Commentary (Ship): Management of Xerostomia Related to Radiotherapy for Head and Neck Cancer

In 2005, an estimated 29,370 new cases of oral cavity and pharyngeal cancers were diagnosed in the United States, accounting for 2.14% of all cancer cases.[1] Over 7,000 individuals will die from these cancers in this country in 2005- approximately one death per hour. Many advances have been made in the diagnosis and treatment of these cancers, yet the mortality rate remains high (5-year survival rate of ~50%). Probably the most important approach is early detection, since early-stage tumors are associated with markedly better survival rates than late-stage cancers that have already spread to regional tissues and lymphatics. Treatment Sequelae
Treatment of oral and pharyngeal cancers generally consists of a combination of radiation therapy and surgery, with chemotherapy recently becoming an accepted treatment option.[2,3] The challenge of effective therapy is to eradicate metaplastic tissue while preserving, as much as possible, a person's quality of life. This requires a large multidisciplinary team of cooperating clinicians working together under extreme time constraints. The therapeutic modalities of surgery, radiotherapy, and chemotherapy cause a multitude of short- and long-term oral and pharyngeal sequelae that lead to an impaired quality of life.[4-6] The most common problems affecting the oral cavity are salivary hypofunction, xerostomia, and mucositis. Radiotherapy dosages in excess of 24 to 26 Gy can cause permanent salivary gland hypofunction,[ 7] and the addition of chemotherapy (eg, cisplatin) to external-beam radiotherapy is associated with grade 3 xerostomia.[2,3] Further oral and pharyngeal disorders include esophagitis, dysphagia, dysgeusia, oral and pharyngeal infections, dental caries, trismus, radiation dermatitis, facial/ esthetic compromises, and myalgia. Patients experience difficulties with phonation, mastication, wearing removable dental prostheses, and restricted head and neck muscular movements. Radiotherapy dosages in excess of 60 Gy to the mandible also increase the risk of patients developing osteoradionecrosis.[8] Management Strategies
The overall approach to the management of radiotherapy-induced salivary hypofunction and xerostomia involves a well-coordinated effort involving multiple health-care providers, starting with the initial diagnosis. Significant oral and pharyngeal adverse events can be reduced and sometimes even prevented if dentists, medical and radiation oncologists, nurses, dietitians, speech and swallowing experts, social workers, and other specialists can coordinate care throughout the course of diagnosis and multimodal therapy.[9,10] The first strategy involves frequent dental evaluations due to the prevalence of complications.[11] Maintenance of proper oral hygiene and hydration are essential, as well as ensuring a low-sugar diet and daily topical fluoride use to prevent dental caries.[12] Dry mucosal surfaces and dysphagia are managed with oral moisturizers, lubricants, and artificial saliva, as well as careful use of fluids during eating. If there are remaining viable salivary glands after radiotherapy (eg, if parotid-sparing techniques were used), stimulation using sugarfree chewing gums, candies, and mints can enhance salivary output.[13] Artificial saliva and lubricants may ameliorate some xerostomic symptoms and improve oral functioning.[14,15] Treating xerostomia with medications that enhance salivation is another therapeutic option for the individual who has sufficient remaining exocrine tissue following cancer-associated surgery and radiotherapy. Pilocarpine is a nonselective muscarinic agonist that can improve salivary output and reduce xerostomic complaints when used following the completion of radiotherapy.[ 16,17] Alternatively, when pilocarpine was administered for xerostomia during radiotherapy, the drug was either not beneficial[18] or only modestly effective.[19] Cevimeline (Evoxac) is another muscarinic agonist used for the reduction of xerostomia in patients with Sjgren's syndrome[20,21] and has been suggested for radiotherapyinduced xerostomia.[22,23] It reportedly has a higher affinity for M1 and M3 muscarinic receptor subtypes.[24] Since M2 and M4 receptors are located on cardiac and lung tissues, cevimeline could enhance salivary secretions while minimizing adverse effects on pulmonary and cardiac function. Another approach is to consider concomitant polypharmacy. The majority of head and neck cancer patients are age 50 years or older,[25] and many are taking medications that cause salivary gland dysfunction.[12] Reducing the use of drugs associated with anticholinergic side effects or substituting with drugs that may have fewer xerostomic side effects is preferred. Furthermore, timing of medication use to avoid nocturnal xerostomia or dividing drug dosages to avoid unwanted side effects from a large single dose should be considered.[26] Over the past decade, there has been some interest in using acupuncture techniques to enhance salivation,[ 27-29] with data suggesting that acupuncture therapy can maintain an improvement in stimulated saliva up to 6 months after the completion of radiotherapy.[30] Preventive Techniques
One of the best hopes for treatment of these disorders is the use of preventive techniques. Salivary-sparing radiotherapy using three-dimensional treatment planning and dose-delivery techniques including intensity-modulated radiotherapy (IMRT) have proven successful in limiting radiation exposure to salivary glands, reducing salivary hypofunction and xerostomia, and preserving a person's quality of life.[31-33] There is an exponential relationship between saliva flow reduction and mean parotid dose for each gland,[34] demonstrating the exquisite sensitivity of salivary glands to radiation dosages. Importantly, it appears that reducing the dose to the salivary glands does not impair radiation efficacy with respect to tumors and lymph nodes considered to be at risk for cancer spread, and that long-term survival may not be reduced with these radiation-sparing techniques.[7,35] Prevention may also include a new category of cytoprotective drugs that could protect oral mucosal and salivary gland tissues during chemotherapy and head and neck radiotherapy. The most commonly used is amifostine (Ethyol), a broad-spectrum cytoand radioprotectant that provides mucosal and organ protection against myelotoxicity, nephrotoxicity, mucositis, and xerostomia associated with various chemotherapy and radiotherapy modalities.[36,37] Amifostine used prior to each radiation treatment in head and neck cancer patients reduces the incidence of xerostomia,[ 38,39] and may prove to be useful for patients receiving IMRT[40] and combined radiochemotherapy.[ 41] Two surgical approaches may assist in the prevention of oral complications of cancer treatments. High- dose-rate intraoperative radiation therapy can deliver a large dose of radiation while the tumor bed is precisely defined, diminish toxicity, shorten overall treatment time, and reduce radiation dosages directly to salivary glands.[41-43] A second technique involves transferring a submandibular gland to the submental region, which can shield the gland from the damage induced by external- beam radiation.[44,45] Finally, new research in the field of gene therapy may make it possible to prevent damage to as well as correct already damaged salivary glands.[46-48] Transferring genes to salivary glands has been demonstrated in animal models. The close access to salivary gland cells via intraoral cannulation of the main excretory ducts permits relatively noninvasive delivery of vectors and gene transfer. With increased pathobiologic understanding and biotechnologic improvements, gene transfer could become a viable treatment modality.[49] Conclusions
In conclusion, the treatment of radiotherapy- induced salivary hypofunction and xerostomia requires a well coordinated approach using multiple health-care practitioners and techniques. With no single modality that has proven entirely efficacious, the best paradigm may involve concomitant treatments, such as salivarysparing radiotherapy, cholinergic agonists, cytoprotective agents, and gene therapy.

Disclosures:

Dr. Ship is a member of the speakers bureau for Medimmune Oncology.

References:

1. Jemal A, Murray T, Ward E, et al: Cancer statistics, 2005. CA Cancer J Clin 55:10-30, 2005.
2. Bernier J, Domenge C, Ozsahin M, et al: Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 350:1945- 1952, 2004.
3. Cooper JS, Pajak TF, Forastiere AA, et al: Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 350:1937-1944, 2004.
4. Kahn ST, Johnstone PAS: Management of xerostomia related to radiotherapy for head and neck cancer. Oncology 19:1827-1832, 2005.
5. Vissink A, Jansma J, Spijkervet FK, et al: Oral sequelae of head and neck radiotherapy. Crit Rev Oral Biol Med 14:199-212, 2003.
6. Malouf JG, Aragon C, Henson BS, et al: Influence of parotid-sparing radiotherapy on xerostomia in head and neck cancer patients. Cancer Detect Prev 27:305-310, 2003.
7. Eisbruch A, Kim HM, Terrell JE, et al: Xerostomia and its predictors following parotid- sparing irradiation of head-and-neck cancer. Int J Radiat Oncol Biol Phys 50:695-704, 2001.
8. Nemeth Z, Somogyi A, Takacsi-Nagy Z, et al: Possibilities of preventing osteoradionecrosis during complex therapy of tumors of the oral cavity. Pathol Oncol Res 6:53-58, 2000.
9. Vissink A, Burlage FR, Spijkervet FK, et al: Prevention and treatment of the consequences of head and neck radiotherapy. Crit Rev Oral Biol Med 14:213-225, 2003.
10. Eisbruch A, Rhodus N, Rosenthal D, et al: The prevention and treatment of radiotherapy- induced xerostomia. Semin Radiat Oncol 13:302-308, 2003.
11. Brennan MT, Shariff G, Lockhart PB, et al: Treatment of xerostomia: A systematic review of therapeutic trials. Dent Clin North Am 46:847-856, 2002.
12. Fox PC: Acquired salivary dysfunction. Drugs and radiation. Ann N Y Acad Sci 842:132- 137, 1998.
13. Davies AN: A comparison of artificial saliva and chewing gum in the management of xerostomia in patients with advanced cancer. Palliat Med 14:197-203, 2000.
14. Regelink G, Vissink A, Reintsema H, et al: Efficacy of a synthetic polymer saliva substitute in reducing oral complaints of patients suffering from irradiation-induced xerostomia. Quintessence Int 29:383-388, 1998.
15. Warde P, Kroll B, O’Sullivan B, et al: A phase II study of Biotene in the treatment of postradiation xerostomia in patients with head and neck cancer. Support Care Cancer 8:203- 208, 2000.
16. Johnson JT, Ferretti GA, Nethery WJ, et al: Oral pilocarpine for post-irradiation xerostomia in patients with head and neck cancer. N Engl J Med 329:390-395, 1993.
17. Hamlar DD, Schuller DE, Gahbauer RA, et al: Determination of the efficacy of topical oral pilocarpine for postirradiation xerostomia in patients with head and neck carcinoma. Laryngoscope 106:972-976, 1996.
18. Fisher J, Scott C, Scarantino CW, et al: Phase III quality-of-life study results: Impact on patients’ quality of life to reducing xerostomia after radiotherapy for head-and-neck cancer- RTOG 97-09. Int J Radiat Oncol Biol Phys 56:832-836, 2003.
19. Zimmerman RP, Mark RJ, Tran LM, et al: Concomitant pilocarpine during head and neck irradiation is associated with decreased posttreatment xerostomia. Int J Radiat Oncol Biol Phys 37:571-575, 1997.
20. Petrone D, Condemi JJ, Fife R, et al: A double-blind, randomized, placebo-controlled study of cevimeline in Sjogren’s syndrome patients with xerostomia and keratoconjunctivitis sicca. Arthritis Rheum 46:748-754, 2002.
21. Fife RS, Chase WF, Dore RK, et al: Cevimeline for the treatment of xerostomia in patients with Sjogren syndrome: A randomized trial. Arch Intern Med 162:1293-300, 2002.
22. Nieuw Amerongen AV, Veerman EC: Current therapies for xerostomia and salivary gland hypofunction associated with cancer therapies. Support Care Cancer 11:226-231, 2003.
23. Porter SR, Scully C, Hegarty AM: An update of the etiology and management of xerostomia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 97:28-46, 2004.
24. Iwabuchi Y, Masuhara T: Sialogogic activities of SNI-2011 compared with those of pilocarpine and McN-A-343 in rat salivary glands: Identification of a potential therapeutic agent for treatment of Sjorgen’s syndrome. Gen Pharmacol 25:123-129, 1994.
25. Silverman S Jr: Precancerous lesions and oral cancer in the elderly. Clin Geriatr Med 8:529-541, 1992.
26. Ship JA, Pillemer SR, Baum BJ: Xerostomia and the geriatric patient. J Am Geriatr Soc 50:535-543, 2002.
27. Wong RK, Jones GW, Sagar SM, et al: A Phase I-II study in the use of acupuncturelike transcutaneous nerve stimulation in the treatment of radiation-induced xerostomia in head-and-neck cancer patients treated with radical radiotherapy. Int J Radiat Oncol Biol Phys 57:472-480, 2003.
28. Johnstone PA, Niemtzow RC, Riffenburgh RH: Acupuncture for xerostomia: Clinical update. Cancer 94:1151-1156, 2002.
29. Blom M, Dawidson I, Fernberg JO, et al: Acupuncture treatment of patients with radiation- induced xerostomia. Eur J Cancer B Oral Oncol 32B:182-190, 1996.
30. Blom M, Lundeberg T: Long-term follow- up of patients treated with acupuncture for xerostomia and the influence of additional treatment. Oral Dis 6:15-24, 2000.
31. Chao KS, Majhail N, Huang CJ, et al: Intensity-modulated radiation therapy reduces late salivary toxicity without compromising tumor control in patients with oropharyngeal carcinoma: A comparison with conventional techniques. Radiother Oncol 61:275-280, 2001.
32. Lin A, Kim HM, Terrell JE, et al: Quality of life after parotid-sparing IMRT for headand- neck cancer: A prospective longitudinal study. Int J Radiat Oncol Biol Phys 57:61-70, 2003.
33. Henson BS, Inglehart MR, Eisbruch A, et al: Preserved salivary output and xerostomia- related quality of life in head and neck cancer patients receiving parotid-sparing radiotherapy. Oral Oncol 37:84-93, 2001.
34. Chao KS, Deasy JO, Markman J, et al: A prospective study of salivary function sparing in patients with head-and-neck cancers receiving intensity-modulated or threedimensional radiation therapy: Initial results. Int J Radiat Oncol Biol Phys 49:907-916, 2001.
35. Dawson LA, Anzai Y, Marsh L, et al: Patterns of local-regional recurrence following parotid-sparing conformal and segmental intensity- modulated radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 46:1117-1126, 2000.
36. Buntzel J, Kuttner K, Frohlich D, et al: Selective cytoprotection with amifostine in concurrent radiochemotherapy for head and neck cancer. Ann Oncol 9:505-509, 1998.
37. Capizzi RL, Oster W: Chemoprotective and radioprotective effects of amifostine: An update of clinical trials. Int J Hematol 72:425- 435, 2000.
38. Brizel DM, Wasserman TH, Henke M, et al: Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. J Clin Oncol 18:3339-3345, 2000.
39. Vacha P, Fehlauer F, Mahlmann B, et al: Randomized phase III trial of postoperative radiochemotherapy +/- amifostine in head and neck cancer. Is there evidence for radioprotection? Strahlenther Onkol 179:385-389, 2003.
40. Thorstad WL, Haughey B, Chao KS: Pilot study of subcutaneous amifostine in patients undergoing postoperative intensity modulated radiation therapy for head and neck cancer: Preliminary data. Semin Oncol 30(6 suppl 18):96- 100, 2003.
41. Hu K, Ship JA, Harrison LB: Rationale for integrating high-dose rate intraoperative radiation (HDR-IORT) and postoperative external beam radiation with subcutaneous amifostine for the management of stage III/IV head and neck cancer. Semin Oncol 30(6 suppl 18):40-48, 2003.
42. Haller JR, Mountain RE, Schuller DE, et al: Mortality and morbidity with intraoperative radiotherapy for head and neck cancer. Am J Otolaryngol 17:308-310, 1996.
43. Nag S, Schuller D, Pak V, et al: Pilot study of intraoperative high dose rate brachytherapy for head and neck cancer. Radiother Oncol 41:125-130, 1996.
44. Jha N, Seikaly H, McGaw T, et al: Submandibular salivary gland transfer prevents radiation- induced xerostomia. Int J Radiat Oncol Biol Phys 46:7-11, 2000.
45. Jha N, Seikaly H, Harris J, et al: Prevention of radiation induced xerostomia by surgical transfer of submandibular salivary gland into the submental space. Radiother Oncol 66:283- 289, 2003.
46. Baum BJ, Goldsmith CM, Hoque AT, et al: Salivary glands as a model for craniofacial applications of gene transfer. Int J Oral Maxillofac Surg 29:163-166, 2000.
47. Hoque AT, Yamano S, Baccaglini L, et al: Using salivary glands as a tissue target for gene therapeutics. J Drug Target 9:485-494, 2001.
48. Vitolo JM, Baum BJ: The use of gene transfer for the protection and repair of salivary glands. Oral Dis 8:183-191, 2002.
49. Yamano S, Baum BJ: Prospects for genebased immunopharmacology in salivary glands. Japan J Pharmacol 82:281-286, 2000.