Clear-cut evidence for routine use of ESA agents remains elusive in meta-studies

April 24, 2009

When it comes to erythropoiesis-stimulating agents in cancer patients, there are three distinct schools of thought: These agents are quite straightforward; they are nothing short of a "minefield or morass"; or they are somewhere in between.

ABSTRACT: A recent meta-analysis of multiple ESA studies did not unearth specific risk factors, but clinicians still need to proceed with caution. Experts discuss three distinct approaches to ESA application.

When it comes to erythropoiesis-stimulating agents in cancer patients, there are three distinct schools of thought: These agents are quite straightforward; they are nothing short of a "minefield or morass"; or they are somewhere in between.

Guidelines from medical societies-including ASH/ASCO, NCCN, and EORTC/EMEA in the EU-are in no short supply. This makes it fairly easy for those who approach ESAs in a straightforward manner: Follow these guidelines, which should be viewed in the context of Black Box warnings on ESAs issued by the FDA.

But the situation becomes somewhat murkier when the individual studies that led to the Black Box warnings are more closely scrutinized by people who have declared ESAs a minefield.

The ongoing controversy over ESAs was reignited with a meta-analysis presented at ASH 2008 in San Francisco (abstract LBA-6), which did not find any specific risk factors associated with the agents.

Senior author Andreas Engert, MD, professor at the University of Cologne in Germany, said that although the investigators looked at the patient-specific data in detail, no risk factors emerged.

"Obviously, patients who had no chemotherapy or treatment fared worse. The question for the majority of patients is whether a risk group can be identified," said Dr. Engert, who has served as a consultant for Roche, Amgen, and Johnson & Johnson.

"We cannot answer the question of whether a particular subgroup of cancer patients on chemotherapy is at higher risk. All groups were at risk on our model," he added. Oncology News International spoke with the authors of the meta-analysis, as well experts in all three ESA camps, about their respective takes on the use of the agents and why the current restrictions may go too far.

Early warnings
In 2007, the FDA issued a Black Box warning stating that ESAs are associated with excess mortality and/or accelerated tumor growth. The label change was based on multiple studies, which critics say utilized higher-than-currently-recommended doses of ESAs and treated patients to higher-than-currently-recommended hemoglobin (Hb) target levels. Summaries of the studies, including CHOIR and CREATE, were provided in a statement by John K. Jenkins, MD, director of the office of new drugs at FDA's Center for Drug Evaluation and Research (www.fda.gov/ola/2007/esa062607.html).

In 2008, two additional studies of women with breast cancer and gynecologic cancer (PREPARE and GOG-191, respectively) showed an increased risk of mortality when the drugs were used for chemotherapy-induced anemia (CIA). In both of those studies, high doses of ESAs were used and patients were treated to target level of Hb > 12 g/dL. Later in 2008, based on all studies to date, the FDA said that labels for ESAs had to carry warnings about the following risks: shortened survival, tumor progression, or recurrence, and serious cardiovascular and thrombovascular events in patients with cancer. Label changes stipulated use of the lowest possible dose of ESA to avoid red blood cell transfusions. ESAs are only to be used for anemia due to chemotherapy and only in patients who are not deemed curable.

The label also states that ESAs should be discontinued after the completion of chemotherapy.

How to treat patients
Alan Lichtin, MD, a staff hematologist/oncologist at the Cleveland Clinic Foundation, was involved with developing the ASH/ASCO guidelines. He said there are basically three options for a patient who is becoming more and more anemic on chemotherapy: hand-holding, transfusions, and ESAs. "ESAs are only indicated for patients on chemotherapy without a curative intent. Adjuvant chemotherapy for a curable malignancy is not a setting for ESAs," he stated. Dr. Lichtin believes that oncologists should stick to the guidelines and Black Box warnings. "If you don't, you expose your patients to risk, and your judgment could be called into question."

He finds the mounting evidence on the potential harms of ESAs convincing, including venous thromboembolism, shortened survival, and potentiation of tumor growth. He noted, however, that "studies suggesting promotion of tumor growth are still early and the evidence is not clear-cut." Dr. Lichtin has received only research support from Amgen for studies on thrombopoietin.

The latest study to weigh in on the question was presented at ASH by Julia Bohlius, MD. Dr. Lichtin and others interviewed by Oncology News International agree that this meta-analysis was well-conducted and included patient-specific data on more than 13,000 cancer patients.

"ESAs may be used when a patient on chemotherapy is becoming more and more anemic," Dr. Lichtin explained.

"The risks and benefits of ESAs and transfusion should be discussed with the patient. If the treatment attempt is not curative and the patient doesn't want a transfusion, then ESAs can be started when the Hb is < 10 g/dL. The aim of therapy is to keep patients from being transfused . . . not to go to Hb 12 g/dL," he said. Reimbursement is usually based on initiating ESAs at Hb < 10 g/dL, he added.

Barry Brooks, MD, chair of the subcommittee on supportive care pathways for US Oncology in Dallas, has been involved in deliberations about ESA use for more than two years.

"The fact is that fewer patients are getting ESAs than in the past and not necessarily for the best reasons," Dr. Brooks stated. "The situation is a minefield, a morass. There are competing interests here, including biotech pharma, CMS, physicians, and patients."

Dr. Brooks disagrees with the 2007 Centers for Medicare & Medicaid Services (CMS) ruling that Hb 10 is both the starting and stopping point for ESAs. "This ruling, made by nonexperts and non-MDs, is a blow with ripple effects on Medicare and Medicaid patients. It was done ostensibly to improve safety, but these drugs are expensive and CMS is very concerned about costs. You can't rule out a financial incentive," he said.

The CMS ruling, in effect, created a two-tiered system where commercially insured and government insured patients are treated differently. "This is counter to our professional goals as physicians," Dr. Brooks said. "We don't always know who is a Medicare patient. We don't put a red M on their foreheads."

Some patients may be exceptions, he continued, such as patients who live in high altitudes and who become symptomatic. "They need an ESA before the Hb reaches 10 g/dL. But there are no exceptions in the CMS world. For commercial patients, you get to use your medical judgment, but for government patients, ‘one size fits all,'" Dr. Brooks said.

He said that the idea that ESAs are harmful in chemotherapy-induced anemia comes from studies that treated patients to higher target Hb than is appropriate, as stipulated in ASH/ASCO and NCCN guidelines.

"There is no evidence that patients with CIA treated in the target range of Hb 10 to 12 g/dL have increased tumor progression," he stated. "Our pathways at US Oncology recognize the potential for overuse of ESAs and restrict their use within the appropriate range."

Regarding the FDA/ODAC ruling that patients with curable cancer should not be treated with ESAs, Dr. Brooks said, "They just made that up to help give CMS cover when the two-tiered system created by the National Coverage Determination threatened to bring down the wrath of Congress. They threw a blanket over all patients with this ruling, lessening the distinction between commercially insured and government insured patients."

The CMS restrictions, he said, "are not primarily about making the world safer for cancer patients, in my opinion. These are draconian measures." Dr. Brooks stressed that this is his personal opinion and not necessarily the view of US Oncology.

"The crux of the situation is that ESAs are restricted to such a degree that patients' quality of life has diminished since ODAC's ruling," he said. "We are dealing with it and we use more transfusions. But transfusions have risks of their own, including blood clot hazards," added Dr. Brooks, who is a consultant for Amgen for denosumab.

He also took issue with the notion of determining which patients are curable. In his practice, he "slugs it out case by case" and will apply for reimbursement for ESAs if, in his judgment, the benefit outweighs the risk in a given patient.

In summary, Dr. Brooks agreed with the formal guidelines and US Oncology Pathway on the use of ESAs.

But Dr. Brooks also cautioned that he has issues with the formal guidelines.

"I have trouble with the CMS and ODAC rulings. They are not based on good science or expert opinion," Dr. Brooks told Oncology News International.

Understanding FDA logic
There is logic behind the FDA/ODC restrictions on ESAs for patients who are not treated with a curative intent, according to J. Douglas Rizzo, MD, associate professor of medicine at the Medical College of Wisconsin Clinical Cancer Center in Milwaukee.

"The logic used by FDA/ODAC appears to be that the risk-benefit ratio threshold should be more favorable when considering use of supportive care drugs like ESAs where a reasonable alternative exists (transfusion), than would otherwise be true if the drug under consideration were used to treat malignancy," Dr. Rizzo said. He commented that although transfusions are generally considered safe, there are relatively few studies characterizing their risk.

Regarding the CMS decision, Dr. Rizzo said it was based on safety, but cost may have been a consideration. "The drug was heavily promoted to physicians and consumers, and ESAs are very expensive drugs that represent a large cost burden to the medical system when considering oncology and renal indications," he noted.

Although he understands the FDA/ODAC restrictions, Dr. Rizzo said that "the existing evidence (on the dangers of ESAs) is difficult to interpret, because of multiple confounding factors, and there are unanswered questions."

It is not clear what factors place cancer patients at increased risk from ESAs. "The recent studies done in cancer patients used higher target Hb, initiated ESAs at higher Hb, used increased ESA dosage, and were conducted in patients with solid tumors who were not getting active therapy (chemotherapy or radiation).

These studies were also conducted in an environment of increased surveillance for survival. We don't know which, if any, of these factors is related to the increased harm associated with ESAs," Dr. Rizzo commented.

Lack of clear evidence regarding factors most associated with harm makes clinical decision-making suboptimal, he added.

Dr. Rizzo called the study by Engert's group "the next opportunity for understanding whether particular patients are at increased risk from ESAs." The study found a survival decrement for all cancer patients, but that patients taking chemotherapy had no significant increase in mortality. These authors used statistical modeling and introduced different factors into that model, such as target Hb and ESA dose. Apparently, none of the risk factors was a significant predictor of harm.

"Dr. Rizzo advised: "For the present, pay careful attention to the guidelines and use good judgement based on FDA warnings." It's questionable whether the quality-of-life benefits are sufficient to justify exposing patients to ESAs," he said.