Weighing the Hazards of Erythropoiesis Stimulation in Patients with Cancer

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THE NEW ENGLAND JOURNAL OF MEDICINE

Volume 356:2445-2448 June 14, 2007 Number 24

Weighing the Hazards of Erythropoiesis Stimulation in Patients with Cancer

Fadlo R. Khuri, M.D.

On May 10, 2007, the Food and Drug Administration (FDA) convened a meeting of

its Oncology Drug Advisory Committee to discuss concerns about risks associated

with the erythropoiesis-stimulating agents (ESAs) used to treat anemia caused by

chemotherapy. The principal ESAs under scrutiny were epoetin alfa (Procrit,

Eprex, and Epogen) and darbepoetin alfa (Aranesp), and the risks - actual or

potential - were thromboembolic disease, promotion of tumor growth, and

decreased survival. The actual risk of thromboembolic events was shown in two

phase 3 clinical trials, reported in the Journal in 2006, that unequivocally

showed an increased risk of death or cardiovascular or thromboembolic events

among patients with chronic renal failure who were treated with ESAs to drive

hemoglobin levels into the normal range (13.5 g per deciliter or higher), as

compared with those treated to achieve levels in a subnormal range (10.5 to 11.5

g per deciliter).

In 1993, the FDA approved epoetin alfa for patients with cancer on the basis of

pooled data from six randomized, double-blind, placebo-controlled trials that

included 131 patients with various types of cancer. The approval focused on the

effectiveness of epoetin alfa in reducing the number of transfusions required to

treat chemotherapy-induced anemia - not the anemia of cancer. In oncology, ESAs

are helpful in supportive care, but the FDA has not approved the use of such

agents to alleviate fatigue or weakness or to improve patients' quality of life.

In 2003, concern about a detrimental effect of ESAs in patients with cancer

arose with the publication of the results of a multicenter, double-blind trial

conducted by Henke et al.1 involving 351 patients with anemia (hemoglobin level,

<12 g per deciliter in women or <13 g per deciliter in men) who had cancer of

the oral cavity, pharynx, or larynx (see table). In this trial, patients were

randomly assigned to receive radiotherapy along with either placebo or epoetin

beta (Neo-Recormon) at a dose of 300 IU per kilogram of body weight three times

weekly, starting 10 to 14 days before radiotherapy and continuing throughout

treatment. The epoetin beta group had substantially shorter progression-free

survival and overall survival than the placebo group.

In another study, the Breast Cancer Erythropoietin Survival Trial (BEST), 939

patients with metastatic breast cancer receiving first-line chemotherapy were

randomly assigned to receive either epoetin alfa (Eprex) at a dose of 40,000 IU

once weekly or placebo for 12 months.2 Treatment with the study drug was

initiated if the hemoglobin level was 13 g per deciliter or lower at baseline or

if it decreased to that point. Overall survival at 1 year was lower in the

epoetin alfa group. The study was stopped early by an independent data and

safety monitoring committee because of higher mortality in the epoetin alfa

group at 4 months. As in the study by Henke et al., the first part of the

survival curve in the BEST trial showed an increased risk of death from cancer,

which is suggestive of enhanced tumor growth.

In May 2004, the results of such studies prompted the FDA to convene an advisory

committee to assess the safety of ESAs in patients with cancer. The committee

agreed on the need for additional large, randomized trials to determine the

safety of ESAs in patients with several types of tumors, including head and

neck, breast, and non-small-cell lung cancer. Accrual was to be completed over a

period of 3 to 5 years, but as of May 2007, enrollment was poor.

Two trials involving patients with small-cell lung cancer showed that the use of

an ESA according to approved guidelines resulted in no apparent reduction in

survival, and a meta-analysis showed equivalent overall survival and disease

control among patients with cancer when ESAs were used within the recommended

dose range. Nevertheless, four recent studies showed evidence of harm associated

with the use of ESAs in patients with cancer. One of these trials aimed to

randomly assign 300 patients with advanced metastatic non-small-cell lung cancer

to receive 12 weekly injections of epoetin alfa or placebo, with a target

hemoglobin level of 12 to 14 g per deciliter.3 The trial was stopped early after

an unplanned safety analysis involving 70 patients revealed a significant

difference in median survival in favor of placebo. In the second study, 522

patients who were scheduled for definitive radiotherapy for head and neck cancer

were randomly assigned to receive darbepoetin alfa or red-cell transfusion.4

This trial was terminated early after a futility analysis indicated that there

was a detrimental effect on local-regional control (the primary end point) and a

trend toward shorter survival in the darbepoetin alfa group. The table includes

the results of two other unpublished trials in which the outcome was worse in

the darbepoetin alfa group than in the control group.

In March 2007, the results of these six trials led the FDA to advise caution in

the use of ESAs. The agency mandated the addition of a black-box warning about

the potential for tumor promotion and thromboembolic events, and FDA

instructions required ESAs to be withheld from patients whose hemoglobin level

exceeded 12 g per deciliter until the level fell below 11 g per deciliter.

Given the recent results, the FDA convened another meeting of the Oncology Drug

Advisory Committee to seek guidance in redefining safe guidelines for ESA use in

patients with cancer. A clear consensus emerged that product labeling should

indicate further restrictions on approved use and that additional trials should

be pursued aggressively to clarify whether ESAs are indeed associated with an

increased risk of tumor growth. The agency heard recommendations that it

consider limiting the use of ESAs in patients with the types of tumors in which

clinical trials have demonstrated adverse outcomes, that it define a hemoglobin

level at which ESA treatment should be initiated in asymptomatic patients, and

that it restrict the duration of use of ESAs in patients with cancer. The

advisory committee did not support a recommendation urging modification of the

hemoglobin level at which ESA administration should be suspended.

Some meeting participants argued that while awaiting definitive data,

oncologists should refrain from using ESAs in patients with squamous-cell cancer

of the head and neck for whom curative therapy was intended. Participants also

advised caution in the use of ESAs in patients undergoing chemotherapy for

breast cancer and non-small-cell lung cancer.

The mechanism underlying the enhanced growth of tumors with higher doses of ESAs

remains uncertain. There is good evidence that hypoxic tumors resist

chemotherapy and radiotherapy. The biology of tumor hypoxia, with enhanced cell

signaling through the Akt-mammalian target of rapamycin (mTOR) axis and

subsequent up-regulation of hypoxia-inducible factor 1, is what inspired the

clinical trials in which ESA treatment was combined with radiotherapy, cytotoxic

chemotherapy, or both in an attempt to overcome hypoxia-induced resistance. But

another possibility is that certain tumor cells have erythropoietin receptors

that stimulate cell growth when they are bound by erythropoietin or an

erythropoietin-like ligand. Squamous-cell lung cancer, squamous-cell tumors of

the head and neck, and breast adenocarcinomas seem to express erythropoietin

receptors, but such receptors' role, if any, in tumor growth is unclear. Henke

et al. showed that erythropoietin receptors were expressed by two thirds of

tumors in their study and that expression of such receptors in

erythropoietin-treated patients was associated with shorter survival.5

Conversely, in vitro studies have shown that stimulating erythropoietin

receptors in cell lines from head and neck cancer and breast cancer causes the

death of cells, though the questionable quality of the reagents used to detect

erythropoietin receptors must be considered in interpreting these data.

In the face of media attention to the hyperbolic advertising by the companies

that make ESAs and the substantial profits accrued by physicians who use such

agents aggressively, the FDA has sought guidance in exercising prudent,

evidence-based judgment. In order to maintain the public trust, the agency

should act transparently in adopting new guidelines, and medical oncologists

should begin using these agents in a compassionate but disciplined fashion,

placing patient benefit above all other considerations.

Source Information

Dr. Khuri is a professor and the section head of hematology and medical oncology

at the Emory Winship Cancer Institute, Atlanta.

An interview with Doroshow, director of the Division of Cancer Treatment

and Diagnosis at the National Cancer Institute, can be heard at www.nejm.org.

References

1.. Henke M, Laszig R, Rübe C, et al. Erythropoietin to treat head and neck

cancer patients with anaemia undergoing radiotherapy: randomised, double-blind,

placebo-controlled trial. Lancet 2003;362:1255-1260

2.. Leyland- B, Semiglazov V, Pawlicki M, et al. Maintaining normal

hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic

breast cancer receiving first-line chemotherapy: a survival study. J Clin Oncol

2005;23:5960-5972.

3.. JR, Ung YC, n JA, et al. Randomized, double-blind,

placebo-controlled trial of erythropoietin in non-small-cell lung cancer with

disease-related anemia. J Clin Oncol 2007;25:1027-1032.

4.. Goldberg P. Danish researchers post long-awaited Aranesp results -- ever

so discreetly. Cancer Lett 2007;33:1-6.

5.. Henke M, Mattern D, Pepe M, et al. Do erythropoietin receptors on cancer

cells explain unexpected clinical findings? J Clin Oncol 2006;24:4708-4713.

[Erratum, J Clin Oncol 2007;25:1457.]