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Abstract & Commentary
Synopsis: In a multicenter trial of anemic head and neck cancer patients, recombinant human erythropoietin (epoetin b) or placebo were administered as adjuncts to radiation therapy. As expected, hemoglobin levels rose in the epoetin-treated patients, but locoregional control and survival were diminished. This surprising result warrants prompt confirmatory study and expanded investigation to determine mechanism. Source: Henke M, et al. Lancet. 2003;362:1255-1260.
The treatment of anemia has become common practice in the overall treatment of cancer patients, due in a large part to the prior demonstration of increased quality of life of treated patients demonstrated in large clinical trials. Because the presence of anemia is associated with poorer outcomes of therapy, there was a question of whether those patients in whom anemia was corrected by recombinant human erythropoietin (rHuEPO) would have more favorable responses to specific anti cancer treatments. In a recent multicenter trial, the opposite was observed.
Henke and colleagues performed an industry-sponsored multicenter, double-blind, placebo-controlled trial in which 351 anemic patients with carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx were randomized to receive rHuEPO (epoetin b) or placebo. To qualify as anemic, hemoglobin level for women patients was < 12 g/dL and for men was < 13 g/dL. Epoetin b was administered at a dose of 300 IU/kg 3 times weekly. The primary end point was locoregional progression-free survival, and the analysis was by intention to treat.
Of the 148 patients treated with epoetin b, 82% achieved hemoglobin concentrations 14g/dL (women) or 15 g/dL (men). For comparison, only 15% of those receiving placebo were observed to have hemoglobin concentrations at that level. However, locoregional progression-free survival was poorer with epoetin b than with placebo (adjusted relative risk, 1.62 [95% confidence interval, 1.22-2.14]; P = .0008). For locoregional progression, the relative risk was 1.69 (1.16-2.47, P = .007) and for survival was 1.39 (1.05-1.84, P = .02). The univariate Kaplan-Meier estimate showed a median locoregional progression-free survival of 754 days for placebo compared with 406 days for epoetin b (P = .04).
Prior to randomization, patients had been stratified by extent of disease, and the planned radiation dose was greater for those with more extensive disease. Overall, the baseline characteristics and demographic data, as well as tumor and treatment features, were well balanced between placebo and treatment groups. Analysis by extent of disease revealed the negative effect of epoetin b treatment in terms of locoregional control and survival for all but those with limited disease.
Overall, 52% of patients in the placebo group and 61% in the epoetin b group died. Of these, 5 placebo and 10 epoetin b patients died from cardiac disorders and 1 placebo and 9 epoetin b patients from general (not cancer) disorders. Toxicity was slightly higher in the epoetin b treatment arm, with 4% vs 7% judged as having drug-related adverse events.
Comment by William B. Ershler, MD
Thus, although epoetin b administration was successful in raising hemoglobin concentrations in the great majority of treated patients, this was not associated with favorable outcomes in terms of tumor control or survival. In fact, the opposite appears to be true. The trial methodology was sound, the experimental groups were well balanced, and, accordingly, it is unlikely that a flaw in study design or conduct can explain the findings. This result clearly runs contrary to what was expected and raises a cautionary flag to the low threshold use of rHuEPO in anemic cancer patients.
The basis for the widespread clinical use of rHuEPO was the demonstrated enhanced quality of life in treated patients.1,2 The effect on tumor biology and clinical outcomes and survival had not, previously, been the focus of attention. Yet, for head and neck cancer, the pretreatment presence of anemia is known to be a negative prognostic factor in terms of locoregional control and survival,3 and it was a logical step to anticipate more favorable outcomes in treated patients. Erythropoietin, may, however, have tumor-enhancing properties, by directly stimulating tumor cells known to have erythropoietin receptors,4 inhibiting tumor cell apoptosis,5,6 or enhancing angiogenesis.7
As with many important clinical trials, the findings raise important questions. Is this a phenomenon specific for squamous cell carcinoma, tumors in the head and neck region, or those treated by relatively high doses of radiation? Or is this a more general occurrence? Additional research to address these questions is of high priority. The concern, however, is who will fund such research? Which cooperative group will take the lead, and how quickly will we get some answers? Until that time when more answers are available, clinicians will need to balance the quality-of-life issue with the potential for enhanced tumor growth when treating anemic cancer patients.
Dr. Ershler is INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.
1. Glaspy J, et al. J Clin Oncol. 1997;15:1218-1234.
2. Demetri GD, et al. J Clin Oncol. 1998;16:3412-3425.
3. Lutterbach J, et al. Int J Radiat Oncol Biol Phys. 2000;48:1345-1350.
4. Miller CB, et al. J Natl Cancer Inst. 1992;84:98-103.
5. Krantz SB. Blood. 1991;77:419-434.
6. Koury MJ, Bondurant MC. Eur J Biochem. 1992;210: 649-663.
7. Yasuda Y, et al. Carcinogenesis. 2003;24:1021-1029.