Use of erythropoiesis-stimulating agents (ESAs) was associated with an increased risk for cancer in patients undergoing dialysis, according to a new study based on data from nearly 9800 individuals.

ESAs are often used to manage anemia in patients with kidney failure, but concerns persist about their promotion of tumor growth, Jae Young Kim, MD, PhD, physician in the Department of Internal Medicine at National Health Insurance Service Ilsan Hospital, Goyang-si, South Korea, and colleagues, noted in their study recently published in JAMA Network Open. 

To examine the association between ESA use and cancer development among patients receiving long-term dialysis, the researchers reviewed data from Korean National Health Insurance Service database for 9776 adults with kidney failure who began long-term dialysis treatment and received ESAs between 2006 and 2017. Each case was matched with four control cases for age, sex, follow-up time, year of dialysis initiation, and dialysis modality. The mean age of the participants was 62.2 years; 64.4% were male.

The primary outcome was a new cancer diagnosis within 6 months of starting dialysis.

The median of the mean weekly dose of the ESAs was 10,325.5 U, 38.7 μg, and 35.0 μg for epoetin alfa, darbepoetin alfa, and methoxy polyethylene glycol-epoetin beta, respectively. 

High-Dose ESAs Linked to Increased Risk

During the follow-up period, a greater proportion of patients who developed cancer had received high-dose ESAs compared to control patients (53.8% vs 48.8%).

In a multivariate analysis, use of high-dose ESAs was significantly associated with an increased risk for cancer compared with low-dose use (adjusted odds ratio [aOR], 1.23; 95% CI, 1.11-1.35).

The most frequent sites for cancer were digestive (620 cases), respiratory (270 cases), and kidney (249 cases). When characterized by site, use of high-dose ESAs was associated with increased risk for digestive system and respiratory system cancers (aOR, 1.37; 95% CI, 1.14-1.65, and aOR, 1.48; 95% CI, 1.12-1.97, respectively). 

High-dose ESA use also was associated with increased risk for cancer in ill-defined and unspecified sites (aOR 1.64; 95% CI, 1.15-2.33) but in no other specific sites. The association was consistent across short-acting and long-acting ESA types.

A subgroup analysis showed no significant interaction between ESA use and cancer diagnosis overall. However, in subgroups stratified by age, the aORs for the association between high-dose ESA use and cancer development were significantly different among patients aged 60 years or older vs those younger than 60 years (aOR, 1.47 vs 0.90; P for interaction < .001).

The findings were limited by the potential bias from unmeasured variables including lifestyle risk factors such as alcohol and tobacco use. Other limitations included the lack of data on hemoglobin levels and iron deficiency and the exclusively Korean study population, the researchers noted.

However, the results suggest the potential for increased risk for new cancer in patients treated with high-dose ESAs, especially those older than 60 years, and support caution in the use of these medications, they concluded.

Risks Remain Unclear

“Concern about the possibility that ESAs, particularly in high doses, may increase occurrence or growth rate of cancer has been around for a long time in patients with CKD [chronic kidney disease], with and without dialysis, as well as in other patient populations,” said Jeffrey S. Berns, MD, professor of medicine and pediatrics at the Hospital of the University of Pennsylvania, Renal, Electrolyte, and Hypertension Division in Philadelphia. 

“This concern has influenced recommendations and clinical practice guidelines about ESA use in CKD and dialysis patients with cancer or a history of cancer; however, the de novo cancer risk attributable to ESAs is really unclear in these patients,” he told Medscape Medical News. 

The current study’s finding that higher ESA doses are associated with more cancer risk was not surprising, said Berns, who was not involved in the study, but the results cannot definitively answer the question of how much ESA treatment is too much. 

The current study keeps open the question of the impact of ESAs on cancer risk, particularly in higher doses; however, the findings were limited by the focus on a Korean population, Berns noted. They may not be generalizable to the US or elsewhere.

In addition, the mean ESA doses in the US are higher than those used in Korea, he said. Therefore, “if there is a dose-related risk threshold, it is possible that most US dialysis patients are above that, but we still need a more definitive answer to this issue in order to understand implications for practice.”

Additional limitations of the current study include a lack of clarity on the cumulative ESA exposure, and whether cumulative exposure vs dose is the culprit — if there is one — behind increased cancer risk, said Berns. “We also have to think about biological plausibility. If someone has been on dialysis and receiving an ESA for 6 months, a year, or even 2 years, then develops a cancer, is it reasonable to think the ESA contributed to that?”

Given the long latency period of many malignancies, it is possible that some patients received a higher ESA dose because they already were developing an unrecognized malignancy that made them less responsive to the ESA, Berns said.

The study was supported by the National Health Insurance Service Ilsan Hospital. The researchers disclosed no financial conflicts of interest. 

Berns disclosed no financial conflicts of interest.