and Hypertension, Department of Medicine, North Shore University Hospital, Long Island Jewish Medical Center Hofstra, North Shore-LlJ School of Medicine, Great Neck, New York, USA Treatment of anemia remains an important component in the care of patients with nondialysis chronic kidney disease (CKD) and end-stage renal disease (ESRD). Erythropoietinstimulating agents (ESAs) remains a key anemia treatment strategy in this patient population. However, anemia management in this group can become more complicated by prior or current history of malignancy. There has been a great deal of work both scientifically and in clinical trials in oncology that have revealed certain concerns and risks of ESA use in patients with cancer. In this review, we will bring together knowledge from nephrology and oncology literature to help nephrologists understand the implications for ESA treatment when CKD/ESRD is complicated by cancer. We also suggest an approach to the management of anemia in this patient group with active or previous malignancy. Kidney International (2014) 86, 34 39; doi: /ki ; published online 8 January 2014 KEYWORDS: anemia; chronic kidney disease; cancer; erythropoietin Anemia remains an important complication of chronic kidney disease (CKD). Although several factors may have a contributing role in the development of anemia in CKD, the most important cause is an inappropriately low secretion of erythropoietin from the diseased kidneys. Erythropoiesisstimulating agents (ESAs) continue to have an important role in the treatment of anemia in patients with CKD. ESA use in this group of patients has been shown to raise hemoglobin (Hgb) levels, decrease blood transfusion requirements, and improve the quality of life and symptoms related to anemia. However, normalization of Hgb levels in CKD patients has been associated with increased thromboembolic (cardiovascular and cerebrovascular) events. Studies reported in the oncology literature have also raised concerns regarding ESA safety, including an increased possible risk of cancer progression leading to poorer outcomes including increased mortality. Anemia management may be challenging in a given advanced nondialysis CKD or end-stage renal disease (ESRD) patient who is found to have cancer. There are several management questions that arise. Currently, there are no guidelines for nephrologists regarding ESA and anemia management in CKD patients with previous or active cancer. This article will review the biology of erythropoietin with emphasis on the relationship with cancer. The current published literature on the subject will be discussed and clinical implications for ESA use in nondialysis CKD and ESRD patients with cancer will also be reviewed. Correspondence: Steven Fishbane, Division of Kidney Diseases and Hypertension, Department of Medicine, North Shore University Hospital, Long Island Jewish Medical Center Hofstra, North Shore-LIJ School of Medicine, 100 Community Drive, 2nd Floor, Great Neck, New York 11021, USA. sfishbane@nshs.edu Received 26 September 2013; revised 24 October 2013; accepted 24 October 2013; published online 8 January 2014 ERYTHROPOIETIN BIOLOGY AND RELEVANCE FOR CANCER Erythropoietin (Epo) is a 30.4-kDa glycoprotein hormone that is normally secreted by the adult kidney and the fetal liver. 1 Interstitial fibroblasts appear to be a major source of renal Epo synthesis. 2 The cellular recognition of tissue hypoxia and resultant stimulation of erythropoiesis start when tissue oxygen tension is decreased. This leads to stabilization of the transcription factor, hypoxia inducible factor-1,which then binds a site on the 3 0 enhancer of the Epo gene that in turn leads to the upregulation of the gene and increased mrna stability. 3,4 The Epo receptor (EpoR) is a 59-kDa peptide that is a member of the cytokine receptor family. When Epo binds to its receptor on the surface of erythroid progenitors, it 34 Kidney International (2014) 86, 34 39

2 AD Hazzan et al.: Treatment with ESAs in CKD patients with cancer mini review prevents cellular apoptosis. It also stimulates the proliferation and the terminal differentiation of cells committed to the erythroid lineage. 1 In addition to erythroid cells, there are other cell types that express the EpoR. Vascular endothelial cells, astrocytes and neurons, cardiac myocytes, retina and kidney, and mammary epithelial cells are some examples. 5 Different functions have been attributed to the EpoR in these cell types, although the nonerythroid function and purpose of Epo are not yet fully elucidated. Vascular endothelial cells express EpoR, and the interactions of Epo with its receptor have compounding effects. There are both in vitro and in vivo studies that show that the Epo EpoR complex promotes proliferation, migration, and differentiation of normal endothelial cells into vascular tubes and hence the formation of new blood vessels. This process is driven by hypoxia and appears to be physiologic. However, it has been shown that this process may also be involved in pathological angiogenesis such as proliferative diabetic retinopathy. 6 Because of the importance of angiogenesis to tumors, the question naturally arises: do cancer cells express the EpoR, and if so are there clinical implications? Initial evaluations for the EpoR on cancer cells tested either for the receptor protein itself or mrna transcripts. The latter studies were probably less informative, as they examined EpoRmRNA levels from bulk tumor tissue, which may be contaminated by other cell types from blood or stromal tissue, thereby yielding potentially nonspecific results. Immunohistochemistry or western blotting with anti-epor antibodies were used for the analysis of EpoR protein. Initial reports indicated that the EpoR protein was found on certain tumor tissues. 7 Subsequent studies, however, found the antibodies used for testing to be nonspecific. 8 Liang et al. 9 have reported high levels of EpoR expression on breast cancer tissue using the anti-epor polyclonal antibody M-20. However, the demonstration that M-20 antibodies stained EpoR knockout tissue raised serious questions as to the validity of these findings. 10 Because of difficulties with anti- EpoR antibody specificity, other studies have focused instead on the functional response of cancer cell lines to EPO stimulation. These studies had conflicting results, but some did indicate a positive functional response. 11 However, even the positive studies lacked negative controls, and any functional response tended to be with molecules not part of the normal EPO signaling pathway, such as STAT5. The recent development of a first specific antibody to the EpoR (A82) with both positive and negative controls has allowed for a more rigorous method for testing for the EpoR protein on cancer cells. 12 In a study of 66 cancer cell lines, Swift et al. 13 found either no or very low levels of the EpoR protein. These more recent studies are important contributions; however, until they are confirmed by additional laboratories, the results cannot be taken as fully conclusive. Therefore, although the most recent data are pointing away from functional EpoR on cancer cells, the literature needs to mature further before definitive conclusions could be reached. If EpoRs are found not to be present on most cancer cells, there still could be indirect effects of ESA treatment. Considerations would include the effect of supraphysiologic Hgb levels as used in most clinical trials, which would increase oxygen delivery to cancer cells and potentially stimulate proliferation. Another hypothetical indirect mechanism was described recently. When stimulated, macrophages express the EpoR. The binding of Epo to these cells can suppress NF-kB activation and proinflammatory genes, resulting in an immunosuppressive effect. 14 Such a mechanism could contribute to adverse effects during ESA treatment. Other indirect pathways have been discussed but would appear to be quite speculative at this point. However, the over-riding question is whether there truly is an effect of ESAs on cancer disease progression. LITERATURE ON ESA USE IN PATIENTS WITH CKD AND CANCER Before examining the oncology literature, we first review the few nephrology studies that have evaluated cancer outcomes. ESAs have been widely used in the nondialysis CKD and ESRD patient population for several decades. ESAs have decreased the incidence of blood transfusions, improved symptoms related to anemia, and probably also improved patients quality of life. However, randomized clinical trials have also identified cardiovascular risk with prolonged treatment with ESAs to Hgb targets higher than 13 g/dl. In addition, treatment to higher Hgb targets clearly increases the risk of thromboembolic events. The Trial to Reduce Cardiovascular Events with Aranesp study was the first renal ESA trial to signal a relationship between ESA use and cancer mortality. 15 As it had the largest patient population studied and longest follow-up, it was the study best designed to find any possible cancer-promoting effect of ESAs. Although there was no significant difference in patients reporting a cancer-related adverse event (darbepoetin alfa group 6.9%, placebo group 6.4% (P ¼ 0.53)), there was a trend towards increased risk of death attributed to cancer (darbepoetin alfa group, 39 deaths, placebo group, 25 deaths (P ¼ 0.08)). Interestingly, an increased risk of death due to malignancy in patients with a previous history of cancer was also noted in the darbepoetin alfa group, with 14 of the 188 such patients assigned to darbepoetin alfa dying from cancer, as compared with one of the 160 patients assigned to placebo (P ¼ 0.002). 15 These results raised concern as to adverse cancer outcomes with treatment to high Hgb targets for extended periods of time with ESAs. Since the Trial to Reduce Cardiovascular Events with Aranesp, there have only been a few studies to evaluate ESA use in CKD patients with cancer. A Japanese study, Surveillance of Epoetin Adverse Events of Stroke and Cancer, in patients with CKD stages 4 and 5 failed to show an increased incidence of cancer. 16 The average Hb (10.1 g/dl), however, was relatively low in this study. It should also be noted that the trial had a very short surveillance time. A study by Seliger et al. 17 found an increased stroke risk in patients with CKD treated with ESAs. Interestingly, the increase in stroke risk applied only to CKD patients with a Kidney International (2014) 86,

3 mini review AD Hazzan et al.: Treatment with ESAs in CKD patients with cancer diagnosis of cancer. 17 It is important to note that in this study the cancer group received higher initial ESA dose even though the pre-esa Hgb was similar in both groups. It would be important to consider the similar hematopoietic responses of the CKD cancer group despite receiving two to four times higher doses of ESA. Although this may support an ESA resistance theory in cancer, more studies are necessary to elucidate this theory, as well as the effect of dose dependency and increasing stroke risk, in CKD patients with cancer. Most of our knowledge on ESAs and cancer risk comes, as expected, from the oncology literature. ESAs have been used in cancer patients because of pervasive anemia, for the most part in an effort to reduce fatigue and related symptoms and to reduce transfusion dependence. In addition, some trials, especially in head and neck cancer, had used ESAs to increase tumor cell oxygenation for what was hypothesized to provide more effective radiotherapy. An early signal of potential problems with ESA treatment in cancer came from the ENHANCE study. This was a trial in head and neck cancer in patients given ESAs while undergoing radiotherapy, without chemotherapy. Patients were treated to Hgb g/dl and, surprisingly, locoregional progression-free survival was found to be poorer with epoetin than with placebo. 18 The Danish Head and Neck Cancer Group (DAHANCA 10) study was a randomized trial of darbepoetin to maintain a Hgb level of g/dl during radiotherapy. Similar to the results of ENHANCE, there was an B10% difference in 3-year locoregional control in favor of the control group (P ¼ 0.01). Both of these studies illustrated the potential harm of using ESAs to achieve high Hgb levels in patients with head and neck cancer not receiving chemotherapy. Perhaps the most useful information on ESAs and outcomes in cancer patients has come from several published meta-analyses. We have considered the outcomes of mortality, thrombosis risk, and cancer disease progression separately. For mortality, these analyses have had mixed results The most recent Cochrane Database analysis published in December 2012 reviewed 91 randomized controlled trials including 20,102 patients. 24 Strong evidence was found that ESAs increased mortality during the active study periods (death occurring up to 30 days after active study protocol) (hazard ratio 1.17; 95% CI ), and borderline evidence that ESAs decreased overall survival (hazard ratio 1.05; 95% CI ). It should be noted that the increase in mortality risk was attributed to studies of patients with baseline Hgb, before ESA treatment, over 12 g/dl. 24 In fact, in the Cochrane analysis, none of the studies had a Hgb ceiling of less than 12 g/dl. In 6% of the studies, the ceiling was 13 g/dl, in 54% it was 14 g/dl, in 24% it was 15 g/dl, and in 5% it was 16 g/dl. Although this suggests that mortality risk might be related to higher Hgb levels or high ESA doses, it does not rule out that the boundary of risk might extend to lower Hgb levels as well. Another important observation has been that the increased mortality risk has been primarily found in studies of cancer patients who were not receiving concurrent chemotherapy. In contrast, there has been no clearly defined trend as to mortality in patients receiving ESAs during chemotherapy treatment. This finding has strongly influenced both regulations and clinical guidelines. Taken together, although the literature is somewhat mixed, we conclude the following: (1) there is an increase in mortality risk with ESA treatment in cancer; (2) although the increased risk appears to be at higher levels of Hgb, safety cannot be assured for more conservative Hgb initiation points or goals; (3) risk clearly appears to be greater when ESAs are used outside of the setting of concurrent chemotherapy; and (4) although it is likely that the risk may depend on the type of cancer, there is insufficient evidence at present to delineate risk profiles in a way that would influence treatment. In addition to mortality risk, a meta-analysis found a substantial increased risk for thromboembolic complications with ESA treatment in cancer (RR 1.52, 95% CI ). 24 This would appear to be intuitive, given the knowledge of ESA treatment and thromboembolic risk in CKD studies. In cancer, there are good reasons to believe that hypercoagulability related to malignancy could contribute to a further increase in thrombotic risk with ESA treatment. Meta-analyses have also examined the effect of ESA treatment on cancer disease progression. Glaspy et al., 22 in their analysis, commented on the generally suboptimal design of the studies as to the analysis of cancer progression. 22 Although only one published study was found to have a truly rigorous design, this study found no significant effect of ESAs on disease progression. 25 Criticisms raised by Glaspy and colleagues 24 included the fact that 92% of studies relied on the investigator to judge disease progression or radiographic assessment without a central review. Their meta-analysis did not find a significant effect in the 25 published studies of ESA on cancer disease progression (overall OR ¼ 1.01; 95% CI: ). In the 21 chemotherapy studies (7908 patients with 4053 ESA-treated patients and 3855 control patients), the results were much the same (OR ¼ 0.95; 95% CI: ) (28). The Cochrane systematic review had similar results. No negative effect of ESA treatment on tumor response (RR 1.02; 95% CI: ) was found. 24 Furthermore, Aapro et al. 26 recently reported a very detailed analysis of cancer disease progression related to ESA treatment and concluded that the current clinical data suggest that ESAs may have little effect on disease progression in chemotherapy patients. 26 Taken together, the diminishing evidence of functional EpoR on cancer cells and the general lack of adverse clinical data suggest that ESA treatment probably does not have a significant systematic effect on the course of cancer. Nonetheless, because of the importance of the subject, continued research must be strongly encouraged. The reason for the increased mortality risk with ESA treatment in cancer is unclear. A first concern might be that ESA treatment resulted in more rapid cancer progression. As discussed above, this is probably not the case. Another mechanism could relate to the Hgb targets for many of the 36 Kidney International (2014) 86, 34 39

4 AD Hazzan et al.: Treatment with ESAs in CKD patients with cancer mini review trials, which were quite high, often g/dl. This could have increased whole-blood viscosity enough to increase thrombosis risk and secondarily mortality. Other mechanisms would be more speculative and, as of the time of this writing, the cause of increased mortality remains incompletely understood. The American Society of Hematology and American Society of Clinical Oncology established the updated clinical practice guidelines in 2010 for the use of ESAs in cancer patients. 27 The guidelines did not specifically address the cancer patients with advanced kidney disease. It is recommended that ESAs should be considered as a treatment option for patients with chemotherapy-associated anemia. Both guideline groups agreed that ESAs are not recommended for patients with cancer and anemia not associated with chemotherapy. Initiation of ESAs should generally be postponed until the Hgb has decreased below 10 g/dl. The decision to initiate ESA in patients with Hb between 10 and 12 would need thoughtful consideration of risks and benefits. There is no guidance as to an optimal target Hgb level. Rather, the lowest possible dose should be used to treat anemia to help avoid blood transfusion. These recommendations are in line with the FDA warnings and labeling. However, the FDA does not recommend the use of ESA in patients with myelosuppressive chemotherapy when the anticipated outcome is cure. This is still controversial in the oncology community, as there is not always a distinction made between curative and palliative treatment. CLINICAL IMPLICATIONS AND RECOMMENDATIONS FOR ESA TREATMENT IN CKD PATIENTS WITH CANCER All treatment decisions involve a balancing of benefit and risks applied in the context of the individual patient s characteristics. With respect to ESA treatment in CKD, decisions usually lever on balancing symptom improvement and transfusion avoidance against cardiovascular and thrombotic risk. The fulcrum of balance shifts as the Hgb target is raised or lowered. This construct may become more complicated when the nondialysis CKD or ESRD patient has a history of cancer or a currently treated malignancy. A cancer diagnosis imputes an additional concern as to whether ESA treatment has an impact on cancer progression. In previous sections, however, the discussion concluded that evidence that ESA treatment has an impact on cancer progression is questionable. To the extent that ESA therapy does not have an impact on cancer, the risks identified from the renal and oncology literature become somewhat congruent, particularly an increased risk of mortality and thrombosis with ESA treatment to higher Hgb targets. If this is true, then the additional diagnosis of cancer should not change the ESA treatment protocols in nondialysis CKD or ESRD patients. However, we will take the position that, although there is no strong evidence that ESA treatment has an adverse effect on cancer progression, as the literature on the subject is still developing, a conservative therapeutic stance is called for. We will approach recommendations from the perspective of three clinical settings: current cancer, previous cancer, and no history of cancer (Figure 1). ESA treatment in patients with nondialysis CKD or ESRD and active cancer The pathobiology of anemia in these patients includes CKDrelated factors such as Epo deficiency, iron deficiency, inflammation, and others, and cancer-related factors such as myelosuppressive chemotherapy (and its intensity and duration), incremental inflammation, and even more frequent ESA treatment in CKD/ESRD Issues to consider regarding cancer No history of cancer Active diagnosis of cancer Past history of cancer Are major risk factors present? No Yes Treat per usual CKD/ESRD protocols Consider conservative Hgb target If acute severe anemia treat with blood transfusion Prior to ESA evaluate for other correctible causes of anemia If ESA is initiated or continued, limit treatment to upper Hgb target 10 g/dl Treat under the APPRISE REMS program Is Yes cancer considered cured? No Follow goals for active cancer Consider continuing conservative treatment Hgb target Place special emphasis on carefully monitoring for and preventing thromboembolic events Figure 1 Approach to issues related to cancer in CKD/ESRD patients treated with ESAs. APPRISE, Assisting Providers and cancer Patients with Risk information for the Safe use of ESAs; CKD, chronic kidney disease; ESA, erythropoiesis-stimulating agents; ESRD, end-stage renal disease; Hgb, hemoglobin; REMS, risk evaluation and mitigation strategy. Kidney International (2014) 86,

5 mini review AD Hazzan et al.: Treatment with ESAs in CKD patients with cancer blood drawing. Taken together, it is likely that anemia is even more severe than typically seen in CKD/ESRD. Several factors should be considered in treatment decisions when active cancer is present: If acute severe, symptomatic anemia is present, then blood transfusion is the treatment of choice. Concerns regarding immune sensitization related to transfusion and a detrimental impact on the ability to receive a subsequent kidney transplant are far less relevant in the patients with active cancer. Before initiating any therapy, an evaluation for the cause of anemia should be conducted with particular emphasis on the possibility of occult blood loss or nutritional deficiencies. Decisions as to the initiation of ESA (or continuation in the nondialysis CKD/ESRD patient already on ESA when cancer is discovered) must balance risk and benefit. As discussed above, incremental risks of ESAs in CKD/ESRD patients with cancer primarily relate to a probable increase in the risk of thrombosis, probable increase in mortality risk, and a possible but unlikely risk of increased tumor progression. It should be repeated here that the increased mortality risk observed in cancer studies was present primarily when the baseline Hgb was 412 g/dl and target Hgb levels were substantially higher than the current guidelines (13 16 g/dl). Nonetheless, until the literature is more fully defined, we would suggest generally limiting the Hgb target to an upper level of 10 g/dl (as opposed to current regulatory and guideline upper levels of g/dl in dialysis patients) (Figure 1 and 2). For the occasional patients who still have anemia-related symptoms, a slightly higher Hgb target may be considered. In addition, intravenous iron may be given to minimize total ESA dose exposure. Among patients with cancer, the only FDA indication for ESA treatment is for anemia caused by current myelosuppressive chemotherapy; there is no indication for patients with cancer not receiving chemotherapy. It is our opinion Potential balance of benefit and risk in ESA treatment in CKD/ESRD complicated by cancer Reduced symptoms and blood transfusions Increasing Hgb target Increased risk of mortality, thrombosis Figure 2 The literature of ESA treatment to high Hgb targets in CKD/ESRD as well as in cancer has indicated an increased risk of adverse outcomes. It is possible, but not proven, that the high Hgb level or the high ESA dose required may be part of the causal pathway. To the extent that this is true, lower Hgb targets may decrease the risk for adverse outcomes while still achieving the beneficial effects of treatment. CKD, chronic kidney disease; ESA, erythropoiesis-stimulating agents; ESRD, end-stage renal disease; Hgb, hemoglobin. that the lack of an indication for these latter patients should not be extrapolated to patients with nondialysis CKD or ESRD. Epo production in these patients is usually severely deficient because of kidney disease. Severe anemia, especially in ESRD patients, results if ESA therapy is not used, and the anemia is likely to be worse among patients with concomitant cancer. The benefits of treatment would appear to outweigh risks in ESRD patients who have cancer and severe anemia (even without concomitant chemotherapy). However, we would suggest that the Hgb upper level target should generally be limited to 10 g/dl. The FDA and some oncology guidelines recommend against the use of ESAs if chemotherapy treatment is with curative intent. Again, as stated above, this is sound advice for cancer patients without advanced kidney disease. However, for all the reasons stated above, ESA treatment is probably reasonable for the nondialysis CKD/ESRD patient receiving chemotherapy with curative intent but with an upper Hgb target of only 10 g/dl. Thrombosis risk must be considered. In addition to thromboembolic risks with CKD, cancer may confer an additive degree of risk. Nephrologists should evaluate risk, with attention to recent thromboembolic events and the patient s history. There is a requirement that ESA treatment in patients with nondialysis CKD/ESRD be preceded by education on risks and benefits. In contrast, when treating cancer patients with ESAs, the FDA has a formal Risk Evaluation and Mitigation Strategy (program. The program for cancer patients is ESA Assisting Providers and cancer Patients with Risk Information for the Safe use of ESAs. This program requires provider certification. Patients with nondialysis CKD/ESRD who have cancer should be treated under the APPRISE program, probably by the nephrologist partnering with an oncologist. The nondialysis CKD/ESRD patient with a previous history of cancer Here, we would recommend that the nephrologist confers with the patient s oncologist to determine whether the cancer is cured and to consider the risk for recurrence and the risk for subsequent tumors related to the primary malignancy or its treatment. If there is strong evidence that the previous cancer is cured with very low risk for recurrence, then some caution with ESA therapy is advised. A cause for concern here comes from the Trial to Reduce Cardiovascular Events with Aranesp study, where there was an increased risk of dying because of malignancy in patients with a history of cancer. However, the target Hgb level in the ESA-treated group was 13 g/dl. As an extension of our discussion of ESA treatment in nondialysis CKD/ESRD patients with current cancer, in those with a previous cancer history, similar caution is advisable. Until the patient is felt to be cured, probably 5 years for many types of cancer, we would treat with ESAs as if active cancer was present, maintaining an upper limit of Hgb of 10 g/dl. Even after a probable cure, a continued cautious approach to 38 Kidney International (2014) 86, 34 39

6 AD Hazzan et al.: Treatment with ESAs in CKD patients with cancer mini review therapy may be justified, including the use of IV iron to reduce overall ESA dose exposure. The nondialysis CKD/ESRD patient with no active or previous cancer When a nondialysis CKD or ESRD patient has no current or past history of cancer, then the implications of ESA therapy with respect to cancer have little bearing. Although it could be a matter of concern if these patients have a high risk for cancer such as strong family history of colon cancer or breast cancer or if the patient is a smoker, any putative role of ESAs in increasing risk in this situation is highly speculative and probably minimal if treatment follows the current guidelines. DISCLOSURE SF has a role in Consulting and Research and is involved in Data Monitoring Committees of Akebia, Glaxo Smith Kline, Fibrogen and Bayer. All the other authors declared no competing interests. REFERENCES 1. Merchionne F, Dammacco F. 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