Secondary Logo

Journal Logo

Role of current strategies for preventing xerostomia in oropharyngeal cancer patients

A literature review

Nazeer, Muhammad R; Jamal, Shizrah; Aziz, Surhan; Ghafoor, Robia

doi: 10.4103/ijssr.ijssr_10_18
Review Article
Free

Xerostomia occurring as sequelae of radiation therapy results in oral complications, i.e., acid erosion, dysphagia, dysgeusia, periodontal diseases, taste disturbance, and dental caries. The best strategy should be to prevent damage of any salivary acini during the course of radiotherapy; therefore, we planned to look for all the strategies for its prevention. We searched PubMed, Google Scholar, and Oral and Dentistry database thoroughly and included all the relevant articles published in the past 12 years (2005–2017). We found the following strategies for the prevention of xerostomia during radiation therapy: amifostine, pilocarpine, Vitamin C, and Vitamin E, acupuncture, bethanechol, botulism toxin, histamine, insulin growth factor, submandibular gland transfer, intensity-modulated radiation therapy, radiation stents, stem cell transplantation, intravenous injection of adipose stem cells, lasers, and lidocaine HCL. These preventive methods not only maintain the morphology and function of salivary glands but also reduces the need for saliva-enhancing therapies later.

Postgraduate Resident, Aga Khan University Hospital, Karachi, Pakistan

Department of Surgery, Aga Khan University Hospital, Karachi, Pakistan

Postgraduate Resident, Aga Khan University Hospital, Karachi, Pakistan

Assistant Professor From the Department of Surgery, Aga Khan University Hospital, Karachi, Pakistan

Address for correspondence:Robia Ghafoor, Assistant Professor From the Department of Surgery, Aga Khan University Hospital, Karachi, Pakistan robia.ghafoor@aku.edu

Back to Top | Article Outline

Introduction

The incidence rate of oropharyngeal cancer is progressively increasing worldwide and is reported to be 11.2%. 1 The management of oropharyngeal cancer generally includes surgery, radiotherapy, and/or chemotherapy. 2 Radiotherapy utilizes a high energy X-ray beam to slow growth of a tumor or destroy its cells. 2 However, like all other treatment modalities, oral complications are reported by patients undergoing radiotherapy of head-and-neck region. These complications include xerostomia, mucositis, candidiasis, taste alterations, trismus, and oral ulcers. 2

Xerostomia can be defined as “subjective complain of dryness of mouth” which occurs either due to decrease in secretion of saliva by salivary gland (hyposalivation) or sometimes the flow rates remain normal, yet the patient is complaining of dryness. 3 The reported prevalence of xerostomia is in the range of 0.9%–64.8%. 4 The cause of xerostomia is multifactorial; 2 , 3 , 4 however, the most common is mentioned in /1.{Table 1}

Xerostomia occurring as a sequelae of radiation therapy adversely affects patient's health and quality of life. 4 Average radiation dose required in cases of oropharyngeal tumor is 70 Gy or more, with a routine fraction of approximately 2 Gy. 4 The total radiation dose given is directly related to the extent of damage to sensitive organs (for example, salivary glands) in oral and pharyngeal region. The parenchymal component of a salivary gland is usually most sensitive to these ionizing radiations, as a result they are likely to get damage during a radiotherapy. The reversible damage usually occurs when the radiation dose is limited to 20–30 Gy. 5 However, when it exceeds up to 50 Gy, irreversible damage can occur within a salivary gland, resulting in degenerative changes in ductal epithelium and connective tissue fibrosis. Serous acini are more sensitive than mucous ones, resulting in thick ropy saliva in patients underwent radiotherapy. 2 , 6

Saliva is the most essential and physiological fluid of human body. It performs certain vital functions such as lubrication, swallowing, speech, taste, protection of mucous membrane and also provides antimicrobial and buffering property. 6 As a result, a hyposalivation following radiotherapy, an individual is prone to health-related risks. 2 As saliva contains certain antimicrobial agents, so host defense is compromise causing an increase in the incidence of dental caries and superinfections such as candidiasis in xerostomic patients. 2 , 6 Xerostomia could lead to increased prevalence of cariogenic microbial flora which includes Streptococcus mutans, Lactobacillus, Actinomyces, Fusobacterium, and Streptococcus sanguinis. 2 Lack of salivary flow is followed by certain complications in oral cavity which include acid erosion, dysphagia, dysgeusia, periodontal diseases, taste disturbance, and most commonly, dental caries. 2 , 4 These difficulties eventually reduce patient's appetite and alter choice of food, resulting in compromised nutrition and health, hence distress general health and quality of life of the patient. 2 , 6

The management of xerostomia in patients underwent radiotherapy is usually palliative, i.e., symptomatic treatment and preventing occurrence of further complications. 2 Hence, a patient after radiotherapy face certain difficulties before consulting a clinician for cure. However, the best strategy should be to prevent damage of any salivary acini during the phase of radiotherapy. Different strategies can be employed to prevent salivary gland damage. 6 These strategies are summarized in /1. Details of each preventive modality are as follows:{Table 2}

Back to Top | Article Outline

Amifostine

Amifostine is an adjuvant drug that can be given for prevention of xerostomia in patients undergoing radiotherapy. 7 Amifostine (cysteamine analog) is a prodrug of aminothiol group which is metabolize at the tissue site by alkaline phosphatase to its active form, i.e., WR-1065 by the process of phosphorylation. The resultant metabolite (WR-1065) is a free thiol molecule that is then taken up by cells. 7 There are two mechanisms by which amifostine protect normal cells from being damaged by the radiotherapy. Lack of alkaline phosphates and acidic medium in tumor cells prevent the action of amifostine in these tissues selectively. 8 Second, the active metabolite in the normal tissues acts as a strong scavenger for oxygen-free radicals and hence provides cytoprotection during radiotherapy. 8

Wasserman et al. reported that when amifostine is injected (intravenous), before each session of radiotherapy results in improvement in xerostomia up to 57%. 9 A systematic review concluded that the administration of amifostine not only reduces xerostomia but also certain other side effects of radiotherapy such as mucositis and dysphagia in oropharyngeal cancer patients. 10 Subcutaneous administration of amifostine has been proven to be safe and easy method when compared to IV administration for preventing xerostomia. 11

Back to Top | Article Outline

Pilocarpine

Pilocarpine is a parasympathomimetic agent that causes stimulation of muscarinic/cholinergic receptors of salivary gland acinar cells. 12 A number of randomized control trials proved the effectiveness of pilocarpine in preventing xerostomia during the course of radiotherapy. The recommended dose is 5–10 mg daily for three times a day. 13 , 14 However, some studies reported that the continued use of pilocarpine is not beneficial in most patients. 15 , 16

Back to Top | Article Outline

Vitamin C and E

Vitamin C and E are natural antioxidants that can also provide protection to salivary glands during the course of radiotherapy. If they are administered at an appropriate time, in effective dosage, it protects the cellular membrane of a gland from oxidative damage by free radicals. 17 , 18 Chung et al. reported that the daily ingestion 1000 mg of Vitamin C and 200 IU of Vitamin E during the phase of radiotherapy preserves the function of the major salivary glands. 17 Several randomized controlled trials demonstrate that vitamins with antioxidant action such as alpha-tocopherol and beta-carotene reduce the negative effects of radiotherapy on the mucosal cells of the larynx, pharynx, and esophagus. 19 , 20

Animal studies revealed that the use of antioxidants may reduce radiation-induced side effects by specially protecting normal cells from oxidative damage. However, the supraphysiological amounts may compromise the efficacy of radiotherapy by protecting tumor cells through nonselective scavenging. 21 , 22 A study endorses Vitamin E to be an important radioprotective agent for salivary gland function, but further research is needed in the future for its application in human beings. 23

Back to Top | Article Outline

Acupuncture

Acupuncture is a relatively new treatment modality that is in practice for several years for managing diverse health-related complains such as pain, neurologic disease, and several musculoskeletal disorders. 24 It causes an increased concentration of a neuropeptide (calcitonin gene-related peptide) and a hormone (vasoactive intestinal polypeptide) in the saliva. Hence, the secretion of saliva is improved in xerostomic patients. 25 Various studies have shown convincing results regarding its use in xerostomic patients. 24 , 26 Meng et al. carried out a randomized controlled trial to prove that acupuncture can reduce xerostomia in patients with the history of radiation therapy. 27 Zhuang et al. concluded that the procedure of acupuncture requires further investigation in terms of total treatment sessions need, manipulation protocol, and the precise combination of acupoints to achieve the best outcome. 24 Therefore, substantial investigation is required before endorsing acupuncture for the treatment of radiation-induced xerostomia.

Back to Top | Article Outline

Bethanechol

It is the product of b-methylcholine which acts on muscarinic-receptor and stimulates gland secretion. 28 Jham et al. concluded that when bethanechol is used prophylactically before radiation therapy, the unstimulated saliva is significantly higher. 28 Therefore, bethanechol causes significant improvement in xerostomia in patients with a history of radiation therapy. Jaguar et al. in his study supported the use of bethanechol during radiotherapy for improving salivary secretion, but at the same time, the study fails to determine long-term effectiveness of bethanechol. 29

Back to Top | Article Outline

Botulism Toxin

Apart from its use in various neurologic disorders, botulinum toxin (BoNT) is now progressively used for the management of salivary gland pathologies such as sialorrhea. 30 An in vitro study done on rats found that when BoNT is injected intraglandular prior radiotherapy, it causes atrophy of a gland and reduction in acinar cells during the period of irradiation. As it makes glandular acini less sensitive to radiations, hence radiation-induced damage can be minimized. 30 Human studies failed to provide enough evidence to support the use of BoNT. Therefore, it requires more evaluation in clinical trials before considering it as a preventive treatment modality. 31

Back to Top | Article Outline

Histamine

Histamine is an amine analog which performs several physiological and pathological activities. 44 Medina et al. demonstrated that histamine preserves a salivary gland from radiation damage by preventing alterations in morphology and histology of a gland. Moreover, histamine partially prevents reduction in submandibular gland proliferation caused by the radiation. 32 Another study showed that when histamine was given in rats, it results in significant reduction in acinar and ductal cell apoptosis. Hence, histamine can be radioprotective. 45 However, future studies are required to establish the efficacy and safety of histamine.

Back to Top | Article Outline

Insulin Growth Factor

An experimental study conducted in mice reported that, when a single dose recombinant insulin growth factor-1 (IGF-1) is injected, it results in improved salivary rates following radiotherapy. IGF-1 activates a signaling pathway (by release of endogenous Akt) which reduces apoptosis in irradiated tissues. 33 Pretreatment with IGF-1 injection arrests cell cycle in tissues during radiotherapy, hence allowing cellular repair afterward maintaining stimulated salivary flow rates. 34

Back to Top | Article Outline

Submandibular Gland Transfer

Submandibular salivary gland can be prevented from the destructive ionizing radiations by transferring it into the submental space behind the digastric muscle. 35 , 46 By this method, a gland can be shielded from radiations' signification and absorb only approximately 5% of the total radiation dose. 46 The effectiveness of submandibular salivary gland transfer was studied in a systematic review. 47 The study concluded that it preserves the baseline stimulated and unstimulated salivary flow rates for up to 3–6 months following radiotherapy. 47 Several studies have reported favorable outcomes with this method, i.e., improvement in salivary flow rates postoperatively. 46 , 47 , 48

Back to Top | Article Outline

Intensity-Modulated Radiation Therapy

Intensity-modulated radiation therapy (IMRT) also abbreviated as IMRT is an advanced imaging technique in which a specific area or whole tumor is focused during radiotherapy sparing the normal tissues. The radiotherapy is under the control of computerized linear accelerators. 36 The advantage of IMRT is that an effective and high precision radiation can safely be given to the tumor. Hence, the major side effect of radiotherapy such as xerostomia is greatly reduced. 36

The efficacy of IMRT in the management of oropharyngeal cancer is mentioned by multiple studies. 36 , 37 Wang and Eisbruch reported that postoperative complication such as xerostomia and dysphagia is reduced in patients receiving IMRT. 36 The quality of life after IMRT is much improved as compared to the conventional radiotherapy without compromising the radiation dose to the tumor. 37 The treatment site should be carefully planned using magnetic resonance imaging or computed tomography before IMRT to determine the precise location of the tumor. 49 Su et al. concluded that the conventional radiotherapy should replace IMRT because of less postoperative complications and better outcomes. 50

Back to Top | Article Outline

Radiation Stents

Radiation stents are customized devices used to protect or shield the normal tissues so that the radiotherapy can be safely administered to the affected area only. As in IMRT, stents reduce the exposure of normal tissues to radiations; therefore, postoperative morbidity associated with radiotherapy is minimal in these patients. 38 Various materials used for the fabrication of stent are heat cure acrylic and alloys (Cerrobend and Lipowitz). 38

Back to Top | Article Outline

Stem Cell Transplantation

Studies have shown that when stem cells are transplanted into a salivary gland, it results in restoration of morphology and function of a gland. Certain stem cells (c-kit stem cells) when injected into the submandibular gland of mice results in normal function. 39 , 40

Back to Top | Article Outline

Intravenous Transplantation of Adipose Stem Cells

Li et al. stated that when adipose tissue-derived stem cells (ADSCs) were immediately injected systemically in mice after the radiation dose, results in preservation of salivary gland function as well as morphology. 41 ADSC protects a salivary gland by enhancing cell proliferation, inhibiting apoptosis, and promoting angiogenesis so that it remains unaffected during the radiation course. 41

Back to Top | Article Outline

Lasers

Gonnelli et al. reported that when low level laser therapy (InGaAlP laser) is delivered during radio and chemotherapy, results in prevention of hyposalivation postoperatively. Therefore, health-related quality of life can be significantly improved afterward. 42 However, the preventive therapy required more investigation in clinical trials.

Back to Top | Article Outline

Lidocaine

Hakim et al. conducted a Phase I clinical trials among rabbits and concluded that administration of lidocaine hydrochloride (10 and 12 mg/kg) before radiotherapy results in signification protection of salivary gland function afterward. The recommended dose is 10–12 mg/kg. 43 Hence, the radiation-related damage to a salivary gland can be avoided. 43 However, the modality requires Phase II trials before considering it as a recommended preventive therapy.

Back to Top | Article Outline

Conclusion

Salivary gland damage due to ionizing radiations adversely affects health-related quality of life. Therefore, preservation of normal salivary gland function is very important in patients undergoing radiotherapy for oropharyngeal cancers. It is very important for a clinician to employ preventive strategies during the phase of radiotherapy to reduce postoperative morbidity. These preventive methods not only maintain the morphology and function of a salivary glands but also reduce the need for salivary enhancing therapies later. By preventing occurrence of xerostomia in these patients, other oral complications such as dental caries, alterations in taste, and dysphasia are also significantly improved.

Financial support and sponsorship

Nil

Conflicts of interest

There are no conflicts of interest

1. NIH Natural Cancer Institute, Surveillance , Epidemiology and End Results Program; 2014. Available from: https://www [Last accessed on Jun ].. 1].;: Available from: https://wwwseercancergov/statfacts/html/oralcavhtml [Last accessed on 2017 Jun 01]
2. Ahadian H, Yassaei S, Bouzarjomehri F, Ghaffari Targhi M, Kheirollahi K. Oral complications of the oromaxillofacial area radiotherapy Asian Pac J Cancer Prev 2017;18:721-5. .;: Oral complications of the oromaxillofacial area radiotherapy Asian Pac J Cancer Prev 2017;18:721-5
3. Wong HM. Oral complications and management strategies for patients undergoing cancer therapy ScientificWorldJournal. 2014;2014:581795
4. Orellana MF, Lagravère MO, Boychuk DG, Major PW, Flores-Mir C. Prevalence of xerostomia in population-based samples: A systematic review J Public Health Dent. 2006;66:152–8
5. Owosho AA, Thor M, Oh JH, Riaz N, Tsai CJ, Rosenberg H, et al The role of parotid gland irradiation in the development of severe hyposalivation (xerostomia) after intensity-modulated radiation therapy for head and neck cancer: Temporal patterns, risk factors, and testing the QUANTEC guidelines J Craniomaxillofac Surg. 2017;45:595–600
6. Fischer DJ, Epstein JB. Management of patients who have undergone head and neck cancer therapy Dent Clin North Am. 2008;52:39–60, viii
7. Kouvaris JR, Kouloulias VE, Vlahos LJ. Amifostine: The first selective-target and broad-spectrum radioprotector Oncologist. 2007;12:738–47
8. Hofer M, Falk M, Komůrková D, Falková I, Bačíková A, Klejdus B, et al Two new faces of amifostine: Protector from DNA damage in normal cells and inhibitor of DNA repair in cancer cells J Med Chem. 2016;59:3003–17
9. Wasserman TH, Brizel DM, Henke M, Monnier A, Eschwege F, Sauer R, et al Influence of intravenous amifostine on xerostomia, tumor control, and survival after radiotherapy for head-and- neck cancer: 2-year follow-up of a prospective, randomized, phase III trial Int J Radiat Oncol Biol Phys. 2005;63:985–90
10. Gu J, Zhu S, Li X, Wu H, Li Y, Hua F, et al Effect of amifostine in head and neck cancer patients treated with radiotherapy: A systematic review and meta-analysis based on randomized controlled trials PLoS One. 2014;9:e95968
11. Nicolatou-Galitis O, Sarri T, Bowen J, Di Palma M, Kouloulias VE, Niscola P, et al Systematic review of amifostine for the management of oral mucositis in cancer patients Support Care Cancer. 2013;21:357–64
12. Rieger JM, Jha N, Lam Tang JA, Harris J, Seikaly H. Functional outcomes related to the prevention of radiation-induced xerostomia: Oral pilocarpine versus submandibular salivary gland transfer Head Neck. 2012;34:168–74
13. Yang WF, Liao GQ, Hakim SG, Ouyang DQ, Ringash J, Su YX, et al Is pilocarpine effective in preventing radiation-induced xerostomia.A systematic review and meta-analysis? Int J Radiat Oncol Biol Phys. 2016;94:503–11
14. Toya S, Mizutani M, Yamaguchi A. The effectiveness of pilocarpine hydrochloride for dry mouth symptoms of Sjögren's syndrome – Examining the adjustments on the number of times of its administration Int J Oral Maxillofac Surg. 2015;44:e298
15. Cheng CQ, Xu H, Liu L, Wang RN, Liu YT, Li J, et al Efficacy and safety of pilocarpine for radiation-induced xerostomia in patients with head and neck cancer: A systematic review and meta-analysis J Am Dent Assoc. 2016;147:236–43
16. Borba PM, De Souza MB, Gusmão G, Silva IH, Gueiros LA, Leão JC, et al Use of pilocarpine 2% associated with artificial saliva for the treatment of xerostomia: Randomized clinical trial Oral Surg Oral Med Oral Pathol Oral Radiol. 2017;124:e145
17. Chung MK, Kim do H, Ahn YC, Choi JY, Kim EH, Son YI, et al Randomized trial of Vitamin C/E complex for prevention of radiation-induced xerostomia in patients with head and neck cancer Otolaryngol Head Neck Surg. 2016;155:423–30
18. Jiang Q. Natural forms of Vitamin E: Metabolism, antioxidant, and anti-inflammatory activities and their role in disease prevention and therapy Free Radic Biol Med. 2014;72:76–90
19. Bairati I, Meyer F, Gélinas M, Fortin A, Nabid A, Brochet F, et al Randomized trial of antioxidant vitamins to prevent acute adverse effects of radiation therapy in head and neck cancer patients J Clin Oncol. 2005;23:5805–13
20. Ozben T. Antioxidant supplementation on cancer risk and during cancer therapy: An update Curr Top Med Chem. 2015;15:170–8
21. Mut-Salud N, Álvarez PJ, Garrido JM, Carrasco E, Aránega A, Rodríguez-Serrano F, et al Antioxidant intake and antitumor therapy: Toward nutritional recommendations for optimal results Oxid Med Cell Longev. 2016;2016:6719534
22. Pisoschi AM, Pop A. The role of antioxidants in the chemistry of oxidative stress: A review Eur J Med Chem. 2015;97:55–74
23. Ramos FM, Pontual ML, de Almeida SM, Bóscolo FN, Tabchoury CP, Novaes PD, et al Evaluation of radioprotective effect of Vitamin E in salivary dysfunction in irradiated rats Arch Oral Biol. 2006;51:96–101
24. Zhuang L, Yang Z, Zeng X, Zhua X, Chen Z, Liu L, et al The preventive and therapeutic effect of acupuncture for radiation-induced xerostomia in patients with head and neck cancer: A systematic review Integr Cancer Ther. 2013;12:197–205
25. Garcia MK, Chiang JS, Cohen L, Liu M, Palmer JL, Rosenthal DI, et al Acupuncture for radiation-induced xerostomia in patients with cancer: A pilot study Head Neck. 2009;31:1360–8
26. Cho JH, Chung WK, Kang W, Choi SM, Cho CK, Son CG, et al Manual acupuncture improved quality of life in cancer patients with radiation-induced xerostomia J Altern Complement Med. 2008;14:523–6
27. Meng Z, Garcia MK, Hu C, Chiang J, Chambers M, Rosenthal DI, et al Randomized controlled trial of acupuncture for prevention of radiation-induced xerostomia among patients with nasopharyngeal carcinoma Cancer. 2012;118:3337–44
28. Jham BC, Teixeira IV, Aboud CG, Carvalho AL, Coelho Mde M, Freire AR, et al A randomized phase III prospective trial of bethanechol to prevent radiotherapy-induced salivary gland damage in patients with head and neck cancer Oral Oncol. 2007;43:137–42
29. Jaguar GC, Lima EN, Kowalski LP, Pellizzon AC, Carvalho AL, Boccaletti KW, et al Double blind randomized prospective trial of bethanechol in the prevention of radiation-induced salivary gland dysfunction in head and neck cancer patients Radiother Oncol. 2015;115:253–6
30. Teymoortash A, Sommer F, Mandic R, Schulz S, Bette M, Aumüller G, et al Intraglandular application of botulinum toxin leads to structural and functional changes in rat acinar cells Br J Pharmacol. 2007;152:161–7
31. Teymoortash A, Pfestroff A, Wittig A, Franke N, Hoch S, Harnisch S, et al Safety and efficacy of botulinum toxin to preserve gland function after radiotherapy in patients with head and neck cancer: A prospective, randomized, placebo-controlled, double-blinded phase I clinical trial PLoS One. 2016;11:e0151316
32. Medina VA, Prestifilippo JP, Croci M, Carabajal E, Bergoc RM, Elverdin JC, et al Histamine prevents functional and morphological alterations of submandibular glands induced by ionising radiation Int J Radiat Biol. 2011;87:284–92
33. Limesand KH, Said S, Anderson SM. Suppression of radiation-induced salivary gland dysfunction by IGF-1 PLoS One. 2009;4:e4663
34. Morgan-Bathke M, Hill GA, Harris ZI, Lin HH, Chibly AM, Klein RR, et al Autophagy correlates with maintenance of salivary gland function following radiation Sci Rep. 2014;4:5206
35. Zhang X, Liu F, Lan X, Yu L, Wu W, Wu X, et al Clinical observation of submandibular gland transfer for the prevention of xerostomia after radiotherapy for nasopharyngeal carcinoma: A prospective randomized controlled study of 32 cases Radiat Oncol. 2014;9:62
36. Wang X, Eisbruch A. IMRT for head and neck cancer: Reducing xerostomia and dysphagia J Radiat Res. 2016;57 Suppl 1:i69–75
37. Zhang B, Mo Z, Du W, Wang Y, Liu L, Wei Y, et al Intensity-modulated radiation therapy versus 2D-RT or 3D-CRT for the treatment of nasopharyngeal carcinoma: A systematic review and meta-analysis Oral Oncol. 2015;51:1041–6
38. Qin WJ, Luo W, Lin SR, Sun Y, Li FM, Liu XQ, et al Sparing normal oral tissues with individual dental stent in radiotherapy for primary nasopharyngeal carcinoma patients Ai Zheng. 2007;26:285–9
39. Feng J, van der Zwaag M, Stokman MA, van Os R, Coppes RP. Isolation and characterization of human salivary gland cells for stem cell transplantation to reduce radiation-induced hyposalivation Radiother Oncol. 2009;92:466–71
40. Lombaert IM, Brunsting JF, Wierenga PK, Faber H, Stokman MA, Kok T, et al Rescue of salivary gland function after stem cell transplantation in irradiated glands PLoS One. 2008;3:e2063
41. Li Z, Wang Y, Xing H, Wang Z, Hu H, An R, et al Protective efficacy of intravenous transplantation of adipose-derived stem cells for the prevention of radiation-induced salivary gland damage Arch Oral Biol. 2015;60:1488–96
42. Gonnelli FA, Palma LF, Giordani AJ, Deboni AL, Dias RS, Segreto RA, et al Low-level laser therapy for the prevention of low salivary flow rate after radiotherapy and chemotherapy in patients with head and neck cancer Radiol Bras. 2016;49:86–91
43. Hakim SG, Benedek GA, Su YX, Jacobsen HC, Klinger M, Dendorfer A, et al Radioprotective effect of lidocaine on function and ultrastructure of salivary glands receiving fractionated radiation Int J Radiat Oncol Biol Phys. 2012;82:e623–30
44. Ohsawa Y, Hirasawa N. The role of histamine H1 and H4 receptors in atopic dermatitis: From basic research to clinical study Allergol Int. 2014;63:533–42
45. Takahashi S, Yoshimura Y, Yamamoto T, Wakita M. Cellular expression of Bcl-2 and bax in atrophic submandibular glands of rats Int J Exp Pathol. 2008;89:303–8
46. Al-Qahtani K, Hier MP, Sultanum K, Black MJ. The role of submandibular salivary gland transfer in preventing xerostomia in the chemoradiotherapy patient Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;101:753–6
47. Sood AJ, Fox NF, O'Connell BP, Lovelace TL, Nguyen SA, Sharma AK, et al Salivary gland transfer to prevent radiation-induced xerostomia: A systematic review and meta-analysis Oral Oncol. 2014;50:77–83
48. Rieger J, Seikaly H, Jha N, Harris J, Williams D, Liu R, et al Submandibular gland transfer for prevention of xerostomia after radiation therapy: Swallowing outcomes Arch Otolaryngol Head Neck Surg. 2005;131:140–5
49. Ai QY, King AD, Mo FKF, Law BKH, Bhatia KS, Ma BB, et al Prediction of distant metastases from nasopharyngeal carcinoma: Improved diagnostic performance of MRI using nodal volume in N1 and N2 stage disease Oral Oncol. 2017;69:74–9
50. Su SF, Han F, Zhao C, Chen CY, Xiao WW, Li JX, et al Long-term outcomes of early-stage nasopharyngeal carcinoma patients treated with intensity-modulated radiotherapy alone Int J Radiat Oncol Biol Phys. 2012;82:327–33
51. . .;:
    Keywords:

    Head and neck cancer; hyposalivation; oropharyngeal cancer; radiation therapy; xerostomia

    © 2018 President and Fellows of Harvard College