Radiotherapy With or Without Erythropoietin for Anemic Patients With Head and Neck Cancer: A Randomized Trial of the Radiation Therapy Oncology Group (RTOG 99-03)

Purpose

To determine whether the addition of recombinant human erythropoietin (Epo) could improve the outcomes of anemic patients receiving definitive radiotherapy for squamous cell carcinoma of the head and neck (SCCHN).

Methods and Materials

Eligible patients had SCCHN, with a plan for continuous-course definitive radiotherapy (66–72 Gy) with or without chemotherapy. Patients with Stage III or IV SCCHN were required to undergo concurrent chemoradiotherapy and/or accelerated fractionation radiotherapy. Preradiotherapy hemoglobin was required to be between 9.0 g/dL and 13.5 g/dL (12.5 g/dL for women). Patients randomized to Epo received 40,000 U once weekly, starting 7–10 days before start of radiotherapy.

Results

A total of 148 patients were enrolled; 141 were evaluable. Median pretreatment hemoglobin was 12.1 g/dL. Hemoglobin levels at 4 weeks rose by an average of 1.66 g/dL in the Epo arm, compared with an average 0.24 g/dL decrease in the control arm (p = 0.0001). Median follow-up was 2.5 years (3.1 years for surviving patients). There was no statistically significant difference in the primary endpoint of local–regional failure (LRF) rate between the treatment arms. The 3-year LRF rate was 36% for control and 44% for Epo (p = 0.56). There were also no significant differences in local–regional progression-free survival (LRPFS), patterns of failure, overall survival, or toxicity. The 3-year LRPFS rate was 52% for control and 47% for Epo. The overall survival rate was 57% and 56%, respectively.

Conclusions

The addition of Epo to definitive radiotherapy for SCCHN did not improve outcomes. The study was not specifically designed to detect a potential negative association between Epo and tumor progression/survival.

Introduction

Anemia is unequivocally associated with poor outcomes after definitive treatment of squamous cell carcinoma of the head and neck (SCCHN), as reviewed by Hu and Harrison (1). The Radiation Therapy Oncology Group (RTOG) studied this issue in a secondary analysis of a large trial of radiotherapy plus hypoxic radiosensitizer therapy (etanidazole) in advanced SCCHN (2). This analysis showed that patients with anemia (defined as hemoglobin [Hgb] <14.5 g/dL for men; <13 g/dL for women) had significantly higher rates of local–regional failure (LRF) (66% vs. 48% at 2 years). Similar results have been reported in analyses of early-stage SCCHN 3, 4, 5.

The reason for the inverse association between Hgb and outcomes is not clear, but a primary focus has been on the possible presence of hypoxia. A full review is beyond the scope of this article; this topic has been vetted in several review articles 6, 7. It is hypothesized that anemia promulgates tumor hypoxia, resulting in multiple adverse biologic effects, including promotion of angiogenesis, resistance to apoptosis, and relative resistance to cytotoxic therapies, all leading to the failure of conventional treatment. Preclinical studies have shown that xenograft tumors in animals rendered anemic by artificial means are highly resistant to typical doses of radiation (8). Dunst et al.(9) showed that Hgb <13 g/dL was strongly associated with tumor hypoxia as measured in vivo in patients with cervix cancer.

Despite encouraging preclinical/translational data, attempts to intervene clinically in this pathway were disappointing, such as randomized trials of radiotherapy with or without misonidazole (10) or etanidazole (2). A trial of transfusion in patients with advanced cervical cancer suggested a beneficial effect (11), but the study was statistically underpowered and may have had some other design flaws, as noted by Fyles et al.(6). A randomized study of transfusion for anemic patients was presented as part of a larger SCCHN study (Danish Head and Neck Cancer Study [DAHANCA]) (12). There were no reported benefits in the transfusion group, although detailed analysis was not presented in the article.

The development of recombinant human erythropoietin (Epo) has impacted favorably on the quality of life of cancer patients with chemotherapy-induced anemia 13, 14. One study suggested an improvement in overall survival (15), with a p value of 0.15, though it should be noted that survival was not one of the major preplanned endpoints of that study. This drug's efficacy at increasing Hgb levels and good safety profile led to the hypothesis that it might be a useful means of increasing radiation sensitivity and improving outcomes in anemic patients with SCCHN. Pilot studies were encouraging 16, 17, 18, 19, showing that Epo was safe and efficiently increased Hgb levels during radiotherapy.

Given encouraging preclinical and clinical data on Epo, the RTOG developed protocol 99-03, a randomized trial to determine whether the addition of Epo to conventional treatment could improve local–regional control and possibly survival in SCCHN.