The reduction of acute and long-term sequellae of chemoradiotherapy can be further achieved by finding tumor-selective radiosensitizers and tissue-selective radioprotectors, and by customizing treatment intensity to the prognosis of the individual patient.
—Avraham Eisbruch, MD
Chemoradiotherapy for head and neck cancer requires intensive supportive care by a knowledgeable and proactive multidisciplinary team, according to Avraham Eisbruch, MD, Professor of Radiation Oncology at the University of Michigan, Ann Arbor.
“Aggressive chemoradiotherapy has improved the cure rates of head and neck cancer, but these improvements have been associated with increased rates and severity of acute and late treatment side effects. Adequate supportive care can reduce these and improve the therapeutic index,” said Dr. Eisbruch, who conducts research in the area of mucositis.
Severe mucositis, late fibrosis and dysphagia are not only troublesome to the patient but are the major factors preventing dose escalation for poor-prognosis patients, he noted. Interventions that may reduce the risk or manage mucositis were discussed by Dr. Eisbruch at the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) International Symposium on Supportive Care in Cancer, held recently in Miami.
The pharmacologic radiation protector amifostine binds to free radicals produced by radiation and interferes with their oxygen binding, which is essential to their damage of the DNA. While the drug’s mechanism is good in theory, issues related to amifostine include a short half-life (which requires administration before each treatment), its cost, and its potential for side effects. Furthermore, while amifostine has shown benefit in mice with head and neck or lung tumors, value has not been proven in these settings for humans, Dr. Eisbruch noted.
Antiviral, antibacterial, and mucosal coating agents are often used without evidence. Based on multiple—mostly conflicting—studies, acyclovir, nystatin, fluconazole, chlorhexidine, and sucralfate cannot be recommended to reduce mucositis risk, he said.
On the other hand, data support the use of keratinocyte growth factor (palifermin [Kepivance]), which stimulates the differentiation of mucosal cells and has proven effective in reducing mucositis after high-dose chemotherapy and bone marrow transplantation. That said, although palifermin significantly reduced severe mucositis and its duration in randomized trials in head and neck cancer, the compound had no effect on narcotic use, patient-reported pain, and chemoradiotherapy compliance.1,2
“We may be using something here that helps the physician but not the patient,” he commented.
Tumors expressing the epidermal growth factor receptor (EGFR) are more resistant to radiotherapy. Drugs that increase the radiosensitivity of EGFR-positive tumor cells may enhance radiotherapy’s efficacy. Cetuximab (Erbitux) given concurrently with radiotherapy improves tumor control and is considered to be tumor-specific, improving the therapeutic index compared with radiosensitization using chemotherapy. However, Dr. Eisbruch cautioned that some studies have shown toxicity, including mucositis, to be increased with concurrent cetuximab and radiotherapy.
“This is also my clinical impression. Some patients develop severe mucositis while others do not, so be careful with this,” he advised.
To better understand the effects of an EGFR inhibitor on mucosal cells in head and neck cancer, Dr. Eisbruch and his team obtained pre- and post-treatment tissue samples and showed that erlotinib inhibited the activation of EGFR and reduced EGFR expression in tumors, but in normal tissue there was substantial heterogeneity in EGFR inhibition.3
“The EGFR therapeutic index (EGFR inhibition in tumor vs normal mucosal cells) seemed to vary greatly among patients,” he said. It may be prudent, therefore, to test the therapeutic index in each patient individually before proceeding with a full course of radiotherapy with cetuximab, he added.
Reduced Treatment Intensity
Another strategy is to reduce the radiation treatment intensity in patients with good prognosis, such as those with human papillomavirus (HPV)-positive tumors. The Eastern Cooperative Oncology Group (ECOG) 1308 trial recently found that if a complete response is achieved with induction chemotherapy, intensity-modulated radiotherapy (IMRT) with 54 Gy delivered concurrently with cetuximab achieves local control in 95% of HPV-positive patients.4
A comparison of IMRT (mean oral dose, 27 Gy) vs conventional radiotherapy (mean, 43 Gy) found significantly less mucositis grade 3 or higher at virtually all time points, with IMRT.5
Dr. Eisbruch also advocates meticulous prophylactic dental care and protection.
Reducing Mucositis-Related Pain
It may be easier to address the pain related to mucositis, he said. These include topical tetracaine, nonsteroidal anti-inflammatory drugs, narcotics, and the long-acting opioid, fentanyl transdermal patch (Duragesic). Dr. Eisbruch commented on the safe use of narcotics.
“The fentanyl patch reduces the need for immediate-release opiates and provides lengthier freedom from pain. Start with the lowest dose to assess response,” he advised. “But remember that fentanyl is more fat-soluble than morphine, so patients with cachexia or significant weight loss have a reduced volume of distribution of fentanyl and are at higher risk of toxicity. Nystatin and fluconazole also reduce the metabolism of narcotics and elevate their blood levels.”
Tricyclic antidepressants reduce patient-reported pain without affecting the severity of mucositis, he added.
Intensive supportive measures in the areas of nutrition and hydration are important to combat dysphagia, weight loss, thick secretions, and so forth. Dr. Eisbruch advocates the use of acetylcysteine for mucus once patients complete radiotherapy. Zinc sulfate as an approach to taste abnormalities was shown effective in uncontrolled trials, but not in more rigorous studies.
Enteral feeding is necessary for some patients, with caveats, he said. It is debated whether feeding tubes are best used prophylactically or when weight loss is ≥ 10%. Two randomized studies found that prophylactic percutaneous endoscopic gastrostomy resulted in less weight loss, improved patient-reported quality of life, and less long-term dysphagia.6,7
“However,” he added, “the benefit may come at the expense of longer dependence on [percutaneous endoscopic gastrostomy] and increased late esophageal strictures requiring dilatation. Feeding tubes also reduce patient motivation to swallow food, and a complete lack of swallowing increases the rate of strictures.”
Dr. Eisbruch’s policy is as follows:
In conclusion, he predicted, “The reduction of acute and long-term sequellae of chemoradiotherapy can be further achieved by finding tumor-selective radiosensitizers and tissue-selective radioprotectors, and by customizing treatment intensity to the prognosis of the individual patient.” ■
Disclosure: Dr. Eisbruch reported no potential conflicts of interest.
1. Le QT, Kim HE, Schneider CJ, et al: Palifermin reduces severe mucositis in definitive chemoradiotherapy of locally advanced head and neck cancer: A randomized, placebo-controlled study. J Clin Oncol 29:2808-2814, 2011.
2. Henke M, Alfonsi M, Foa P, et al: Palifermin decreases severe oral mucositis of patients undergoing postoperative radiochemotherapy for head and neck cancer: A randomized, placebo-controlled trial. J Clin Oncol 29:2815-2820, 2011.
3. Tsien CI, Nyati MK, Ahsan A, et al: Effect of erlotinib on epidermal growth factor receptor and downstream signaling in oral cavity squamous cell carcinoma. Head Neck 35:1323-1330, 2013.
4. Cmelak A, Shuli L, Shanthi M, et al: E1308: Reduced-dose IMRT in human papilloma virus-associated resectable oropharyngeal squamous carcinomas after clinical complete response to induction chemotherapy. ASCO Annual Meeting. Abstract LBA6006. Presented June 2, 2014.
5. Vergeer MR, Doornaert PA, Rietveld DH, et al: Intensity-modulated radiotherapy reduces radiation-induced morbidity and improves health-related quality of life: Results of a nonrandomized prospective study using a standardized follow-up program. Int J Radiat Oncol Biol Phys 74:1-8, 2009.
6. Salas S, Baumstarck-Barrau K, Alfonsi M, et al: Impact of the prophylactic gastrostomy for unresectable squamous cell head and neck carcinomas treated with radio-chemotherapy on quality of life: Prospective randomized trial. Radiother Oncol 93:503-509, 2009.
7. Silander E, Nyman J, Bove M, et al: Impact of prophylactic percutaneous endoscopic gastrostomy on malnutrition and quality of life in patients with head and neck cancer: A randomized study. Head Neck 34:1-9, 2012.