Alpha Omega Alpha Honor Medical Society

2011 Research Abstract

Radiosensitivity in Fanconi Anemia Patients with Head and Neck Squamous Cell Carcinomas

Investigator: Andrew Birkeland, Weill Cornell Medical College

Mentor: David Kutler, Department of Otolaryngology, Weill Cornell Medical College

Background: Fanconi anemia (FA) is a rare recessive disorder caused by mutations in one of at least 14 known genes in the FA pathway. Genes in this pathway are involved in interstrand cross-link and double-strand break DNA repair. It is characterized clinically by aplastic anemia, congenital malformations and increased risk of malignancy, in particular head and neck squamous cell carcinomas (HNSCC). These patients are known to be sensitive to chemotherapy, but radiation sensitivity is not as well characterized. This is an important issue as radiation is a main treatment modality for HNSCC.

Objective: The goal of this project was to describe the complications and toxicities for post-operative radiation therapy in FA patients treated for HNSCC. In addition, we sought to develop keratinocyte cellular models to study radiation sensitivity in cells with reduced FA protein expression. Design: We collected data from FA patients enrolled in the International Fanconi Anemia Registry at The Rockefeller University who developed head and neck squamous cell carcinoma and received post-operative radiation. Additional patient histories and data were collected from community and tertiary care hospitals throughout the United States. Main outcome measures were demographics of FA patients, radiation doses, and radiation side effects and toxicities.

Immortalized human keratinocytes (ATCC) and oral keratinocytes (Rheinwald lab, Harvard) were used. We developed shRNA plasmids for FANCA, FANCD2, FANCI, and FANCM for infection. Cells will be assayed for survival when exposed to increasing doses of radiation.

Results: 12 Fanconi anemia patients (7 male, 5 female) were identified. Patients developed cancers at a mean age of 35.5 years (range 20 to 48). Seven patients were in complementation group FA-A, one in FA-C, one in FA-J, and one in FA-P. Two are currently untyped. Sites of primary cancer were oral cavity (8/12), larynx (2/12), pharynx (1/12), and unknown (1/12). Median radiation dose was 5590 cGy (range: 2500 to 7020). The most common toxicities were mucositis (9/12), dysphagia (8/12), and pancytopenia (6/12). Other complications included esophageal stenosis, laryngeal edema, and wound breakdown. Radiotherapy could not be completed in 5/12 cases. Overall 8/12 patients died, 4 during the course of radiation. The post-operative disease-free survival time ranged from 0 to 55 months.

Comparison of survival between knockdown and control keratinocyte cell lines in response to radiation will be assessed in the future.

Conclusions: Fanconi anemia patients have a high rate of complications to radiation therapy. Common radiation toxicities, particularly mucositis, are especially prevalent and difficult to manage in this population. Pancytopenia is common and may lead to further complications, particularly bleeding and infection. Overall survival is poor. Further study of FA patients’ response to radiation should be attempted in order to establish appropriate doses to balance treating disease while limiting toxicity. In the future, developing cellular models to assess radiation toxicity will be important to further characterize the effects of radiation on FA cells and to develop therapies to decrease radiation toxicity.

Updated on July 9, 2012.


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