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.
MASCC’s 2005 guidelines for limiting the effect of oral mucositis are the most recent. They include:
- Midline radiation blocks and three-dimensional RT to reduce mucosal injury.
- Use of benzydamine to prevent radiation-induced mucositis with moderate-dose RT.
- Oral cryotherapy for 30 minutes for patients receiving bolus 5-fluorouracil (5-FU) and bolus edatrexate.
- Cryotherapy for patients receiving high-dose melphalan.
Mucositis Treatment
The only agent approved for prevention of oral mucositis is palifermin (Kepivance), a modified recombinant keratinocyte growth factor. It has a number of biologic activities that appear to protect the mucosal epithelium: inhibition of epithelial cell apoptosis and DNA damage; upregulation of detoxifying enzymes; downregulation of proinflammatory cytokines; and enhanced migration, proliferation, and differentiation of epithelial cells.
When given intravenously (40 mcg/kg) for three days prior to chemotherapy and three days following, it reduces the incidence, severity, and duration of oral mucositis and decreases febrile neutropenia and the need for opioid analgesia and tube feeding.
A report by Patrick Stiff, MD, in 2006 in the Journal of Clinical Oncology confirmed that palifermin has clinical benefit when used with stem cell transplant. Two hundred twelve patients received palifermin or placebo before and after total body irradiation (12 Gy), etoposide 60 mg/kg, and cyclophosphamide 100 mg/kg.
Patient self-assessment and physicians’ observations were similar. Those who received palifermin had significant improvements in ability to swallow, drink, and eat, and they needed fewer narcotics.
Another 2006 JCO report by Lee S. Rosen, MD, compared placebo and palifermin for three days before each of two cycles of 5-FU/leucovorin in patients with colorectal cancer. The incidence of grade 2 or higher mucositis was lower in palifermin patients than in the placebo group: 29% vs 61% in the first cycle, and 11% vs 47% in the second cycle. The drug was well tolerated and resulted in a statistically significant and clinically meaningful reduction in mucositis.
The only other effective treatment is low-level laser therapy, which can delay the rate of mucositis by as much as 60%, as well as progression of mild toxicity to a more severe form in patients who have undergone stem cell transplant. It significantly reduces pain.
Cetuximab
Perhaps the best news for head and neck cancer patients in recent years is addition of cetuximab to surgery, chemotherapy, and radiation. The FDA approved it as a radiation sensitizing agent and for treatment of recurrent metastatic disease.
Cetuximab in combination with RT has demonstrated enhanced tumor control without increased significant toxicity. Because of this success, researchers are evaluating its use as part of multimodality treatment in locally advanced disease.
Dr. Bonner published a study of 424 patients in a 2006 NEJM. They had stage 3 or 4 disease that had not metastasized and were randomly assigned to receive radiation alone or radiation plus weekly cetuximab. The radiation dose was the same for all but differed in fractionization. Median survival for the cetuximab group was 49 months compared with 29 months for the radiation alone group. Of the former, 55% survived for three years, compared with 45% of the latter. The cetuximab group also had better locoregional control, but both had metastasis at about the same rate.
The Erbitux in First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer (EXTREME) trial was presented at the 2007 American Society for Therapeutic Radiology and Oncology (ASTRO) Annual Meeting. It endeavored to determine if adding cetuximab to platinum-based chemotherapy is clinically beneficial; 442 patients with stage 3 or 4 cancer were enrolled. Half received 5-FU plus carboplatin or cisplatin, and the other half received the same regimen plus cetuximab. The cetuximab group survived a median of 10.1 months compared to 7.4 months for the chemo-alone group.
This is the first demonstration of a survival improvement in the palliative setting for any therapy in head and neck cancer, said Marshall R. Posner, MD, Medical Director of the Head and Neck Oncology Program at Dana Farber Cancer Institute. Moreover, standard therapy cannot be used long term because many patients eventually develop numbness and problems with their immune system. Cetuximab can be continued for longer and thus can be more effective for palliation.
Despite these two trials, there is no definitive conclusion about the clinical benefits of cetuximab. For this reason, Dr. Bonner and colleagues conducted a retrospective review of 29 patients at the University of Alabama to compare addition of cetuximab or platinum-based chemotherapy to RT.
There was no significant difference between the two treatment regimens. Thus, said Dr. Bonner, Cetuximab with RT may be comparable to chemo with RT, which means it is an important option. Moreover, it is less toxic, and may be beneficial for patients at a lower risk of distant metastases and who are unsuitable for platinum-based chemotherapy.
©2008 The Triological Society