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Meta-Analysis
. 2017 Jul 31;7(7):CD012744.
doi: 10.1002/14651858.CD012744.

Pharmacological interventions for preventing dry mouth and salivary gland dysfunction following radiotherapy

Philip Riley  1 , Anne-Marie Glenny, Fang Hua, Helen V Worthington
Affiliations
Meta-Analysis

Pharmacological interventions for preventing dry mouth and salivary gland dysfunction following radiotherapy

Philip Riley et al. Cochrane Database Syst Rev. .

Abstract

Background: Salivary gland dysfunction is an 'umbrella' term for the presence of either xerostomia (subjective sensation of dryness), or salivary gland hypofunction (reduction in saliva production). It is a predictable side effect of radiotherapy to the head and neck region, and is associated with a significant impairment of quality of life. A wide range of pharmacological interventions, with varying mechanisms of action, have been used for the prevention of radiation-induced salivary gland dysfunction.

Objectives: To assess the effects of pharmacological interventions for the prevention of radiation-induced salivary gland dysfunction.

Search methods: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 14 September 2016); the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 8) in the Cochrane Library (searched 14 September 2016); MEDLINE Ovid (1946 to 14 September 2016); Embase Ovid (1980 to 14 September 2016); CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1937 to 14 September 2016); LILACS BIREME Virtual Health Library (Latin American and Caribbean Health Science Information database; 1982 to 14 September 2016); Zetoc Conference Proceedings (1993 to 14 September 2016); and OpenGrey (1997 to 14 September 2016). We searched the US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases.

Selection criteria: We included randomised controlled trials, irrespective of their language of publication or publication status. Trials included participants of all ages, ethnic origin and gender, scheduled to receive radiotherapy on its own or in addition to chemotherapy to the head and neck region. Participants could be outpatients or inpatients. We included trials comparing any pharmacological agent regimen, prescribed prophylactically for salivary gland dysfunction prior to or during radiotherapy, with placebo, no intervention or an alternative pharmacological intervention. Comparisons of radiation techniques were excluded.

Data collection and analysis: We used standard methodological procedures expected by Cochrane.

Main results: We included 39 studies that randomised 3520 participants; the number of participants analysed varied by outcome and time point. The studies were ordered into 14 separate comparisons with meta-analysis only being possible in three of those.We found low-quality evidence to show that amifostine, when compared to a placebo or no treatment control, might reduce the risk of moderate to severe xerostomia (grade 2 or higher on a 0 to 4 scale) at the end of radiotherapy (risk ratio (RR) 0.35, 95% confidence interval (CI) 0.19 to 0.67; P = 0.001, 3 studies, 119 participants), and up to three months after radiotherapy (RR 0.66, 95% CI 0.48 to 0.92; P = 0.01, 5 studies, 687 participants), but there is insufficient evidence that the effect is sustained up to 12 months after radiotherapy (RR 0.70, 95% CI 0.40 to 1.23; P = 0.21, 7 studies, 682 participants). We found very low-quality evidence that amifostine increased unstimulated salivary flow rate up to 12 months after radiotherapy, both in terms of mg of saliva per 5 minutes (mean difference (MD) 0.32, 95% CI 0.09 to 0.55; P = 0.006, 1 study, 27 participants), and incidence of producing greater than 0.1 g of saliva over 5 minutes (RR 1.45, 95% CI 1.13 to 1.86; P = 0.004, 1 study, 175 participants). However, there was insufficient evidence to show a difference when looking at stimulated salivary flow rates. There was insufficient (very low-quality) evidence to show that amifostine compromised the effects of cancer treatment when looking at survival measures. There was some very low-quality evidence of a small benefit for amifostine in terms of quality of life (10-point scale) at 12 months after radiotherapy (MD 0.70, 95% CI 0.20 to 1.20; P = 0.006, 1 study, 180 participants), but insufficient evidence at the end of and up to three months postradiotherapy. A further study showed no evidence of a difference at 6, 12, 18 and 24 months postradiotherapy. There was low-quality evidence that amifostine is associated with increases in: vomiting (RR 4.90, 95% CI 2.87 to 8.38; P < 0.00001, 5 studies, 601 participants); hypotension (RR 9.20, 95% CI 2.84 to 29.83; P = 0.0002, 3 studies, 376 participants); nausea (RR 2.60, 95% CI 1.81 to 3.74; P < 0.00001, 4 studies, 556 participants); and allergic response (RR 7.51, 95% CI 1.40 to 40.39; P = 0.02, 3 studies, 524 participants).We found insufficient evidence (that was of very low quality) to determine whether or not pilocarpine performed better or worse than a placebo or no treatment control for the outcomes: xerostomia, salivary flow rate, survival, and quality of life. There was some low-quality evidence that pilocarpine was associated with an increase in sweating (RR 2.98, 95% CI 1.43 to 6.22; P = 0.004, 5 studies, 389 participants).We found insufficient evidence to determine whether or not palifermin performed better or worse than placebo for: xerostomia (low quality); survival (moderate quality); and any adverse effects.There was also insufficient evidence to determine the effects of the following interventions: biperiden plus pilocarpine, Chinese medicines, bethanechol, artificial saliva, selenium, antiseptic mouthrinse, antimicrobial lozenge, polaprezinc, azulene rinse, and Venalot Depot (coumarin plus troxerutin).

Authors' conclusions: There is some low-quality evidence to suggest that amifostine prevents the feeling of dry mouth in people receiving radiotherapy to the head and neck (with or without chemotherapy) in the short- (end of radiotherapy) to medium-term (three months postradiotherapy). However, it is less clear whether or not this effect is sustained to 12 months postradiotherapy. The benefits of amifostine should be weighed against its high cost and side effects. There was insufficient evidence to show that any other intervention is beneficial.

PubMed Disclaimer

Conflict of interest statement

Philip Riley: no interests to declare. Philip is an Editor with Cochrane Oral Health. Anne‐Marie Glenny: no interests to declare. Anne‐Marie is Deputy Co‐ordinating Editor of Cochrane Oral Health. Fang Hua: no interests to declare. Fang is an Editor with Cochrane Oral Health. Helen V Worthington: no interests to declare. Helen is Co‐ordinating Editor of Cochrane Oral Health.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 Pilocarpine versus no treatment/placebo, Outcome 1 Xerostomia.
1.2
1.2. Analysis
Comparison 1 Pilocarpine versus no treatment/placebo, Outcome 2 Xerostomia (LENT‐SOMA scale).
1.3
1.3. Analysis
Comparison 1 Pilocarpine versus no treatment/placebo, Outcome 3 Xerostomia.
1.4
1.4. Analysis
Comparison 1 Pilocarpine versus no treatment/placebo, Outcome 4 Salivary flow rate (unstimulated).
1.5
1.5. Analysis
Comparison 1 Pilocarpine versus no treatment/placebo, Outcome 5 Salivary flow rate (stimulated).
1.6
1.6. Analysis
Comparison 1 Pilocarpine versus no treatment/placebo, Outcome 6 Salivary flow rate (> 0 g) unstimulated.
1.7
1.7. Analysis
Comparison 1 Pilocarpine versus no treatment/placebo, Outcome 7 Salivary flow rate (> 0 g) stimulated.
1.8
1.8. Analysis
Comparison 1 Pilocarpine versus no treatment/placebo, Outcome 8 Overall survival.
1.9
1.9. Analysis
Comparison 1 Pilocarpine versus no treatment/placebo, Outcome 9 Quality of life.
2.1
2.1. Analysis
Comparison 2 Biperiden plus pilocarpine versus no treatment, Outcome 1 Salivary flow rate (unstimulated).
2.2
2.2. Analysis
Comparison 2 Biperiden plus pilocarpine versus no treatment, Outcome 2 Salivary flow rate (> 0 g) unstimulated.
3.1
3.1. Analysis
Comparison 3 Amifostine versus no treatment/placebo, Outcome 1 Xerostomia (0 to 4 scale ‐ grade 2 or above).
3.2
3.2. Analysis
Comparison 3 Amifostine versus no treatment/placebo, Outcome 2 Salivary flow rate (unstimulated).
3.3
3.3. Analysis
Comparison 3 Amifostine versus no treatment/placebo, Outcome 3 Salivary flow rate (unstimulated) ‐ incidence of > 0.1 g in 5 min.
3.4
3.4. Analysis
Comparison 3 Amifostine versus no treatment/placebo, Outcome 4 Salivary flow rate (stimulated).
3.5
3.5. Analysis
Comparison 3 Amifostine versus no treatment/placebo, Outcome 5 Salivary flow rate (stimulated) ‐ incidence of > 0.1 g in 5 min.
3.6
3.6. Analysis
Comparison 3 Amifostine versus no treatment/placebo, Outcome 6 Overall survival at 12 to 24 months postradiotherapy.
3.8
3.8. Analysis
Comparison 3 Amifostine versus no treatment/placebo, Outcome 8 Progression‐free survival at 12 to 24 months postradiotherapy.
3.9
3.9. Analysis
Comparison 3 Amifostine versus no treatment/placebo, Outcome 9 Progression‐free survival.
3.11
3.11. Analysis
Comparison 3 Amifostine versus no treatment/placebo, Outcome 11 Locoregional tumour control at 12 to 24 months postradiotherapy.
3.13
3.13. Analysis
Comparison 3 Amifostine versus no treatment/placebo, Outcome 13 Disease‐free survival.
3.15
3.15. Analysis
Comparison 3 Amifostine versus no treatment/placebo, Outcome 15 Quality of life (Patient Benefit Questionnaire).
4.1
4.1. Analysis
Comparison 4 Amifostine (comparison of dosages), Outcome 1 Xerostomia (0 to 4 scale ‐ grade 2 or above).
5.1
5.1. Analysis
Comparison 5 Amifostine (intravenous versus subcutaneous), Outcome 1 Xerostomia (0 to 4 scale ‐ grade 2 or above).
5.2
5.2. Analysis
Comparison 5 Amifostine (intravenous versus subcutaneous), Outcome 2 Overall survival.
5.3
5.3. Analysis
Comparison 5 Amifostine (intravenous versus subcutaneous), Outcome 3 Locoregional tumour control.
6.1
6.1. Analysis
Comparison 6 Chinese medicine versus no treatment/placebo, Outcome 1 Xerostomia.
6.2
6.2. Analysis
Comparison 6 Chinese medicine versus no treatment/placebo, Outcome 2 Xerostomia.
6.3
6.3. Analysis
Comparison 6 Chinese medicine versus no treatment/placebo, Outcome 3 Salivary flow rate (stimulated).
6.4
6.4. Analysis
Comparison 6 Chinese medicine versus no treatment/placebo, Outcome 4 Overall survival (12 months postRT).
6.5
6.5. Analysis
Comparison 6 Chinese medicine versus no treatment/placebo, Outcome 5 Quality of life (EORTC‐C30).
7.1
7.1. Analysis
Comparison 7 Palifermin versus placebo, Outcome 1 Xerostomia (0 to 4 scale ‐ grade 2 or above).
7.2
7.2. Analysis
Comparison 7 Palifermin versus placebo, Outcome 2 Overall survival at 42 to 72 months from baseline.
7.3
7.3. Analysis
Comparison 7 Palifermin versus placebo, Outcome 3 Progression‐free survival at 42 to 72 months from baseline.
8.1
8.1. Analysis
Comparison 8 Bethanechol versus placebo, Outcome 1 Xerostomia (0 to 3 scale ‐ grade 2 or above).
8.2
8.2. Analysis
Comparison 8 Bethanechol versus placebo, Outcome 2 Salivary flow rate (unstimulated) ‐ ml/min.
8.3
8.3. Analysis
Comparison 8 Bethanechol versus placebo, Outcome 3 Salivary flow rate (stimulated) ‐ ml/min.
9.1
9.1. Analysis
Comparison 9 Bethanechol versus artificial saliva, Outcome 1 Xerostomia (dry mouth? yes/no).
9.2
9.2. Analysis
Comparison 9 Bethanechol versus artificial saliva, Outcome 2 Salivary flow rate (unstimulated) ‐ ml/min.
9.3
9.3. Analysis
Comparison 9 Bethanechol versus artificial saliva, Outcome 3 Salivary flow rate (stimulated) ‐ ml/min.
9.4
9.4. Analysis
Comparison 9 Bethanechol versus artificial saliva, Outcome 4 Overall survival.
11.1
11.1. Analysis
Comparison 11 Antimicrobial lozenge versus placebo, Outcome 1 Xerostomia (QoL response for dryness).
11.2
11.2. Analysis
Comparison 11 Antimicrobial lozenge versus placebo, Outcome 2 Quality of life.
12.1
12.1. Analysis
Comparison 12 Polaprezinc versus azulene oral rinse, Outcome 1 Xerostomia (grade 2 or above).
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References

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Sangthawan 2001 {published data only}
    1. Sangthawan D, Watthanaarpornchai S, Phungrassami T. Randomized double blind, placebo‐controlled study of pilocarpine administered during head and neck irradiation to reduce xerostomia. Journal of the Medical Association of Thailand 2001;84(2):195‐203. - PubMed
    1. Sangthawan D, Watthanaarpornchai S, Phungrassami T. Randomized double blind, placebo‐controlled study of pilocarpine administered during head and neck irradiation to reduce xerostomia. Radiation Oncology Association of Thailand 2002;7:242. - PubMed
Vacha 2003 {published data only}
    1. Vacha P, Fehlauer F, Mahlmann B, Marx M, Hinke A, Sommer K, et al. Randomized phase III trial of postoperative radiochemotherapy +/‐ amifostine in head and neck cancer. Is there evidence for radioprotection?. Strahlentherapie und Onkologie 2003;179(6):385‐9. - PubMed
    1. Vacha P, Marx M, Engel A, Richter E, Feyerabend T. Side effects of postoperative radiochemotherapy with amifostine versus radiochemotherapy alone in head and neck tumors. Preliminary results of a prospective randomized trial. Strahlentherapie und Onkologie 1999;175 Suppl 4:18‐22. - PubMed
Valdez 1993 {published data only}
    1. Valdez IH, Wolff A, Atkinson JC, Macynski AA, Fox PC. Use of pilocarpine during head and neck radiation therapy to reduce xerostomia and salivary dysfunction. Cancer 1993;71(5):1848‐51. - PubMed
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Veerasarn 2006 {published and unpublished data}
    1. Veerasarn V, Phromratanapongse P, Suntornpong N, Lorvidhaya V, Chitapanarux I, Tesavibul C, et al. Effect of amifostine to prevent radiotherapy‐induced acute and late toxicity in head and neck cancer patients who had normal or mild impaired salivary gland dysfunction. European Journal of Cancer Supplements 2003;1(5):S273. [Abs No 908] - PubMed
    1. Veerasarn V, Phromratanapongse P, Suntornpong N, Lorvidhaya V, Sukthomya V, Chitapanarux I, et al. Effect of amifostine to prevent radiotherapy‐induced acute and late toxicity in head and neck cancer patients who had normal or mild impaired salivary gland function. Journal of the Medical Association of Thailand 2006;89(12):2056‐67. - PubMed
Wang 1998 {published data only}
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Warde 2002 {published data only}
    1. Warde P, O'Sullivan B, Aslanidis J, Kroll B, Lockwood G, Math M, et al. A phase III placebo‐controlled trial of oral pilocarpine in patients undergoing radiotherapy for head and neck cancer. International Journal of Radiation Oncology, Biology, Physics 2002;54(1):9‐13. - PubMed
Watanabe 2010 {published data only}
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References to studies excluded from this review

Anné 2002 {published data only}
    1. Anné PR. Phase II trial of subcutaneous amifostine in patients undergoing radiation therapy for head and neck cancer. Seminars in Oncology 2002;29(6 Suppl 19):80‐3. - PubMed
Bagga 2007 {published data only}
    1. Bagga P, Anand AK, Raina A, Choudhary PS, Chaudhoory AR. Evaluation of pilocarpine for the prevention of radiation induced xerostomia in head and neck cancers. Annals of Oncology 2007;18(Suppl 9):ix177. [Abs No 62]
Bakowski 1978 {published data only}
    1. Bakowski MT, Macdonald E, Mould RF, Cawte P, Sloggem J, Barrett A, et al. Double blind controlled clinical trial of radiation plus razoxane (ICRF 159) versus radiation plus placebo in the treatment of head and neck cancer. International Journal of Radiation Oncology, Biology, Physics 1978;4(1‐2):115‐9. - PubMed
Belcaro 2008 {published data only}
    1. Belcaro G, Cesarone MR, Genovesi D, Ledda A, Vinciguerra G, Ricci A, et al. Pycnogenol may alleviate adverse effects in oncologic treatment. Panminerva Medica 2008;50(3):227‐34. - PubMed
Bohuslavizki 1998 {published data only}
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    1. Bohuslavizki KH, Klutmann S, Brenner W, Kröger S, Buchert R, Bleckmann C, et al. Radioprotection of salivary glands by amifostine in high‐dose radioiodine treatment. Results of a double‐blinded, placebo‐controlled study in patients with differentiated thyroid cancer. Strahlentherapie und Onkologie 1999;175(Suppl 4):6‐12. - PubMed
    1. Bohuslavizki KH, Klutmann S, Brenner W, Mester J, Henze E, Clausen M. Salivary gland protection by amifostine in high‐dose radioiodine treatment: results of a double‐blind placebo‐controlled study. Journal of Clinical Oncology 1998;16(11):3542‐9. - PubMed
    1. Bohuslavizki KH, Klutmann S, Jenicke L, Kröger S, Buchert R, Mester J, et al. Salivary gland protection by S‐2‐(3‐amino‐propylamino)‐ethylphosphorothioic acid (amifostine) in high‐dose radioiodine treatment: results obtained in a rabbit animal model and in a double‐blind multi‐arm trial. Cancer Biotherapy & Radiopharmaceuticals 1999;14(5):337‐47. - PubMed
Borg 2007 {published data only}
    1. Borg M, Krishnan S, Olver L, Stein B, Chatterton B, Coates E, et al. Randomised double‐blind trial of amifostine vs placebo for radiation‐induced xerostomia in patients with head and neck cancer. ANZ Journal of Surgery 2007;77(12):A3.
Bourhis 2000 {published data only}
    1. Bourhis J, Crevoisier R, Abdulkarim B, Deutsch E, Lusinchi A, Luboinski B, et al. A randomized study of very accelerated radiotherapy with and without amifostine in head and neck squamous cell carcinoma. International Journal of Radiation Oncology, Biology, Physics 2000;46(5):1105‐8. - PubMed
Braaksma 2002 {published data only}
    1. Braaksma M, Levendag P. Tools for optimal tissue sparing in concomitant chemoradiation of advanced head and neck cancer: subcutaneous amifostine and computed tomography‐based target delineation. Seminars in Oncology 2002;29(6 Suppl 19):63‐70. - PubMed
Braaksma 2005 {published data only (unpublished sought but not used)}
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Chambers 2005 {published data only}
    1. Chambers MS, Posner MR, Jones CU, Weber RS, Vitti R. Two phase III clinical studies of cevimeline for post‐radiation xerostomia in patients with head and neck cancer. Journal of Clinical Oncology 2005;23(16 Suppl):5503.
Demiroz 2012 {published data only}
    1. Demiroz C, Ozcan L, Cebelli G, Karadag O, Ozsahin EM. The effect of amifostine on acute and late radiation side effects in head and neck cancer patients. Turkiye Klinikleri Journal of Medical Sciences 2012;32:1207‐16.
Fallahi 2013 {published data only}
    1. Fallahi B, Beiki D, Abedi SM, Saghari M, Fard‐Esfahani A, Akhzari F, et al. Does vitamin E protect salivary glands from I‐131 radiation damage in patients with thyroid cancer?. Nuclear Medicine Communications 2013;34(8):777‐86. - PubMed
Fan 2011 {published data only}
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Franzén 1995 {published data only}
    1. Franzén L, Henriksson R, Littbrand B, Zackrisson B. Effects of sucralfate on mucositis during and following radiotherapy of malignancies in the head and neck region. A double‐blind placebo‐controlled study. Acta Oncologica (Stockholm, Sweden) 1995;34(2):219‐23. - PubMed
Fuertes 2004 {published data only}
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Goyal 2007 {published data only}
    1. Goyal S, Sharma DN, Julka PK, Rath GK. Effect of oral pilocarpine on xerostomia and quality of life in patients receiving curative radiotherapy for head and neck cancers. Journal of Clinical Oncology 2007;25(18 Suppl):6088.
Gu 2014 {published data only}
    1. Gu J, Zhu S, Li X, Wu H, Li Y, Hua F. 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(5):e95968. - PMC - PubMed
Johnson 2002 {published data only}
    1. Johnson DJ, Scott CB, Marks JE, Seay TE, Atkins JN, Berk LB, et al. Assessment of quality of life and oral function of patients participating in a phase II study of radioprotection of oral and pharyngeal mucosa by the prostaglandin E(1) analog misoprostol (RTOG 96‐07). International Journal of Radiation Oncology, Biology, Physics 2002;54(5):1455‐9. - PubMed
Karacetin 2004 {published data only}
    1. Karacetin D, Yücel B, Leblebicioglu B, Aksakal O, Maral O, Incekara O. A randomized trial of amifostine as radioprotector in the radiotherapy of head and neck cancer. Journal of BUON 2004;9(1):23‐6. - PubMed
Koukourakis 2000 {published data only}
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Kumarchandra 2010 {published data only}
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Manoor 2014 {published data only}
    1. Manoor Maiya V, Vaid N, Basu S, Vatyam S, Hegde S, Deshmukh S, et al. The use of xylitol for the prevention of xerostomia in patients receiving intensity modulated radiation therapy for head and neck cancers. International Journal of Radiation Oncology, Biology, Physics 2014;90(1 Suppl):S562.
Mateos 2001 {published data only}
    1. Mateos JJ, Setoain X, Ferre J, Rovirosa A, Navalpotro B, Martin F, et al. Salivary scintigraphy for assessing the protective effect of pilocarpine in head and neck irradiated tumours. Nuclear Medicine Communications 2001;22(6):651‐6. - PubMed
Mitine 2000 {published data only}
    1. Mitine C, Chaltin M, Salembier C, Merlo P, Beauduin M. Head and neck radiotherapy: does pilocarpine hydrochloride reduce radiation‐induced xerostomia?. Proceedings of the management of head and neck tumors: what are the challenges for the third millennium; 1999 Dec 3‐4; Brussels (Belgium). European Laryngological Society, 1999.
Mix 2013 {published data only}
    1. Mix MD, Jameson M, Tills M, Dibaj S, Groman A, Jaggernauth W, et al. Randomized double‐blind, placebo‐controlled, multicenter phase 2 trial of selenomethionine as a modulator of efficacy and toxicity of chemoradiation in locally‐advanced squamous cell carcinoma of the head and neck. International Journal of Radiation Oncology, Biology, Physics 2013;87(2 Suppl):S466‐7.
Nicolatou‐Galitis 2003 {published data only}
    1. Nicolatou‐Galitis O, Sotiropoulou‐Lontou A, Velegraki A, Pissakas G, Kolitsi G, Kyprianou K, et al. Oral candidiasis in head and neck cancer patients receiving radiotherapy with amifostine cytoprotection. Oral Oncology 2003;39:397‐401. - PubMed
Norberg‐Spaak 1996 {published data only}
    1. Norberg‐Spaak LE, Lundquist PG, Berndtson M, Klintenberg C. Can pilocarpine treatment during irradiation prevent salivary gland damage?. Swedish Dental Journal 1996;20:234.
Norberg‐Spaak 1997 {published data only}
    1. Norberg‐Spaak LE. Can pilocarpine treatment during irradiation prevent salivary gland damage. Clinical Otolaryngology and Allied Sciences 1997;22:88.
Nyárády 2006 {unpublished data only}
    1. Nyárády Z, Németh A, Bán A, Mukics A, Nyárády J, Ember I, et al. A randomized study to assess the effectiveness of orally administered pilocarpine during and after radiotherapy of head and neck cancer. Anticancer Research 2006;26(2B):1557‐62. - PubMed
    1. Nyárády Z, Németh Á, Mukics A, Olasz L. Relieving symptoms of xerostomia with oral pilocarpine (Salagen) during irradiation in head‐and‐neck cancer. Journal of Cranio‐Maxillo‐Facial Surgery 2004;32 Suppl 1:230. [Abs No 459]
Park 2012 {published data only}
    1. Park J, McGuire DB, Kang H. Effects of cold sterile normal saline (CSNS) mouth care in head and neck cancer (HNC) patients undergoing concurrent chemoradiotherapy (CCRT). Supportive Care in Cancer 2012;20(1 Suppl):S246‐7. [Abs No 1028]
Park 2012a {published data only}
    1. Park K‐N, Son Y‐I, Baek CH. Protection of radiotherapy‐induced xerostomia with vitamin E+C complex. Otolaryngology ‐ Head and Neck Surgery 2012;147(2 Suppl):P174.
Peters 1999 {published data only}
    1. Peters K, Mücke R, Hamann D, Ziegler PG, Fietkau R. Supportive use of amifostine in patients with head and neck tumours undergoing radio‐chemotherapy. Is it possible to limit the duration of the application of amifostine?. Strahlentherapie und Onkologie 1999;175 Suppl 4:23‐6. - PubMed
Qian 2003 {published data only}
    1. Qian Y. Effects of Traditional Chinese Medicine on Salivary Glands of Patients with Head and Neck Cancer During Radiotherapy [Dissertation]. China National Knowledge Infrastructure (CNKI), 2003.
Resubal 2011 {published data only}
    1. Resubal JR, Calaguas MJ. The effect of zilongjin(r) in patients with head and neck cancer needing radiotherapy with and without chemotherapy. Radiotherapy and Oncology 2011;99(Suppl 1):S336.
Rieger 2012 {published data only}
    1. 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(2):168‐74. - PubMed
Rischin 2010 {published data only}
    1. Rischin D, Peters LJ, O'Sullivan B, Giralt J, Fisher R, Yuen K, et al. Tirapazamine, cisplatin, and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART): a phase III trial of the Trans‐Tasman Radiation Oncology Group. Journal of Clinical Oncology 2010;28(18):2989‐95. - PubMed
Rudat 2005 {published data only}
    1. Rudat V, Münter M, Rades D, Grötz K, Haberkorn U, Brenner W. The effect of amifostine or IMRT to preserve the parotid function after radiotherapy of the head and neck region measured by quantitative salivary gland scintigraphy. Journal of Clinical Oncology 2005;23(16 Suppl):5502. - PubMed
Schönekäs 1999 {published data only}
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Sharma 2012 {published data only}
    1. Sharma A, Rath GK, Chaudhary SP, Thakar A, Mohanti BK, Bahadur S. Lactobacillus brevis CD2 lozenges reduce radiation‐ and chemotherapy‐induced mucositis in patients with head and neck cancer: a randomized double‐blind placebo‐controlled study. European Journal of Cancer 2012;48(6):875‐81. - PubMed
Strnad 1997 {published data only}
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Su 2006 {published data only}
    1. Su YB, Vickers AJ, Zelefsky MJ, Kraus DH, Shaha AR, Shah JP, et al. Double‐blind, placebo‐controlled, randomized trial of granulocyte‐colony stimulating factor during postoperative radiotherapy for squamous head and neck cancer. Cancer Journal (Sudbury, Mass.) 2006;12(3):182‐8. - PubMed
Takahashi 1986 {published data only}
    1. Takahashi I, Nagai T, Miyaishi K, Maehara Y, Niibe H. Clinical study of the radioprotective effects of amifostine (YM‐08310, WR‐2721) on chronic radiation injury. International Journal of Radiation Oncology, Biology, Physics 1986;12(6):935‐8. - PubMed
Thorstad 2003 {published data only}
    1. 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. Seminars in Oncology 2003;30(6 Suppl 18):96‐100. - PubMed
Uchiyama 2005 {published data only}
    1. Uchiyama Y, Murakami S, Kakimoto N, Nakatani A, Furukawa S. Effectiveness of cepharanthin in decreasing interruptions during radiation therapy for oral cancer. Oral Radiology 2005;21(1):41‐4.
Zale 1993 {published data only}
    1. Zale M, Chambers MS, Khan Z. Pilocarpine effects on xerostomia associated with radiation therapy. Journal of Dental Research 1993;72(Abs Spec Issue):375. [Abs No 2175]
Zimmerman 1997 {published data only}
    1. Zimmerman RP, Mark RJ, Juillard GF. Timing of pilocarpine treatment during head and neck radiotherapy: concomitant administration reduces xerostomia better than post‐radiation pilocarpine. International Journal of Radiation Oncology, Biology, Physics 1996;36 Suppl 1(1):236. [Abs No 155]
    1. Zimmerman RP, Mark RJ, Tran LM, Juillard GF. Concomitant pilocarpine during head and neck irradiation is associated with decreased posttreatment xerostomia. International Journal of Radiation Oncology, Biology, Physics 1997;37(3):571‐5. - PubMed
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References to studies awaiting assessment

Yu 2009 {published data only}
    1. Yu DS, Zhao W, Wu XL, Huang ZY, Huang RB. Amifostine in prevention of radiation‐induced xerostomia. Journal of Sun Yat‐Sen University (Medical Sciences) 2009;30(4S):86‐7, 95.

References to ongoing studies

NCT02430298 {published data only}
    1. NCT02430298. Topical/oral melatonin for preventing concurrent radiochemotherapy induced oral mucositis/xerostomia cancer patients [Topical and oral melatonin for preventing concurrent radiochemotherapy induced oral mucositis and xerostomia in head and neck cancer patients]. clinicaltrials.gov/show/NCT02430298 (first received 28 January 2014).

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References to other published versions of this review

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