Cetuximab and Anemia Prevention in Head and Neck Cancer Patients Undergoing Radiotherapy

Introduction: Anemia is a major complication of treatment and a frequent cause of morbidity in cancer patients. Radiation therapy (RT) induces an inflammatory response and increased levels of interleukin-6 (IL-6), potentially causing anemia of chronic inflammation or worsening of pre-existing anemia. Head and neck cancers often overexpress epidermal growth factor receptors (EGFR), which can also lead to increased IL-6 levels. Cetuximab, an EGFR inhibitor, has been previously associated with a decreased incidence of anemia when added to cytotoxic chemotherapy (Vermorken et al,N Engl J Med, 2008). One study has also reported significantly lower rates of anemia in patients that received cetuximab with RT compared to those that received RT alone (Bonner et al,N Engl J Med, 2006). We hypothesized that cetuximab could prevent RT-induced anemia, possibly by decreasing IL-6 levels as a result of EGFR blockade.

Methods: After obtaining IRB approval, we queried our institutional head and neck cancers database for nonmetastatic squamous cell carcinomas diagnosed between 2006 and 2018 that were treated with adjuvant or definitive RT with or without concomitant Cetuximab. Demographic data and tumor characteristics were collected, as well as pre and post RT laboratory values. We only included patients who had at least one complete blood count in the 3 months preceding treatment and another one up to 4 months after treatment. The primary outcome was the prevalence of anemia after RT. Secondary outcomes included mean hemoglobin levels and improvement of hemoglobin levels after RT conclusion. Anemia was defined as a hemoglobin level lower than 12g/dL in females and 13g/dL in males. Improvement of hemoglobin levels was defined as resolution of anemia after treatment in patients with anemia at baseline or an increase of at least 1g/dL in the rest of the included patients.

Results: A total of 171 patients were identified, 85 in the cetuximab plus RT group and 86 in the RT-only group. Demographic characteristics were well-balanced among study groups, except for the Charlson comorbidity index, which was higher in the RT-only group (p=0.04). Most patients were treated in a definitive setting (61.4%), and the remainder received treatment in the adjuvant setting (38.6%). The cetuximab group had more patients with advanced disease (75.3% vs. 40.7%, p<0.001) and worse clinical and radiologic response rates to treatment. All-cause mortality was higher in the group of patients that received cetuximab (69.4% vs. 46.5%, p=0.004). The prevalence of anemia before treatment was similar, but there were lower rates of anemia in the RT-only group after treatment (63.5% vs. 44.2%, p=0.017), with a mean hemoglobin level of 11.98g/dL vs. 12.9g/dL for cetuximab combine with RT vs. RT alone (p=0.003). There was no difference in the levels prior to treatment (12.20g/dL vs 12.48g/dL, p =0.39). There was no difference in the percentage of patients that had improvement of hemoglobin levels between groups, although the majority achieved an improvement (69.4% vs. 80.2%, p=0.14). The prevalence of chronic kidney disease, vitamin B12 deficiency, folate deficiency, iron deficiency and iron overload was similar between groups. The overall survival was not statistically different for patients that had improvement in hemoglobin levels compared to those who did not.

Conclusion: Cetuximab was not associated with lower rates of anemia after RT for nonmetastatic head and neck cancer patients compared to RT alone. It is possible that the heterogeneity of the research population due to the retrospective nature of this study contributed to our findings. Prospective studies are needed to better assess the effect of Cetuximab in anemia during RT.

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