ERYTHROPOIETIN USE MAY BE HARMFUL IN HEAD-NECK CANCER

Long-term analysis of Radiation Therapy Oncology Group (RTOG) 9903demonstrates that the addition of erythropoietin did not improve local-regional control for anemic patients with head and neck squamous cell carcinoma who receive radiation therapy or chemoradiation, according to a study published by Shenouda et al in the International Journal of Radiation Oncology • Biology • Physics.

This study is a long-term analysis of RTOG 9903, originally published in 2007, to determine if there were additional failures, second primaries, and/or toxicities at a longer follow-up of 8 years. 

Study Methodology

RTOG 9903, an open-label, phase III, randomized trial, examined whether the addition of erythropoietin to radiation therapy would improve disease control in anemic patients with head and neck squamous cell carcinoma. The study accrued 148 patients from June 2000 to November 2003, and 54 cancer centers participated in the trial. Eligible patients had head and neck squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx; had a Zubrod performance status of 0 to 2; and hemoglobin levels ≤ 13.5 g/dL for males and ≤ 12.5 g/dL for females. After enrollment in the study, four patients were considered ineligible, and three patients withdrew from the trial.

Of the 141 patients included in the study, 69 were randomly assigned to receive radiation therapy or chemotherapy plus radiation, and 72 were randomly assigned to receive radiation therapy or chemotherapy plus radiation with erythropoietin. Patients randomly assigned to receive erythropoietin received the first dose 7 to 10 days prior to beginning radiation therapy, and then received erythropoietin in a weekly dose of 40,000 units throughout treatment, unless hemoglobin levels exceeded 16 g/dL for males or 14 g/dL for females. Patients whose hemoglobin levels did not increase ≥1 g/dL after four doses of erythropoietin received a dose increase to 60,000 units. 

During treatment, patients were evaluated weekly for toxicities and review of their complete blood count. Follow-up was conducted at 2 and 4 weeks after treatment was completed, then every 3 months for the first 2 years post-treatment, every 6 months for the next 3 years, and annually thereafter. For this long-term analysis, the median follow-up for surviving patients was 7.95 years (range = 1.66–10.08 years), and 3.33 years for all patients (range = 0.03–10.08 years).

Study Findings

This new analysis of RTOG 9903 found that at 5-year follow-up, the local-regional failure rate was 39.4% for patients who received radiation therapy or chemoradiation without erythropoietin and 46.2% for patients who received erythropoietin (hazard ratio [HR] = 1.27 on univariate analysis and 1.40 on multivariate analysis). The 5-year local-regional progression-free survival rate was 37.6% for patients who did not receive erythropoietin and 31.5% for patients who received erythropoietin (HR = 1.28 on univariate analysis and 1.39 on multivariate analysis).

The 5-year overall survival rate was 38.2% for patients who did not receive erythropoietin and 36.9% for patients who received erythropoietin (HR = 1.13 on univariate analysis and 1.23 on multivariate analysis). The 5-year distant metastases rate was 14.5% for patients who did not receive erythropoietin and 15.6% for patients who received erythropoietin (HR = 1.03 on univariate analysis and 1.07 on multivariate analysis).

None of the differences were statistically significant. However, the hazard ratios in this long-term follow-up demonstrated improved outcomes for the patients who did not receive erythropoietin.

“It is well-known that cancer patients with anemia have lower cure rates than patients with normal hemoglobin levels. RTOG 9903 was aimed at improving the outcomes of anemic patients with head and neck squamous cell carcinoma, by restoring their hemoglobin levels to normal,” said George Shenouda, MD, lead author of the study, and Associate Professor of Oncology and Otolaryngology at McGill University Health Centre.

“The initial analysis of the results was unexpected and led to the study’s early closure, because of a possible detrimental effect of erythropoietin. While erythropoietin improved hemoglobin levels, the control rates were not similarly improved. This long-term analysis confirms that erythropoietin is not the appropriate treatment option for our anemic head and neck squamous cell carcinoma cancer patients. It is important for us to be aware that erythropoietin is a growth factor and, as such, may stimulate the growth of cancer cells, resulting in decreased tumor control. Carefully designed clinical trials are required to address how to treat anemia in our cancer patients,” Dr. Shenouda stated.