New Treatment for Head and Neck Cancer Means Longer-Lasting Toxicity

Better chemotherapy and aggressive chemoradiation have contributed to improved locoregional control and survival for head and neck cancer. But, said Barbara Murphy, MD, Director of the Pain and Symptom Management Program and Director of the Head and Neck Research Program at Vanderbilt-Ingram Cancer Center in Nashville, TN, Using multimodality treatment, especially chemoradiation, results in increased acute and late toxicity.

James A. Bonner, MD, Professor and Chairman of the Department of Radiation Oncology at the University of Alabama at Birmingham, agreed. Treatment is much more aggressive today than it was 10 or 15 years ago. But that intensity ramps up side effects.

Toxicity Is Inevitable

Radiation and chemotherapy share some common side effects, said Dr. Murphy, but they also vary by type of therapy. Almost no patient escapes toxicity, some of which is severe enough to necessitate dose reductions or cessation of treatment. The thing we have to be most concerned about is the risk-benefit ratio. Yes, we’re curing some patients, and we’ve had a lot of success in extending survival, but at what cost in permanent damage? she asked.

Some toxic effects are tied to the type of treatment, but others are more difficult to characterize: fatigue, anorexia, taste alterations, neurocognitive alterations, and deconditioning. New research has shown that they can be explained by accumulated free radical damage, DNA damage, telomere shortening or depletion, neuroendocrine dysfunction, or immunologic dysfunction. The latter may be mediated through cytokines and other inflammatory pathways such as IL-1β, TNF-α, or lipopolysaccharides.

Dr. Murphy said that because of the increasing number of survivors, it has become evident that acute effects of therapy often last longer than the traditional three months; acute and late effects may be distinct from each other; and late effects cause profound and long-lasting alterations in function and diminished quality of life.

Oral Mucositis

Oral complications in general arise from complex interactions from a variety of sources: direct tissue damage, immune dysfunction, myelosuppression, and total dose of radiation. They can be acute or late, temporary or permanent.

Dr. Murphy told ENT Today that as a result of recent observations, she has developed a five-stage model of the pathogenesis of mucositis:

• Initiation results when radiation- and/or chemotherapy-induced DNA damage produces reactive oxygen species (ROS). These, in turn, induce local tissue damage.
• Local tissues respond by activation of transcription factors (p53 or NF-kB, for example), production and release of proinflammatory cytokines, and activation of proapoptotic pathways. Cytokines stimulate connective tissue, which results in decreased oxygen in epithelial cells, causing damage and death. Sphingomyelinase or ceramide synthase pathway activation further contributes to cell membrane damage and apoptosis.
• Positive feedback loops allow proliferation and augmentation of the biological processes initiated in the previous stage.
• Tissue damage becomes clinically visible as mucosal ulceration. Microorganisms may colonize the ulcerative lesions, invading the submucosa, leading to mononuclear cell stimulation and further release of proinflammatory cytokines, further injuring tissue by promoting expression of proapoptotic genes.
• Healing begins only when radiation and chemotherapy end, and the triggers for these biological events are removed.

One of the highlights of the 2007 symposium of the Multinational Association of Supportive Care in Cancer (MASCC) was a paper showing that dark agouti rats overexpressed p53, NF-kB, COX-1, and COX-2 after only one week of exposure to radiation therapy (RT). When the rats were given irinotecan, they also showed evidence of tissue damage. The implication for humans is that various types of toxicity appear faster and more often than previously believed.