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1
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Watanapokasin N, Rawangban W, Tangjaturonrasme N. As-Needed Pilocarpine for Radiation-Induced Xerostomia in Head and Neck Cancers. Laryngoscope 2024; 134:4542-4548. [PMID: 38813852 DOI: 10.1002/lary.31544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 05/03/2024] [Accepted: 05/14/2024] [Indexed: 05/31/2024]
Abstract
OBJECTIVES This study aimed to evaluate the efficacy of as-needed pilocarpine for the management of radiation-induced xerostomia. Additionally, the study sought to assess the side effects associated with an as-needed regimen. METHODS A randomized, double-blinded, placebo-controlled crossover study was conducted on patients who had undergone radiation therapy for head and neck cancers and developed xerostomia. Participants took pilocarpine or placebo as needed for symptom relief at 2 weeks per treatment, which included a one-week washout period. The primary outcome measure was the severity of dry mouth symptoms, quantified using the Xerostomia Inventory (XI). The primary outcome was the change in the XI score. RESULTS Among the 20 participants who completed the crossover study, there was a significant reduction in XI scores during the treatment phase with pilocarpine compared to the scores during the placebo phase. The mean difference in XI scores was -18.05 (95% CI: -17.17, -6.13, p < 0.001), with a-49.77 ± 3.22% change (p < 0.001). Only one participant withdrew due to pilocarpine side effects. CONCLUSION As-needed pilocarpine administration is effective in relieving symptoms of radiation-induced xerostomia, with fewer side effects and reduced treatment costs compared to fixed-dose regimens. This study guides the potential shift toward flexible dosing strategies in clinical practice, promoting enhanced patient-centered, tailored care and adherence. LEVEL OF EVIDENCE: 2 According to the Oxford Center for Evidence-Based Medicine 2011 level of evidence guidelines Laryngoscope, 134:4542-4548, 2024.
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Affiliation(s)
- Natcha Watanapokasin
- Department of Otolaryngology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Worawat Rawangban
- Department of Otolaryngology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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2
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Kittichet R, Chitapanarux I, Kittidachanan K, Sripan P. A real-life experience of long-term use of pilocarpine in irradiated head and neck cancer patients. Oral Dis 2024; 30:4312-4319. [PMID: 38409744 DOI: 10.1111/odi.14905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 01/13/2024] [Accepted: 02/06/2024] [Indexed: 02/28/2024]
Abstract
AIMS To assess long-term efficacy and side effects of pilocarpine on irradiated head and neck cancer (HNC) patients in both for prevention and treatment of radiation-induced xerostomia (RIX). METHODS Retrospective observational study was conducted. Eligibility criteria included irradiated HNC patients who received pilocarpine at least 12 weeks either for prevention (group A) or for treatment (group B) of RIX. We collected the documented Late Effect Normal Tissue Task Force-Subjective, Objective, Management, Analytics subjective/objective grades of RIX before (only group B) and the latest visit for pilocarpine prescription, dosage, side effects, duration of treatment, and the cause of discontinuation. RESULTS Between December 2007 and June 2022, 182 patients were enrolled including 95 patients (52%) in group A and 87 patients (48%) in group B. Group A patients reported grades 1, 2, 3, and 4 objective RIX in 0%, 7%, 93%, and 0%. Grade 1, 2, and 3 subjective RIX were 57%, 28%, and 15%. All patients in group B had grade 3 both objective/subjective RIX. The overall improvement of objective/subjective RIX was found in 40%/83%. Discontinuation was found in 51% of patients due to tolerable symptoms or deterioration of the patient's status. CONCLUSIONS Based on this retrospective analysis, long-term use of pilocarpine in irradiated HNC appears feasible for both prevention and treatment of RIX.
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Affiliation(s)
- Rungarun Kittichet
- Division of Radiation Oncology, Department of Radiology, Faculty of Medicine, Prince of Songkhla University, Songkhla, Thailand
| | - Imjai Chitapanarux
- Division of Radiation Oncology, Department of Radiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Northern Thai Research Group of Radiation Oncology (NTRG-RO), Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Kittikun Kittidachanan
- Northern Thai Research Group of Radiation Oncology (NTRG-RO), Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Patumrat Sripan
- Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand
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3
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Staruch M, Speth MM, Neyer P, Riesterer O, Aebersold DM, Stieb S. Radiation-associated changes in saliva composition of head and neck cancer patients: A systematic review. Radiother Oncol 2024; 196:110279. [PMID: 38648994 DOI: 10.1016/j.radonc.2024.110279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 04/04/2024] [Accepted: 04/11/2024] [Indexed: 04/25/2024]
Abstract
Xerostomia is a common radiation-associated toxicity in patients with head and neck cancer. Although several studies examined the decrease in saliva production due to radiotherapy (RT) and investigated the factors associated with this side effect, little is known about the change in radiation-associated saliva composition. This systematic review is the first to summarize existing data and give an overview of the change in pH/buffer capacity, electrolytes, proteins, enzymes, and mucins due to radiation to the salivary glands. Literature search was performed in PubMed and Embase with 47 articles finally eligible for the review, analyzing the saliva composition at several time points before, during and/or after RT, or comparing findings in irradiated patients to a healthy control group. Overall, RT leads to a substantial decrease in salivary pH and buffer capacity. For sodium, chloride and calcium ion, as well as amylase, an increased concentration or activity during RT was reported in most of the studies, followed by a subsequent decrease either already during RT or after the end of treatment. Different trends have been described for the total protein concentration during and after RT. Lactoferrin, however, increased considerably, especially in the first phase of RT. Mucin 5B (MUC5B) concentrations showed a slight increase during RT and concentrations around baseline values again six months post-radiotherapy.
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Affiliation(s)
- Michal Staruch
- Radiation Oncology Center KSA-KSB, Cantonal Hospital Aarau, Aarau, Switzerland; Department of Radiation Oncology, University Hospital Bern, University of Bern, Bern, Switzerland
| | - Marlene M Speth
- Otorhinolaryngology, Cantonal Hospital Aarau, Aarau, Switzerland
| | - Peter Neyer
- Department of Laboratory Medicine, Cantonal Hospital Aarau, Aarau, Switzerland
| | - Oliver Riesterer
- Radiation Oncology Center KSA-KSB, Cantonal Hospital Aarau, Aarau, Switzerland
| | - Daniel M Aebersold
- Department of Radiation Oncology, University Hospital Bern, University of Bern, Bern, Switzerland
| | - Sonja Stieb
- Radiation Oncology Center KSA-KSB, Cantonal Hospital Aarau, Aarau, Switzerland.
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Nathan CAO, Asarkar AA, Entezami P, Corry J, Strojan P, Poorten VV, Makitie A, Eisbruch A, Robbins KT, Smee R, St John M, Chiesa-Estomba C, Winter SC, Beitler JJ, Ferlito A. Current management of xerostomia in head and neck cancer patients. Am J Otolaryngol 2023; 44:103867. [PMID: 36996514 DOI: 10.1016/j.amjoto.2023.103867] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023]
Abstract
Radiotherapy (RT) continues to play a key role in the management of head and neck cancer (HNC). Xerostomia remains a principal detriment to the quality of life (QoL) for 80 % of surviving patients receiving head and neck radiation. Radiation-induced injury to the salivary glands is dose-dependent, and thus efforts have been focused on decreasing radiation to the salivary glands. Decreased saliva production reduces both short-term and long-term quality of life in head and neck survivors by impacting on taste and contributing to dysphagia. Several radioprotective agents to the salivary gland have been investigated. Although not widely practiced, surgical transfer of the submandibular gland prior to RT is the mainstay of surgical options in preventing xerostomia. This review focuses on the strategies to improve xerostomia following radiation therapy in head and neck cancers.
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Affiliation(s)
- Cherie-Ann O Nathan
- Department of Otolaryngology/Head and Neck Surgery, LSU Health Sciences Center, Shreveport, LA, USA; Otolaryngology Section, Surgical Service, Overton Brooks VA Medical Center, Shreveport, LA, USA.
| | - Ameya A Asarkar
- Department of Otolaryngology/Head and Neck Surgery, LSU Health Sciences Center, Shreveport, LA, USA
| | - Payam Entezami
- Department of Otolaryngology/Head and Neck Surgery, LSU Health Sciences Center, Shreveport, LA, USA; Otolaryngology Section, Surgical Service, Overton Brooks VA Medical Center, Shreveport, LA, USA
| | - June Corry
- Department of Radiation Oncology, Genesiscare St Vincent's Hospital, Melbourne, Victoria, Australia
| | - Primoz Strojan
- Department of Radiation Oncology, Institute of Oncology, Ljubljana, Slovenia
| | - Vincent Vander Poorten
- Otorhinolaryngology-Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium; Department of Oncology, Section Head and Neck Oncology, KU Leuven, Leuven, Belgium
| | - Antti Makitie
- Department of Otorhinolaryngology, Head and Neck Surgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Avraham Eisbruch
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA
| | - K T Robbins
- Department of Otolaryngology/Head and Neck Surgery, Southern Illinois University, School of Medicine, Springfield, IL, USA
| | - Robert Smee
- Department of Radiation Oncology, The Prince of Wales Cancer Centre, Sydney, NSW, Australia
| | - Maie St John
- Department of Otolaryngology/Head and Neck Surgery, UCLA, CA, USA
| | - Carlos Chiesa-Estomba
- Otorhinolaryngology - Head & Neck Department - Donostia University Hospital, Biodonostia Research Institute, Deusto University, Spain
| | - Stuart C Winter
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | | | - Alfio Ferlito
- International Head and Neck Scientific Group, Padua, Italy
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5
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Steenbakkers RJHM, van Rijn-Dekker MI, Stokman MA, Kierkels RGJ, van der Schaaf A, van den Hoek JGM, Bijl HP, Kramer MCA, Coppes RP, Langendijk JA, van Luijk P. Parotid Gland Stem Cell Sparing Radiation Therapy for Patients With Head and Neck Cancer: A Double-Blind Randomized Controlled Trial. Int J Radiat Oncol Biol Phys 2022; 112:306-316. [PMID: 34563635 DOI: 10.1016/j.ijrobp.2021.09.023] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/08/2021] [Accepted: 09/13/2021] [Indexed: 02/08/2023]
Abstract
PURPOSE Radiation therapy for head and neck cancer frequently leads to salivary gland damage and subsequent xerostomia. The radiation response of the parotid glands of rats, mice, and patients critically depends on dose to parotid gland stem cells, mainly located in the gland's main ducts (stem cell rich [SCR] region). Therefore, this double-blind randomized controlled trial aimed to test the hypothesis that parotid gland stem cell sparing radiation therapy preserves parotid gland function better than currently used whole parotid gland sparing radiation therapy. METHODS AND MATERIALS Patients with head and neck cancer (n = 102) treated with definitive radiation therapy were randomized between standard parotid-sparing and stem cell sparing (SCS) techniques. The primary endpoint was >75% reduction in parotid gland saliva production compared with pretreatment production (FLOW12M). Secondary endpoints were several aspects of xerostomia 12 months after treatment. RESULTS Fifty-four patients were assigned to the standard arm and 48 to the SCS arm. Only dose to the SCR regions (contralateral 16 and 11 Gy [P = .004] and ipsilateral 26 and 16 Gy [P = .001] in the standard and SCS arm, respectively) and pretreatment patient-rated daytime xerostomia (35% and 13% [P = .01] in the standard and SCS arm, respectively) differed significantly between the arms. In the SCS arm, 1 patient (2.8%) experienced FLOW12M compared with 2 (4.9%) in the standard arm (P = 1.00). However, a trend toward better relative parotid gland salivary function in favor of SCS radiation therapy was shown. Moreover, multivariable analysis showed that mean contralateral SCR region dose was the strongest dosimetric predictor for moderate-to-severe patient-rated daytime xerostomia and grade ≥2 physician-rated xerostomia, the latter including reported alteration in diet. CONCLUSIONS No significantly better parotid function was observed in SCS radiation therapy. However, additional multivariable analysis showed that dose to the SCR region was more predictive of the development of parotid gland function-related xerostomia endpoints than dose to the entire parotid gland.
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Affiliation(s)
- Roel J H M Steenbakkers
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
| | - Maria I van Rijn-Dekker
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Monique A Stokman
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Roel G J Kierkels
- Department of Radiation Oncology, Radiotherapiegroep, Deventer, The Netherlands
| | - Arjen van der Schaaf
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Johanna G M van den Hoek
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Hendrik P Bijl
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Maria C A Kramer
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Robert P Coppes
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Biomedical Sciences of Cell and Systems, Section Molecular Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Johannes A Langendijk
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Peter van Luijk
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
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6
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Mercadante V, Jensen SB, Smith DK, Bohlke K, Bauman J, Brennan MT, Coppes RP, Jessen N, Malhotra NK, Murphy B, Rosenthal DI, Vissink A, Wu J, Saunders DP, Peterson DE. Salivary Gland Hypofunction and/or Xerostomia Induced by Nonsurgical Cancer Therapies: ISOO/MASCC/ASCO Guideline. J Clin Oncol 2021; 39:2825-2843. [PMID: 34283635 DOI: 10.1200/jco.21.01208] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
PURPOSE To provide evidence-based recommendations for prevention and management of salivary gland hypofunction and xerostomia induced by nonsurgical cancer therapies. METHODS Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) and ASCO convened a multidisciplinary Expert Panel to evaluate the evidence and formulate recommendations. PubMed, EMBASE, and Cochrane Library were searched for randomized controlled trials published between January 2009 and June 2020. The guideline also incorporated two previous systematic reviews conducted by MASCC/ISOO, which included studies published from 1990 through 2008. RESULTS A total of 58 publications were identified: 46 addressed preventive interventions and 12 addressed therapeutic interventions. A majority of the evidence focused on the setting of radiation therapy for head and neck cancer. For the prevention of salivary gland hypofunction and/or xerostomia in patients with head and neck cancer, there is high-quality evidence for tissue-sparing radiation modalities. Evidence is weaker or insufficient for other interventions. For the management of salivary gland hypofunction and/or xerostomia, intermediate-quality evidence supports the use of topical mucosal lubricants, saliva substitutes, and agents that stimulate the salivary reflex. RECOMMENDATIONS For patients who receive radiation therapy for head and neck cancer, tissue-sparing radiation modalities should be used when possible to reduce the risk of salivary gland hypofunction and xerostomia. Other risk-reducing interventions that may be offered during radiation therapy for head and neck cancer include bethanechol and acupuncture. For patients who develop salivary gland hypofunction and/or xerostomia, interventions include topical mucosal lubricants, saliva substitutes, and sugar-free lozenges or chewing gum. For patients with head and neck cancer, oral pilocarpine and oral cevimeline, acupuncture, or transcutaneous electrostimulation may be offered after radiation therapy.Additional information can be found at www.asco.org/supportive-care-guidelines.
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Affiliation(s)
- Valeria Mercadante
- University College London and University College London Hospitals Trust, London, United Kingdom
| | | | | | - Kari Bohlke
- American Society of Clinical Oncology, Alexandria, VA
| | | | | | - Robert P Coppes
- University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Niels Jessen
- Danish Cancer Society Network for Patients with Head and Neck Cancer, Copenhagen, Denmark
| | | | | | | | - Arjan Vissink
- University of Groningen and University Medical Center Groningen, Groningen, the Netherlands
| | - Jonn Wu
- Vancouver Cancer Centre, British Columbia Cancer Agency, and University of British Columbia, Vancouver, BC, Canada
| | - Deborah P Saunders
- North East Cancer Centre, Northern Ontario School of Medicine, Sudbury, ON, Canada
| | - Douglas E Peterson
- School of Dental Medicine & Neag Comprehensive Cancer Center, UConn Health, Farmington, CT
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7
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Huang SH, de Almeida JR, Watson E, Glogauer M, Xu W, Keshavarzi S, O'Sullivan B, Ringash J, Hope A, Bayley A, Bratman SV, Cho J, Giuliani M, Kim J, Waldron J, Spreafico A, Goldstein DP, Chepeha DB, Li T, Hosni A. Short-term and long-term unstimulated saliva flow following unilateral vs bilateral radiotherapy for oropharyngeal carcinoma. Head Neck 2020; 43:456-466. [PMID: 33058305 DOI: 10.1002/hed.26496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 08/31/2020] [Accepted: 09/22/2020] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND We aimed to compare unstimulated saliva flow using 3-minute modified Schirmer test (MST) following bilateral vs unilateral radiotherapy (RT) in oropharyngeal carcinoma (OPC). METHODS We reviewed OPC patients treated with definitive intensity-modulated radiation therapy (IMRT) between 2011 and 2017. MST was measured at baseline, 1-/6-/12-/24-month post-RT. MST values were compared between bilateral-RT vs unilateral-RT groups. Multivariable logistic regression analysis (MVA) identified predictors of hyposalivation (MST < 25 mm). RESULTS Total 498 bilateral-RT and 36 unilateral-RT patients were eligible. The MST values at 1-/6-/12-/24-month post-RT were all significantly reduced from baseline for the entire cohort. Baseline unilateral-RT and bilateral-RT MST values (in mm) were similar (P = .2), but much higher for unilateral-RT 1-month (mean: 19.1 vs 13.0, P = .03), 6-month (20.5 vs 9.3, P < .001), 12-month (20.1 vs 11.9, P < .01), and 24-month post-RT (22.2 vs 13.9, P = .04). MVA confirmed that unilateral RT reduced the likelihood of hyposalivation vs bilateral RT (OR 2.36, P = .006). CONCLUSION Unilateral RT reduces unstimulated salivary flow in OPC patients.
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Affiliation(s)
- Shao Hui Huang
- Department of Radiation Oncology, Princess Margaret Cancer Centre/University of Toronto, Toronto, Ontario, Canada.,Department of Otolaryngology-Head & Neck Surgery/Surgical Oncology, Princess Margaret Cancer Centre/University of Toronto, Toronto, Ontario, Canada
| | - John R de Almeida
- Department of Otolaryngology-Head & Neck Surgery/Surgical Oncology, Princess Margaret Cancer Centre/University of Toronto, Toronto, Ontario, Canada
| | - Erin Watson
- Department of Dental Oncology and Maxillofacial Prosthetics, Princess Margaret Cancer Centre/University of Toronto, Toronto, Ontario, Canada
| | - Michael Glogauer
- Department of Dental Oncology and Maxillofacial Prosthetics, Princess Margaret Cancer Centre/University of Toronto, Toronto, Ontario, Canada
| | - Wei Xu
- Department of Biostatistics, Princess Margaret Cancer Centre / University of Toronto, Toronto, Ontario, Canada
| | - Sareh Keshavarzi
- Department of Biostatistics, Princess Margaret Cancer Centre / University of Toronto, Toronto, Ontario, Canada
| | - Brian O'Sullivan
- Department of Radiation Oncology, Princess Margaret Cancer Centre/University of Toronto, Toronto, Ontario, Canada.,Department of Otolaryngology-Head & Neck Surgery/Surgical Oncology, Princess Margaret Cancer Centre/University of Toronto, Toronto, Ontario, Canada
| | - Jolie Ringash
- Department of Radiation Oncology, Princess Margaret Cancer Centre/University of Toronto, Toronto, Ontario, Canada.,Department of Otolaryngology-Head & Neck Surgery/Surgical Oncology, Princess Margaret Cancer Centre/University of Toronto, Toronto, Ontario, Canada
| | - Andrew Hope
- Department of Radiation Oncology, Princess Margaret Cancer Centre/University of Toronto, Toronto, Ontario, Canada
| | - Andrew Bayley
- Department of Radiation Oncology, Princess Margaret Cancer Centre/University of Toronto, Toronto, Ontario, Canada
| | - Scott V Bratman
- Department of Radiation Oncology, Princess Margaret Cancer Centre/University of Toronto, Toronto, Ontario, Canada
| | - John Cho
- Department of Radiation Oncology, Princess Margaret Cancer Centre/University of Toronto, Toronto, Ontario, Canada
| | - Meredith Giuliani
- Department of Radiation Oncology, Princess Margaret Cancer Centre/University of Toronto, Toronto, Ontario, Canada
| | - John Kim
- Department of Radiation Oncology, Princess Margaret Cancer Centre/University of Toronto, Toronto, Ontario, Canada
| | - John Waldron
- Department of Radiation Oncology, Princess Margaret Cancer Centre/University of Toronto, Toronto, Ontario, Canada.,Department of Otolaryngology-Head & Neck Surgery/Surgical Oncology, Princess Margaret Cancer Centre/University of Toronto, Toronto, Ontario, Canada
| | - Anna Spreafico
- Department of Medical Oncology, Princess Margaret Cancer Centre/University of Toronto, Toronto, Ontario, Canada
| | - David P Goldstein
- Department of Otolaryngology-Head & Neck Surgery/Surgical Oncology, Princess Margaret Cancer Centre/University of Toronto, Toronto, Ontario, Canada
| | - Douglas B Chepeha
- Department of Otolaryngology-Head & Neck Surgery/Surgical Oncology, Princess Margaret Cancer Centre/University of Toronto, Toronto, Ontario, Canada
| | - Tong Li
- Department of Radiation Oncology, Princess Margaret Cancer Centre/University of Toronto, Toronto, Ontario, Canada
| | - Ali Hosni
- Department of Radiation Oncology, Princess Margaret Cancer Centre/University of Toronto, Toronto, Ontario, Canada
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8
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Jensen SB, Vissink A, Limesand KH, Reyland ME. Salivary Gland Hypofunction and Xerostomia in Head and Neck Radiation Patients. J Natl Cancer Inst Monogr 2020; 2019:5551361. [PMID: 31425600 DOI: 10.1093/jncimonographs/lgz016] [Citation(s) in RCA: 118] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 05/21/2019] [Accepted: 05/26/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The most manifest long-term consequences of radiation therapy in the head and neck cancer patient are salivary gland hypofunction and a sensation of oral dryness (xerostomia). METHODS This critical review addresses the consequences of radiation injury to salivary gland tissue, the clinical management of salivary gland hypofunction and xerostomia, and current and potential strategies to prevent or reduce radiation injury to salivary gland tissue or restore the function of radiation-injured salivary gland tissue. RESULTS Salivary gland hypofunction and xerostomia have severe implications for oral functioning, maintenance of oral and general health, and quality of life. Significant progress has been made to spare salivary gland function chiefly due to advances in radiation techniques. Other strategies have also been developed, e.g., radioprotectors, identification and preservation/expansion of salivary stem cells by stimulation with cholinergic muscarinic agonists, and application of new lubricating or stimulatory agents, surgical transfer of submandibular glands, and acupuncture. CONCLUSION Many advances to manage salivary gland hypofunction and xerostomia induced by radiation therapy still only offer partial protection since they are often of short duration, lack the protective effects of saliva, or potentially have significant adverse effects. Intensity-modulated radiation therapy (IMRT), and its next step, proton therapy, have the greatest potential as a management strategy for permanently preserving salivary gland function in head and neck cancer patients.Presently, gene transfer to supplement fluid formation and stem cell transfer to increase the regenerative potential in radiation-damaged salivary glands are promising approaches for regaining function and/or regeneration of radiation-damaged salivary gland tissue.
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Affiliation(s)
- Siri Beier Jensen
- Department of Dentistry and Oral Health, Faculty of Health, Aarhus University, Aarhus, Denmark
| | - Arjan Vissink
- Department of Oral and Maxillofacial Surgery, University of Groningen, University Medical Center, Groningen, The Netherlands
| | | | - Mary E Reyland
- Department of Craniofacial Biology, School of Dental Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO
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9
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Barazzuol L, Coppes RP, van Luijk P. Prevention and treatment of radiotherapy-induced side effects. Mol Oncol 2020; 14:1538-1554. [PMID: 32521079 PMCID: PMC7332214 DOI: 10.1002/1878-0261.12750] [Citation(s) in RCA: 117] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 05/29/2020] [Accepted: 06/02/2020] [Indexed: 01/10/2023] Open
Abstract
Radiotherapy remains a mainstay of cancer treatment, being used in roughly 50% of patients. The precision with which the radiation dose can be delivered is rapidly improving. This precision allows the more accurate targeting of radiation dose to the tumor and reduces the amount of surrounding normal tissue exposed. Although this often reduces the unwanted side effects of radiotherapy, we still need to further improve patients' quality of life and to escalate radiation doses to tumors when necessary. High-precision radiotherapy forces one to choose which organ or functional organ substructures should be spared. To be able to make such choices, we urgently need to better understand the molecular and physiological mechanisms of normal tissue responses to radiotherapy. Currently, oversimplified approaches using constraints on mean doses, and irradiated volumes of normal tissues are used to plan treatments with minimized risk of radiation side effects. In this review, we discuss the responses of three different normal tissues to radiotherapy: the salivary glands, cardiopulmonary system, and brain. We show that although they may share very similar local cellular processes, they respond very differently through organ-specific, nonlocal mechanisms. We also discuss how a better knowledge of these mechanisms can be used to treat or to prevent the effects of radiotherapy on normal tissue and to optimize radiotherapy delivery.
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Affiliation(s)
- Lara Barazzuol
- Department of Biomedical Sciences of Cells and SystemsUniversity Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
- Department of Radiation OncologyUniversity Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
| | - Rob P. Coppes
- Department of Biomedical Sciences of Cells and SystemsUniversity Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
- Department of Radiation OncologyUniversity Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
| | - Peter van Luijk
- Department of Biomedical Sciences of Cells and SystemsUniversity Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
- Department of Radiation OncologyUniversity Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
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10
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Serrano Martinez P, Cinat D, van Luijk P, Baanstra M, de Haan G, Pringle S, Coppes RP. Mouse parotid salivary gland organoids for the in vitro study of stem cell radiation response. Oral Dis 2020; 27:52-63. [PMID: 32531849 PMCID: PMC7818507 DOI: 10.1111/odi.13475] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 05/18/2020] [Accepted: 06/01/2020] [Indexed: 12/15/2022]
Abstract
OBJECTIVE Hyposalivation-related xerostomia is an irreversible, untreatable, and frequent condition after radiotherapy for head and neck cancer. Stem cell therapy is an attractive option of treatment, but demands knowledge of stem cell functioning. Therefore, we aimed to develop a murine parotid gland organoid model to explore radiation response of stem cells in vitro. MATERIALS AND METHODS Single cells derived from murine parotid gland organoids were passaged in Matrigel with defined medium to assess self-renewal and differentiation potential. Single cells were irradiated and plated in a 3D clonogenic stem cell survival assay to assess submandibular and parotid gland radiation response. RESULTS Single cells derived from parotid gland organoids were able to extensively self-renew and differentiate into all major tissue cell types, indicating the presence of potential stem cells. FACS selection for known salivary gland stem cell markers CD24/CD29 did not further enrich for stem cells. The parotid gland organoid-derived stem cells displayed radiation dose-response curves similar to the submandibular gland. CONCLUSIONS Murine parotid gland organoids harbor stem cells with long-term expansion and differentiation potential. This model is useful for mechanistic studies of stem cell radiation response and suggests similar radiosensitivity for the parotid and submandibular gland organoids.
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Affiliation(s)
- Paola Serrano Martinez
- Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.,Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Davide Cinat
- Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.,Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Peter van Luijk
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Mirjam Baanstra
- Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.,Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Gerald de Haan
- European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Sarah Pringle
- Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Robert P Coppes
- Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.,Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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11
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Yilmaz B, Nisli S, Ergul N, Gursu RU, Acikgoz O, Çermik TF. Effect of External Cooling on 177Lu-PSMA Uptake by the Parotid Glands. J Nucl Med 2019; 60:1388-1393. [PMID: 30850503 DOI: 10.2967/jnumed.119.226449] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 03/04/2019] [Indexed: 12/13/2022] Open
Abstract
Recent years have seen the start of treatment of metastatic castration-resistant prostate cancer with prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (PRLT), especially 177Lu-PSMA-617. However, PRLT has side effects on the salivary glands that limit the safety of the treatment. The current study aimed to show the effect of external cooling with ice packs on 177Lu-PSMA-617 uptake by the parotid glands (PGs). Methods: The study included 19 patients (mean age, 72.9 y) with metastatic castration-resistant prostate cancer who had been referred for the first time for 177Lu-PSMA-617 treatment and underwent pretreatment 68Ga-PSMA-11 PET/CT. Before the initiation of PRLT, the SUVmax and SUVmean of the right and left PGs were measured on 68Ga-PSMA PET/CT. Frozen ice packs were then affixed over the right PG of each patient for approximately 5 h; 1 h after they were affixed, PRLT was administered. At 4 h after PRLT, head-and-neck SPECT/CT was performed, and at both 4 and 24 h after PRLT, whole-body planar scintigraphy was performed. Regions and volumes of interest were applied for the right and left PGs, and the counts and volumes were determined. Results: Before PRLT, 68Ga-PSMA-11 PET/CT showed no significant difference in SUVmax or SUVmean between the right and left PGs (P > 0.05). At 4 and 24 h after PRLT, planar imaging showed no significant difference in counts between the cooled and noncooled PGs (P > 0.05). Furthermore, at 4 h after PRLT, SPECT/CT showed no significant difference in counts or volumes between the cooled and noncooled PGs (P > 0.05). Conclusion: External cooling does not reduce uptake of 177Lu-PSMA-617 by the PGs.
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Affiliation(s)
- Burcak Yilmaz
- Nuclear Medicine Department, Istanbul Research and Training Hospital, University of Health Sciences, Istanbul, Turkey
| | - Serap Nisli
- Nuclear Medicine Department, Istanbul Research and Training Hospital, University of Health Sciences, Istanbul, Turkey
| | - Nurhan Ergul
- Nuclear Medicine Department, Istanbul Research and Training Hospital, University of Health Sciences, Istanbul, Turkey
| | - Riza Umar Gursu
- Medical Oncology Department, Istanbul Research and Training Hospital, University of Health Sciences, Istanbul, Turkey; and
| | - Ozgur Acikgoz
- Medical Oncology Department, Kanuni Sultan Suleyman Research and Training Hospital, University of Health Sciences, Istanbul, Turkey
| | - Tevfik Fikret Çermik
- Nuclear Medicine Department, Istanbul Research and Training Hospital, University of Health Sciences, Istanbul, Turkey
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12
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Ma SJ, Rivers CI, Serra LM, Singh AK. Long-term outcomes of interventions for radiation-induced xerostomia: A review. World J Clin Oncol 2019; 10:1-13. [PMID: 30627521 PMCID: PMC6318483 DOI: 10.5306/wjco.v10.i1.1] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Revised: 12/07/2018] [Accepted: 12/17/2018] [Indexed: 02/06/2023] Open
Abstract
Xerostomia, or dry mouth, is a significant problem affecting quality of life in patients treated with radiation therapy for head and neck cancer. Strategies for reduction of xerostomia burden vary widely, with options including: sialagogue medications, saliva substitutes, acupuncture, vitamins, hyperbaric oxygen, submandibular gland transfer, and acupuncture or associated treatments. In this review, we sought to evaluate long-term outcomes of patients treated with various interventions for radiation-induced xerostomia. A literature search was performed using the terms "xerostomia" and "radiation" or "radiotherapy"; all prospective clinical trials were evaluated, and only studies that reported 1 year follow up were included. The search results yielded 2193 studies, 1977 of which were in English. Of those, 304 were clinical trials or clinical studies. After abstract review, 23 trials were included in the review evaluating the following treatment modalities: pilocarpine (three); cevimeline (one); amifostine (eleven); submandibular gland transfer (five); acupuncture like transcutaneous electrical nerve stimulation (ALTENS) (one); hyperbaric oxygen (one); and acupuncture (one). Pilocarpine, cevimeline, and amifostine have been shown in some studies to improve xerostomia outcomes, at the cost of toxicity. ALTENS has similar efficacy with fewer side effects. Submandibular gland transfer is effective but requires an elective surgery, and thus may not always be appropriate or practical. The use of intensity-modulated radiation therapy, in addition to dose de-escalation in select patients, may result in fewer patients with late xerostomia, reducing the need for additional interventions.
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Affiliation(s)
- Sung Jun Ma
- University at Buffalo, The State University of New York, Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY 14214, United States
- Department of Radiation Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, United States
| | - Charlotte I Rivers
- University at Buffalo, The State University of New York, Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY 14214, United States
- Department of Radiation Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, United States
| | - Lucas M Serra
- University at Buffalo, The State University of New York, Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY 14214, United States
- Department of Radiation Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, United States
| | - Anurag K Singh
- University at Buffalo, The State University of New York, Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY 14214, United States
- Department of Radiation Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, United States
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13
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Pilocarpine effect on dose rate of salivary gland in differentiated thyroid carcinoma patients treated with radioiodine. Nucl Med Commun 2018. [PMID: 29517578 DOI: 10.1097/mnm.0000000000000820] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVE Although different methods have been suggested on reducing salivary gland radiation after radioiodine administration, an effective preventive or therapeutic measure is still up for debate. The aim of this study was to evaluate the effect of pilocarpine, as a sialagogue drug on the radioiodine content of the salivary gland, and radioiodine-induced symptoms of salivary gland dysfunction. PATIENTS AND METHODS Patients who were referred for radioiodine therapy were randomized into pilocarpine and placebo groups. The patients as well as the nurse who administered the tablets, and the specialist who analyzed the images, were all unaware of the patients' group. Anterior and posterior planar images including that of both the head and neck were obtained 2, 6, 12, 24, and 48 h after the administration of radioiodine in all patients, and round regions of interest were drawn for both left and right parotid glands, with a rectangular region of interest in the region of the cerebrum as background. All patients were interrogated once, 6 months after radioiodine administration, by a phone call for subjective evaluation of symptoms related to salivary gland damage. RESULTS There was no significant difference between the two groups with regard to the mean age, sex, and initial iodine activity. The geometric mean of background-corrected count per administered dose and acquisition time was calculated for the bilateral parotid glands. This normalized parotid count showed a significant reduction in net parotid count in both groups during the first 48 h after radioiodine administration. However, no significant difference was found between the groups according to the amount and pattern of dose reduction in this time period. CONCLUSION This study revealed that pilocarpine had no significant effect on the radioiodine content of parotid glands during the first 48 h after radioiodine administration. No significant difference was found in the incidence of symptoms between the two groups treated with placebo and pilocarpine.
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Ferreira JN, Zheng C, Lombaert IM, Goldsmith CM, Cotrim AP, Symonds JM, Patel VN, Hoffman MP. Neurturin Gene Therapy Protects Parasympathetic Function to Prevent Irradiation-Induced Murine Salivary Gland Hypofunction. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2018; 9:172-180. [PMID: 29560384 PMCID: PMC5857485 DOI: 10.1016/j.omtm.2018.02.008] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Accepted: 02/15/2018] [Indexed: 11/18/2022]
Abstract
Head and neck cancer patients treated with irradiation often present irreversible salivary gland hypofunction for which no conventional treatment exists. We recently showed that recombinant neurturin, a neurotrophic factor, improves epithelial regeneration of mouse salivary glands in ex vivo culture after irradiation by reducing apoptosis of parasympathetic neurons. Parasympathetic innervation is essential to maintain progenitor cells during gland development and for regeneration of adult glands. Here, we investigated whether a neurturin-expressing adenovirus could be used for gene therapy in vivo to protect parasympathetic neurons and prevent gland hypofunction after irradiation. First, ex vivo fetal salivary gland culture was used to compare the neurturin adenovirus with recombinant neurturin, showing they both improve growth after irradiation by reducing neuronal apoptosis and increasing innervation. Then, the neurturin adenovirus was delivered to mouse salivary glands in vivo, 24 hr before irradiation, and compared with a control adenovirus. The control-treated glands have ∼50% reduction in salivary flow 60 days post-irradiation, whereas neurturin-treated glands have similar flow to nonirradiated glands. Further, markers of parasympathetic function, including vesicular acetylcholine transporter, decreased with irradiation, but not with neurturin treatment. Our findings suggest that in vivo neurturin gene therapy prior to irradiation protects parasympathetic function and prevents irradiation-induced hypofunction.
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Affiliation(s)
- Joao N.A. Ferreira
- Matrix and Morphogenesis Section, National Institute of Dental and Craniofacial Research, NIH, DHHS, Bethesda, MD 20892, USA
| | - Changyu Zheng
- Translational Research Core, National Institute of Dental and Craniofacial Research, NIH, DHHS, Bethesda, MD 20892, USA
| | - Isabelle M.A. Lombaert
- Matrix and Morphogenesis Section, National Institute of Dental and Craniofacial Research, NIH, DHHS, Bethesda, MD 20892, USA
| | - Corinne M. Goldsmith
- Translational Research Core, National Institute of Dental and Craniofacial Research, NIH, DHHS, Bethesda, MD 20892, USA
| | - Ana P. Cotrim
- Translational Research Core, National Institute of Dental and Craniofacial Research, NIH, DHHS, Bethesda, MD 20892, USA
| | - Jennifer M. Symonds
- Matrix and Morphogenesis Section, National Institute of Dental and Craniofacial Research, NIH, DHHS, Bethesda, MD 20892, USA
| | - Vaishali N. Patel
- Matrix and Morphogenesis Section, National Institute of Dental and Craniofacial Research, NIH, DHHS, Bethesda, MD 20892, USA
| | - Matthew P. Hoffman
- Matrix and Morphogenesis Section, National Institute of Dental and Craniofacial Research, NIH, DHHS, Bethesda, MD 20892, USA
- Corresponding author: Matthew P. Hoffman, Matrix and Morphogenesis Section, National Institute of Dental and Craniofacial Research, NIH, DHHS, 30 Convent Drive, Building 30/5A509, Bethesda, MD 20892, USA.
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15
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Peng X, Varendi K, Maimets M, Andressoo JO, Coppes RP. Role of glial-cell-derived neurotrophic factor in salivary gland stem cell response to irradiation. Radiother Oncol 2017; 124:448-454. [PMID: 28784438 DOI: 10.1016/j.radonc.2017.07.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Revised: 07/06/2017] [Accepted: 07/06/2017] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND PURPOSE Recently, stem cell therapy has been proposed to allow regeneration of radiation damaged salivary glands. It has been suggested that glial-cell-derived neurotrophic factor (GDNF) promotes survival of mice salivary gland stem cells (mSGSCs). The purpose of this study was to investigate the role of GDNF in the modulation of mSGSC response to irradiation and subsequent salivary gland regeneration. METHODS Salivary gland sphere derived cells of Gdnf hypermorphic (Gdnfwt/hyper) and wild type mice (Gdnfwt/wt) were irradiated (IR) with γ-rays at 0, 1, 2, 4 and 8Gy. mSGSC survival and stemness were assessed by calculating surviving fraction measured as post-IR sphere forming potential and population doublings. Flow cytometry was used to determine the CD24hi/CD29hi stem cell (SC) population. QPCR and immunofluorescence was used to detect GDNF expression. RESULTS The IR survival responses of mSGSCs were similar albeit resulted in larger spheres and an increased cell number in the Gdnfwt/hyper compared to Gdnfwt/wt group. Indeed, mSGSC of Gdnfwt/hyper mice showed high sphere forming efficiency upon replating. Interestingly, GDNF expression co-localized with receptor tyrosine kinase (RET) and was upregulated after IR in vitro and in vivo, but normalized in vivo after mSGSC transplantation. CONCLUSION GDNF does not protect mSGSCs against irradiation but seems to promote mSGSCs proliferation through the GDNF-RET signaling pathway. Post-transplantation stimulation of GDNF/RET pathway may enhance the regenerative potential of mSGSCs.
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Affiliation(s)
- Xiaohong Peng
- Departments of Cell Biology and Radiation Oncology, University Medical Centrum Groningen, University of Groningen, The Netherlands
| | - Kärt Varendi
- Institute of Biotechnology, University of Helsinki, Finland
| | - Martti Maimets
- Departments of Cell Biology and Radiation Oncology, University Medical Centrum Groningen, University of Groningen, The Netherlands; BRIC-Biotech Research and Innovation Centre, Copenhagen, Denmark
| | - Jaan-Olle Andressoo
- Institute of Biotechnology, University of Helsinki, Finland; Institute of Biosciences and Medical Technology - BioMediTech, University of Tampere, Finland
| | - Rob P Coppes
- Departments of Cell Biology and Radiation Oncology, University Medical Centrum Groningen, University of Groningen, The Netherlands.
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Riley P, Glenny A, Hua F, Worthington HV, Cochrane Oral Health Group. Pharmacological interventions for preventing dry mouth and salivary gland dysfunction following radiotherapy. Cochrane Database Syst Rev 2017; 7:CD012744. [PMID: 28759701 PMCID: PMC6483146 DOI: 10.1002/14651858.cd012744] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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.
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Affiliation(s)
- Philip Riley
- Division of Dentistry, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterCochrane Oral HealthJR Moore BuildingOxford RoadManchesterUKM13 9PL
| | - Anne‐Marie Glenny
- The University of ManchesterDivision of Dentistry, School of Medical Sciences, Faculty of Biology, Medicine and HealthJR Moore BuildingOxford RoadManchesterUKM13 9PL
| | - Fang Hua
- Division of Dentistry, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterCochrane Oral HealthJR Moore BuildingOxford RoadManchesterUKM13 9PL
| | - Helen V Worthington
- Division of Dentistry, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterCochrane Oral HealthJR Moore BuildingOxford RoadManchesterUKM13 9PL
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Yun KL, Wang ZY. Target/signalling pathways of natural plant-derived radioprotective agents from treatment to potential candidates: A reverse thought on anti-tumour drugs. Biomed Pharmacother 2017; 91:1122-1151. [DOI: 10.1016/j.biopha.2017.05.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Revised: 04/15/2017] [Accepted: 05/01/2017] [Indexed: 02/07/2023] Open
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Current Status of Targeted Radioprotection and Radiation Injury Mitigation and Treatment Agents: A Critical Review of the Literature. Int J Radiat Oncol Biol Phys 2017; 98:662-682. [PMID: 28581409 DOI: 10.1016/j.ijrobp.2017.02.211] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 02/22/2017] [Accepted: 02/23/2017] [Indexed: 01/17/2023]
Abstract
As more cancer patients survive their disease, concerns about radiation therapy-induced side effects have increased. The concept of radioprotection and radiation injury mitigation and treatment offers the possibility to enhance the therapeutic ratio of radiation therapy by limiting radiation therapy-induced normal tissue injury without compromising its antitumor effect. Advances in the understanding of the underlying mechanisms of radiation toxicity have stimulated radiation oncologists to target these pathways across different organ systems. These generalized radiation injury mechanisms include production of free radicals such as superoxides, activation of inflammatory pathways, and vascular endothelial dysfunction leading to tissue hypoxia. There is a significant body of literature evaluating the effectiveness of various treatments in preventing, mitigating, or treating radiation-induced normal tissue injury. Whereas some reviews have focused on a specific disease site or agent, this critical review focuses on a mechanistic classification of activity and assesses multiple agents across different disease sites. The classification of agents used herein further offers a useful framework to organize the multitude of treatments that have been studied. Many commonly available treatments have demonstrated benefit in prevention, mitigation, and/or treatment of radiation toxicity and warrant further investigation. These drug-based approaches to radioprotection and radiation injury mitigation and treatment represent an important method of making radiation therapy safer.
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Gonnelli FAS, Palma LF, Giordani AJ, Deboni ALS, Dias RS, Segreto RA, Segreto HRC. Low-Level Laser for Mitigation of Low Salivary Flow Rate in Head and Neck Cancer Patients Undergoing Radiochemotherapy: A Prospective Longitudinal Study. Photomed Laser Surg 2016; 34:326-30. [DOI: 10.1089/pho.2016.4104] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Fernanda Aurora Stabile Gonnelli
- Division of Radiotherapy, Department of Imaging Diagnosis, Universidade Federal de São Paulo/Escola Paulista de Medicina/Hospital São Paulo – UNIFESP/EPM/HSP, São Paulo/SP, Brazil
| | - Luiz Felipe Palma
- Division of Radiotherapy, Department of Imaging Diagnosis, Universidade Federal de São Paulo/Escola Paulista de Medicina/Hospital São Paulo – UNIFESP/EPM/HSP, São Paulo/SP, Brazil
| | - Adelmo José Giordani
- Division of Radiotherapy, Department of Imaging Diagnosis, Universidade Federal de São Paulo/Escola Paulista de Medicina/Hospital São Paulo – UNIFESP/EPM/HSP, São Paulo/SP, Brazil
| | - Aline Lima Silva Deboni
- Division of Radiotherapy, Department of Imaging Diagnosis, Universidade Federal de São Paulo/Escola Paulista de Medicina/Hospital São Paulo – UNIFESP/EPM/HSP, São Paulo/SP, Brazil
| | - Rodrigo Souza Dias
- Division of Radiotherapy, Department of Imaging Diagnosis, Universidade Federal de São Paulo/Escola Paulista de Medicina/Hospital São Paulo – UNIFESP/EPM/HSP, São Paulo/SP, Brazil
| | - Roberto Araújo Segreto
- Division of Radiotherapy, Department of Imaging Diagnosis, Universidade Federal de São Paulo/Escola Paulista de Medicina/Hospital São Paulo – UNIFESP/EPM/HSP, São Paulo/SP, Brazil
| | - Helena Regina Comodo Segreto
- Division of Radiotherapy, Department of Imaging Diagnosis, Universidade Federal de São Paulo/Escola Paulista de Medicina/Hospital São Paulo – UNIFESP/EPM/HSP, São Paulo/SP, Brazil
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Nejaim Y, I V Silva A, V Vasconcelos T, J N L Silva E, M de Almeida S. Evaluation of radioprotective effect of aloe vera and zinc/copper compounds against salivary dysfunction in irradiated rats. J Oral Sci 2016; 56:191-4. [PMID: 25231144 DOI: 10.2334/josnusd.56.191] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
The aim of this study was to evaluate the radioprotective and reparative effects of compounds based on aloe vera, zinc, and copper against salivary gland dysfunction in Wistar rats. A total of 150 Wistar rats were randomly divided into 12 groups, in which the animals received aloe vera and/or zinc and copper. In eight of these groups the animals were also subjected to irradiation before or after administration of the substances. After 27 days, sialometry tests were performed. Data were analyzed using ANOVA and the Tukey test (P < 0.05). Rats that had been administered aloe vera before or after irradiation showed a significantly higher salivary flow rate than rats that had been simply irradiated. When both substances were administered, a statistically significant difference in the salivary flow rate was observed in comparison with the irradiation alone group seven days after irradiation. The present results suggest that aloe vera exerts positive protective and reparative effects, and can be considered a potential radioprotective substance.
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Affiliation(s)
- Yuri Nejaim
- Department of Oral Diagnosis, Piracicaba Dental School, State University of Campinas
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Lombaert I, Movahednia MM, Adine C, Ferreira JN. Concise Review: Salivary Gland Regeneration: Therapeutic Approaches from Stem Cells to Tissue Organoids. Stem Cells 2016; 35:97-105. [PMID: 27406006 PMCID: PMC6310135 DOI: 10.1002/stem.2455] [Citation(s) in RCA: 96] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Revised: 05/31/2016] [Accepted: 06/18/2016] [Indexed: 12/21/2022]
Abstract
The human salivary gland (SG) has an elegant architecture of epithelial acini, connecting ductal branching structures, vascular and neuronal networks that together function to produce and secrete saliva. This review focuses on the translation of cell- and tissue-based research toward therapies for patients suffering from SG hypofunction and related dry mouth syndrome (xerostomia), as a consequence of radiation therapy or systemic disease. We will broadly review the recent literature and discuss the clinical prospects of stem/progenitor cell and tissue-based therapies for SG repair and/or regeneration. Thus far, several strategies have been proposed for the purpose of restoring SG function: (1) transplanting autologous SG-derived epithelial stem/progenitor cells; (2) exploiting nonepithelial cells and/or their bioactive lysates; and (3) tissue engineering approaches using 3D (three-dimensional) biomaterials loaded with SG cells and/or bioactive cues to mimic in vivo SGs. We predict that further scientific improvement in each of these areas will translate to effective therapies toward the repair of damaged glands and the development of miniature SG organoids for the fundamental restoration of saliva secretion.
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Affiliation(s)
- Isabelle Lombaert
- Department of Biologic & Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, Michigan, USA.,Biointerfaces Institute, North Campus Research Complex, University of Michigan, Ann Arbor, Michigan, USA
| | - Mohammad M Movahednia
- Department of Oral & Maxillofacial Surgery, Faculty of Dentistry, National University of Singapore, 119083, Singapore
| | - Christabella Adine
- Department of Oral & Maxillofacial Surgery, Faculty of Dentistry, National University of Singapore, Singapore
| | - Joao N Ferreira
- Department of Oral & Maxillofacial Surgery, Faculty of Dentistry, National University of Singapore, Singapore
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Gupta N, Pal M, Rawat S, Grewal MS, Garg H, Chauhan D, Ahlawat P, Tandon S, Khurana R, Pahuja AK, Mayank M, Devnani B. Radiation-induced dental caries, prevention and treatment - A systematic review. Natl J Maxillofac Surg 2016; 6:160-6. [PMID: 27390489 PMCID: PMC4922225 DOI: 10.4103/0975-5950.183870] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Treatment of head and neck cancers (HNCs) involves radiotherapy. Patients undergoing radiotherapy for HNCs are prone to dental complications. Radiotherapy to the head and neck region causes xerostomia and salivary gland dysfunction which dramatically increases the risk of dental caries and its sequelae. Radiation therapy (RT) also affects the dental hard tissues increasing their susceptibility to demineralization following RT. Postradiation caries is a rapidly progressing and highly destructive type of dental caries. Radiation-related caries and other dental hard tissue changes can appear within the first 3 months following RT. Hence, every effort should be focused on prevention to manage patients with severe caries. This can be accomplished through good preoperative dental treatment, frequent dental evaluation and treatment after RT (with the exception of extractions), and consistent home care that includes self-applied fluoride. Restorative management of radiation caries can be challenging. The restorative dentist must consider the altered dental substrate and a hostile oral environment when selecting restorative materials. Radiation-induced changes in enamel and dentine may compromise bonding of adhesive materials. Consequently, glass ionomer cements have proved to be a better alternative to composite resins in irradiated patients. Counseling of patients before and after radiotherapy can be done to make them aware of the complications of radiotherapy and thus can help in preventing them.
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Affiliation(s)
- Nishtha Gupta
- Department of Conservative Dentistry and Endodontics, PDM Dental College and Research Institute, Bahadurgarh, Haryana, India
| | - Manoj Pal
- Department of Radiation Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
| | - Sheh Rawat
- Department of Radiation Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
| | - Mandeep S Grewal
- Department of Conservative Dentistry and Endodontics, PDM Dental College and Research Institute, Bahadurgarh, Haryana, India
| | - Himani Garg
- Department of Conservative Dentistry and Endodontics, PDM Dental College and Research Institute, Bahadurgarh, Haryana, India
| | - Deepika Chauhan
- Department of Radiation Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
| | - Parveen Ahlawat
- Department of Radiation Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
| | - Sarthak Tandon
- Department of Radiation Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
| | - Ruparna Khurana
- Department of Radiation Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
| | - Anjali K Pahuja
- Department of Radiation Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
| | - Mayur Mayank
- Department of Radiation Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India
| | - Bharti Devnani
- Department of Radiation Oncology, SGPGI, Lucknow, Uttar Pradesh, India
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Clinical Studies of Nonpharmacological Methods to Minimize Salivary Gland Damage after Radioiodine Therapy of Differentiated Thyroid Carcinoma: Systematic Review. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2016; 2016:6795076. [PMID: 27446226 PMCID: PMC4944032 DOI: 10.1155/2016/6795076] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 05/23/2016] [Accepted: 06/05/2016] [Indexed: 11/24/2022]
Abstract
Purpose. To systematically review clinical studies examining the effectiveness of nonpharmacological methods to prevent/minimize salivary gland damage due to radioiodine treatment of differentiated thyroid carcinoma (DTC). Methods. Reports on relevant trials were identified by searching the PubMed, CINHAL, Cochrane, and Scopus electronic databases covering the period 01/2000–10/2015. Inclusion/exclusion criteria were prespecified. Search yielded eight studies that were reviewed by four of the present authors. Results. Nonpharmacological methods used in trials may reduce salivary gland damage induced by radioiodine. Sialogogues such as lemon candy, vitamin E, lemon juice, and lemon slice reduced such damage significantly (p < 0.0001, p < 0.05, p < 0.10, and p < 0.05, resp.). Parotid gland massage also reduced the salivary damage significantly (p < 0.001). Additionally, vitamin C had some limited effect (p = 0.37), whereas no effect was present in the case of chewing gum (p = 0.99). Conclusion. The review showed that, among nonpharmacological interventions, sialogogues and parotid gland massage had the greatest impact on reducing salivary damage induced by radioiodine therapy of DTC. However, the studies retrieved were limited in number, sample size, strength of evidence, and generalizability. More randomized controlled trials of these methods with multicenter scope and larger sample sizes will provide more systematic and reliable results allowing more definitive conclusions.
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van Luijk P, Pringle S, Deasy JO, Moiseenko VV, Faber H, Hovan A, Baanstra M, van der Laan HP, Kierkels RGJ, van der Schaaf A, Witjes MJ, Schippers JM, Brandenburg S, Langendijk JA, Wu J, Coppes RP. Sparing the region of the salivary gland containing stem cells preserves saliva production after radiotherapy for head and neck cancer. Sci Transl Med 2016; 7:305ra147. [PMID: 26378247 DOI: 10.1126/scitranslmed.aac4441] [Citation(s) in RCA: 162] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Each year, 500,000 patients are treated with radiotherapy for head and neck cancer, resulting in relatively high survival rates. However, in 40% of patients, quality of life is severely compromised because of radiation-induced impairment of salivary gland function and consequent xerostomia (dry mouth). New radiation treatment technologies enable sparing of parts of the salivary glands. We have determined the parts of the major salivary gland, the parotid gland, that need to be spared to ensure that the gland continues to produce saliva after irradiation treatment. In mice, rats, and humans, we showed that stem and progenitor cells reside in the region of the parotid gland containing the major ducts. We demonstrated in rats that inclusion of the ducts in the radiation field led to loss of regenerative capacity, resulting in long-term gland dysfunction with reduced saliva production. Then we showed in a cohort of patients with head and neck cancer that the radiation dose to the region of the salivary gland containing the stem/progenitor cells predicted the function of the salivary glands one year after radiotherapy. Finally, we showed that this region of the salivary gland could be spared during radiotherapy, thus reducing the risk of post-radiotherapy xerostomia.
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Affiliation(s)
- Peter van Luijk
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, Netherlands.
| | - Sarah Pringle
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, Netherlands. Department of Cell Biology, University Medical Center Groningen, University of Groningen, 9713AV Groningen, Netherlands
| | - Joseph O Deasy
- Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Vitali V Moiseenko
- Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA 92093, USA
| | - Hette Faber
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, Netherlands. Department of Cell Biology, University Medical Center Groningen, University of Groningen, 9713AV Groningen, Netherlands
| | - Allan Hovan
- British Columbia Cancer Agency-Vancouver Centre, Vancouver, British Columbia V5Z 4E6, Canada
| | - Mirjam Baanstra
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, Netherlands. Department of Cell Biology, University Medical Center Groningen, University of Groningen, 9713AV Groningen, Netherlands
| | - Hans P van der Laan
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, Netherlands
| | - Roel G J Kierkels
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, Netherlands
| | - Arjen van der Schaaf
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, Netherlands
| | - Max J Witjes
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, Netherlands
| | - Jacobus M Schippers
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, Netherlands. Accelerator Department, Paul Scherrer Institut, CH-5212 Villigen, Switzerland
| | - Sytze Brandenburg
- KVI Center for Advanced Radiation Technology, University of Groningen, 9747 AA Groningen, Netherlands
| | - Johannes A Langendijk
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, Netherlands
| | - Jonn Wu
- British Columbia Cancer Agency-Vancouver Centre, Vancouver, British Columbia V5Z 4E6, Canada
| | - Robert P Coppes
- Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, Netherlands. Department of Cell Biology, University Medical Center Groningen, University of Groningen, 9713AV Groningen, Netherlands.
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Gil-Montoya JA, Silvestre FJ, Barrios R, Silvestre-Rangil J. Treatment of xerostomia and hyposalivation in the elderly: A systematic review. Med Oral Patol Oral Cir Bucal 2016; 21:e355-66. [PMID: 27031061 PMCID: PMC4867210 DOI: 10.4317/medoral.20969] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Accepted: 01/28/2016] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Therapeutic strategies for xerostomia, regardless of etiology, have so far not had definitive or clearly effective results. OBJECTIVES To systematically revise the latest scientific evidence available regarding the treatment of dry mouth, regardless of the cause of the problem. MATERIAL AND METHODS The literature search was conducted in March 2015, using the Medline and Embase databases. The "Clinical Trial", from 2006 to March 2015, was carried out in English and only on human cases. The draft of the systematic review and assessment of the methodological quality of the trials was carried out following the criteria of PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and the "Oxford Quality Scale". RESULTS Finally, a total of 26 trials were identified that met the previously defined selection and quality criteria; 14 related to drug treatments for dry mouth, 10 with non-pharmacological treatment and 2 with alternative treatments. CONCLUSIONS Pilocarpine continues to be the best performing sialogogue drug for subjects with xerostomia due to radiation on head and neck cancer or diseases such as Sjogren's Syndrome. For patients with dry mouth caused solely by medication, there are some positive indications from the use of malic acid, along with other elements that counteract the harmful effect on dental enamel. In general, lubrication of oral mucous membrane reduces the symptoms, although the effects are short-lived.
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Affiliation(s)
- J-A Gil-Montoya
- Facultad de Odontología, C/ Campus de Cartuja s/n 18071, Granada, Spain,
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Prestifilippo JP, Fernández-Solari J, Martinel Lamas DJ, Rios CE, Mohn C, Perazzo JC, Rivera ES, Elverdin JC, Medina VA. Pharmacological targeting of histamine H4receptor in periodontal disease. Oral Dis 2016; 22:423-9. [DOI: 10.1111/odi.12467] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Revised: 01/08/2016] [Accepted: 02/10/2016] [Indexed: 12/29/2022]
Affiliation(s)
- JP Prestifilippo
- Physiology Department; School of Dentistry; University of Buenos Aires; Buenos Aires Argentina
| | - J Fernández-Solari
- Physiology Department; School of Dentistry; University of Buenos Aires; Buenos Aires Argentina
- National Scientific and Technical Research Council (CONICET); Buenos Aires Argentina
| | - DJ Martinel Lamas
- Laboratory of Radioisotopes; School of Pharmacy and Biochemistry; University of Buenos Aires; Buenos Aires Argentina
- Laboratory of Cellular and Molecular Biology; Institute for Biomedical Research (BIOMED); School of Medical Sciences; CONICET; Pontifical Catholic University of Argentina (UCA); Buenos Aires Argentina
| | - CE Rios
- Physiology Department; School of Dentistry; University of Buenos Aires; Buenos Aires Argentina
| | - C Mohn
- Physiology Department; School of Dentistry; University of Buenos Aires; Buenos Aires Argentina
- National Scientific and Technical Research Council (CONICET); Buenos Aires Argentina
| | - JC Perazzo
- Pathophysiology; School of Pharmacy and Biochemistry; University of Buenos Aires; Buenos Aires Argentina
| | - ES Rivera
- Laboratory of Radioisotopes; School of Pharmacy and Biochemistry; University of Buenos Aires; Buenos Aires Argentina
| | - JC Elverdin
- Physiology Department; School of Dentistry; University of Buenos Aires; Buenos Aires Argentina
| | - VA Medina
- Laboratory of Radioisotopes; School of Pharmacy and Biochemistry; University of Buenos Aires; Buenos Aires Argentina
- Laboratory of Cellular and Molecular Biology; Institute for Biomedical Research (BIOMED); School of Medical Sciences; CONICET; Pontifical Catholic University of Argentina (UCA); Buenos Aires Argentina
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Xerostomia: current streams of investigation. Oral Surg Oral Med Oral Pathol Oral Radiol 2016; 122:53-60. [PMID: 27189896 DOI: 10.1016/j.oooo.2016.03.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Revised: 01/13/2016] [Accepted: 03/04/2016] [Indexed: 12/12/2022]
Abstract
Xerostomia is the subjective feeling of dry mouth, and it is often related to salivary hypofunction. Besides medication-related salivary hypofunction, Sjögren syndrome and head-and-neck radiation are two common etiologies that have garnered considerable attention. Approaches to treating and/or preventing salivary hypofunction in patients with these conditions will likely incorporate gene therapy, stem cell therapy, and tissue engineering. Advances in these disciplines are central to current research in the cure for xerostomia and will be key to eventual treatment.
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Baum BJ. Radiation-induced salivary hypofunction may become a thing of the past. Oral Dis 2016; 22:81-4. [DOI: 10.1111/odi.12388] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Zeidan YH, Xiao N, Cao H, Kong C, Le QT, Sirjani D. Botulinum Toxin Confers Radioprotection in Murine Salivary Glands. Int J Radiat Oncol Biol Phys 2015; 94:1190-7. [PMID: 26907915 DOI: 10.1016/j.ijrobp.2015.12.371] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Revised: 12/19/2015] [Accepted: 12/22/2015] [Indexed: 11/17/2022]
Abstract
PURPOSE Xerostomia is a common radiation sequela, which has a negative impact on the quality of life of patients with head and neck cancer. Current treatment strategies offer only partial relief. Botulinum toxins (BTX) have been successfully used in treating a variety of radiation sequelae such as cystitis, proctitis, fibrosis, and facial pain. The purpose of this study was to evaluate the effect of BTX on radiation-induced salivary gland damage. METHODS AND MATERIALS We used a previously established model for murine salivary gland irradiation (IR). The submandibular glands (SMGs) of C5BL/6 mice (n=6/group) were injected with saline or BTX 72 hours before receiving 15 Gy of focal irradiation. Saliva flow was measured 3, 7, and 28 days after treatment. The SMGs were collected for immunohistochemistry, confocal microscopy, and Western blotting. A cytokine array consisting of 40 different mouse cytokines was used to evaluate cytokine profiles after radiation treatment. RESULTS Irradiated mice showed a 50% reduction in saliva flow after 3 days, whereas mice preinjected with BTX had 25% reduction in saliva flow (P<.05). Cell death detected by TUNEL staining was similar in SMG sections of both groups. However, neutrophil infiltrate, detected by myeloperoxidase staining, was 3-fold lower for the BTX treated mice. A cytokine array showed a 2-fold upregulation of LPS-induced chemokine (LIX/CXCL5) 3 days after IR. BTX pretreatment reduced LIX levels by 40%. At 4 weeks after IR, the saline (control) group showed a 40% reduction in basal SMG weight, compared with 20% in the BTX group. Histologically, BTX-pretreated glands showed relative preservation of acinar structures after radiation. CONCLUSIONS These data suggest that BTX pretreatment ameliorates radiation-induced saliva dysfunction. Moreover, we demonstrate a novel role for CXCL5 in the acute phase of salivary gland damage after radiation. These results carry important clinical implications for the treatment of xerostomia in patients with head and neck cancer.
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Affiliation(s)
- Youssef H Zeidan
- Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida.
| | - Nan Xiao
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California
| | - Hongbin Cao
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California
| | - Christina Kong
- Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, California; Department of Pathology, Stanford University School of Medicine, Stanford, California
| | - Quynh-Thu Le
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California
| | - Davud Sirjani
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California
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Is Pilocarpine Effective in Preventing Radiation-Induced Xerostomia? A Systematic Review and Meta-analysis. Int J Radiat Oncol Biol Phys 2015; 94:503-11. [PMID: 26867879 DOI: 10.1016/j.ijrobp.2015.11.012] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Revised: 09/29/2015] [Accepted: 11/04/2015] [Indexed: 01/03/2023]
Abstract
PURPOSE To evaluate the efficacy of concomitant administration of pilocarpine on radiation-induced xerostomia in patients with head and neck cancers. METHODS AND MATERIALS The PubMed, Web of Science, Cochrane Library, and ClinicalTrials were searched to identify randomized, controlled trials studying the effect of concomitant administration of pilocarpine for radiation-induced xerostomia. Included trials were systematically reviewed, and quantifiable outcomes were pooled for meta-analysis. Outcomes of interest included salivary flow, clinician-rated xerostomia grade, patient-reported xerostomia scoring, quality of life, and adverse effects. RESULTS Six prospective, randomized, controlled trials in 8 articles were included in this systematic review. The total number of patients was 369 in the pilocarpine group and 367 in the control group. Concomitant administration of pilocarpine during radiation could increase the unstimulated salivary flow rate in a period of 3 to 6 months after treatment, and also reduce the clinician-rated xerostomia grade. Patient-reported xerostomia was not significantly impacted by pilocarpine in the initial 3 months but was superior at 6 months. No significant difference of stimulated salivary flow rate could be confirmed between the 2 arms. Adverse effects of pilocarpine were mild and tolerable. CONCLUSIONS The concomitant administration of pilocarpine during radiation increases unstimulated salivary flow rate and reduces clinician-rated xerostomia grade after radiation. It also relieves patients' xerostomia at 6 months and possibly at 12 months. However, pilocarpine has no effect on stimulated salivary flow rate.
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Cheng CQ, Xu H, Liu L, Wang RN, Liu YT, Li J, Zhou XK. 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 2015; 147:236-43. [PMID: 26563850 DOI: 10.1016/j.adaj.2015.09.014] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Revised: 09/16/2015] [Accepted: 09/17/2015] [Indexed: 01/23/2023]
Abstract
BACKGROUND Pilocarpine has been used widely in the treatment of dry mouth and glaucoma. In this review, the authors assessed the efficacy and safety of pilocarpine for patients with head and neck cancer who have radiation-induced xerostomia. TYPES OF STUDIES REVIEWED The authors conducted a systematic search including meta-analyses and randomized controlled trials in the following databases: MEDLINE, Embase, Cochrane Library, and Science Citation Index Expanded. The primary outcome was the severity of xerostomia (measured using visual analog scale [VAS] scores). Adverse events were other outcomes of interest. The authors performed meta-analyses where appropriate. The authors used the Cochrane Collaboration's tool for assessing risk of bias to assess the quality of the study. RESULTS The authors identified 6 studies (including 752 patients in total). The results of a meta-analysis of 3 articles showed that pilocarpine was associated with a 12-point increase in VAS score (mean difference, 12.00; 95% confidence interval [CI], 1.93-22.08; P = .02) and higher rates of adverse events compared with placebo in terms of sweating (odds ratio [OR], 3.71; 95% CI, 2.34-5.86; P < .00001). There were no differences in rhinitis (OR, 1.21; 95% CI, 0.68-2.16; P = .52) and nausea (OR, 1.44; 95% CI, 0.83-2.49; P = .19). CONCLUSIONS AND PRACTICAL IMPLICATIONS On the basis of the best available evidence, the results of this meta-analysis provide evidence that pilocarpine offers statistically significant clinical benefits for the symptomatic treatment of radiation-induced xerostomia in patients with head and neck cancer. However, the authors of this systematic review found the best available evidence in the meta-analysis in 3 studies, 1 of which showed no effect. The authors of this systematic review suggest that these patients take 5 milligrams of pilocarpine 3 times daily, and that there is need for further study.
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Wu F, Weng S, Li C, Sun J, Li L, Gao Q. Submandibular Gland Transfer for the Prevention of Postradiation Xerostomia in Patients with Head and Neck Cancer: A Systematic Review and Meta-Analysis. ORL J Otorhinolaryngol Relat Spec 2015; 77:70-86. [DOI: 10.1159/000371854] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
<b><i>Background:</i></b> Submandibular gland transfer has been widely used to prevent postradiation xerostomia in head-and-neck cancers. However, there are still some controversies. <b><i>Methods:</i></b> Six databases were searched, data extraction was performed and the risk of bias was assessed by 2 reviewers independently. The meta-analysis was performed using Review Manager, version 5.2. <b><i>Results:</i></b> A total of 7 trials (12 articles) and 369 participants were included. <b><i>Conclusions:</i></b> The present clinical evidence suggests that submandibular gland transfer might be highly effective to prevent postradiation xerostomia in head-and-neck cancers without serious adverse events. However, more randomized controlled trials are still needed to confirm this conclusion.
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De Felice F, Musio D, Terenzi V, Valentini V, Cassoni A, Tombolini M, De Vincentiis M, Tombolini V. Treatment improvement and better patient care: which is the most important one in oral cavity cancer? Radiat Oncol 2014; 9:263. [PMID: 25479896 PMCID: PMC4263000 DOI: 10.1186/s13014-014-0263-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2014] [Accepted: 11/15/2014] [Indexed: 11/10/2022] Open
Abstract
Due to substantial improvement in diagnosis and treatment of oral cavity cancer, a better understanding of the patient care needs to be revised. We reviewed literature related to OCC and discussed current general management approaches and related long-term radiation toxicities to emphasize the multidisciplinary team involvement. New technical modalities and patient quality of life parameters should be an integral and paramount state in the clinical evaluation to significantly contribute to reduce secondary side effects.
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Affiliation(s)
- Francesca De Felice
- Department of Radiotherapy, Policlinico Umberto I "Sapienza", University of Rome, Viale Regina Elena 326, 00161, Rome, Italy.
| | - Daniela Musio
- Department of Radiotherapy, Policlinico Umberto I "Sapienza", University of Rome, Viale Regina Elena 326, 00161, Rome, Italy.
| | - Valentina Terenzi
- Department of Maxillofacial Surgery, Policlinico Umberto I "Sapienza", University of Rome, Viale Regina Elena 326, 00161, Rome, Italy.
| | - Valentino Valentini
- Department of Maxillofacial Surgery, Policlinico Umberto I "Sapienza", University of Rome, Viale Regina Elena 326, 00161, Rome, Italy.
| | - Andrea Cassoni
- Department of Maxillofacial Surgery, Policlinico Umberto I "Sapienza", University of Rome, Viale Regina Elena 326, 00161, Rome, Italy.
| | - Mario Tombolini
- Department Organs of Sense, Policlinico Umberto I "Sapienza", University of Rome, Viale Regina Elena 326, 00161, Rome, Italy.
| | - Marco De Vincentiis
- Department Organs of Sense, Policlinico Umberto I "Sapienza", University of Rome, Viale Regina Elena 326, 00161, Rome, Italy.
| | - Vincenzo Tombolini
- Department of Radiotherapy, Policlinico Umberto I "Sapienza", University of Rome, Viale Regina Elena 326, 00161, Rome, Italy. .,Spencer-Lorillard Foundation, Viale Regina Elena 262, 00161, Rome, Italy.
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Benderitter M, Caviggioli F, Chapel A, Coppes RP, Guha C, Klinger M, Malard O, Stewart F, Tamarat R, van Luijk P, Limoli CL. Stem cell therapies for the treatment of radiation-induced normal tissue side effects. Antioxid Redox Signal 2014; 21:338-55. [PMID: 24147585 PMCID: PMC4060814 DOI: 10.1089/ars.2013.5652] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
SIGNIFICANCE Targeted irradiation is an effective cancer therapy but damage inflicted to normal tissues surrounding the tumor may cause severe complications. While certain pharmacologic strategies can temper the adverse effects of irradiation, stem cell therapies provide unique opportunities for restoring functionality to the irradiated tissue bed. RECENT ADVANCES Preclinical studies presented in this review provide encouraging proof of concept regarding the therapeutic potential of stem cells for treating the adverse side effects associated with radiotherapy in different organs. Early-stage clinical data for radiation-induced lung, bone, and skin complications are promising and highlight the importance of selecting the appropriate stem cell type to stimulate tissue regeneration. CRITICAL ISSUES While therapeutic efficacy has been demonstrated in a variety of animal models and human trials, a range of additional concerns regarding stem cell transplantation for ameliorating radiation-induced normal tissue sequelae remain. Safety issues regarding teratoma formation, disease progression, and genomic stability along with technical issues impacting disease targeting, immunorejection, and clinical scale-up are factors bearing on the eventual translation of stem cell therapies into routine clinical practice. FUTURE DIRECTIONS Follow-up studies will need to identify the best possible stem cell types for the treatment of early and late radiation-induced normal tissue injury. Additional work should seek to optimize cellular dosing regimes, identify the best routes of administration, elucidate optimal transplantation windows for introducing cells into more receptive host tissues, and improve immune tolerance for longer-term engrafted cell survival into the irradiated microenvironment.
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Affiliation(s)
- Marc Benderitter
- 1 Laboratory of Radiopathology and Experimental Therapies, IRSN , PRP-HOM, SRBE, Fontenay-aux-Roses, France
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Vissink A, Luijk P, Langendijk JA, Coppes RP. Current ideas to reduce or salvage radiation damage to salivary glands. Oral Dis 2014; 21:e1-10. [DOI: 10.1111/odi.12222] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Revised: 12/23/2013] [Accepted: 12/23/2013] [Indexed: 12/14/2022]
Affiliation(s)
- A Vissink
- Department of Oral and Maxillofacial Surgery University of Groningen University Medical Center Groningen Groningen The Netherlands
| | - P Luijk
- Department of Oral and Maxillofacial Surgery University of Groningen University Medical Center Groningen Groningen The Netherlands
| | - JA Langendijk
- Department of Radiation Oncology University of Groningen University Medical Center Groningen Groningen The Netherlands
| | - RP Coppes
- Department of Radiation Oncology University of Groningen University Medical Center Groningen Groningen The Netherlands
- Department of Cell Biology Section of Radiation and Stress Biology University of Groningen University Medical Center Groningen Groningen The Netherlands
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Late Toxicities after Conventional Radiotherapy for Nasopharyngeal Carcinoma: Incidence and Risk Factors. ACTA ACUST UNITED AC 2014. [DOI: 10.1155/2014/268340] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Background. To determine the incidence and analyze the factors affecting late toxicity for nasopharyngeal carcinoma patients treated with conventional radiotherapy. Patients and Methods. Retrospective analysis was performed on 239 NPC patients treated between 1993 and 2004 in our institution. One hundred and fifty-seven patients were treated with conventional fractionation (2 Gy per fraction, 5 fractions per week) and eighty-two patients with hyperfractionated radiotherapy (1.6 Gy per fraction twice a day, 5 days per week). One hundred fifty nine patients underwent neoadjuvant cisplatin based chemotherapy. Late toxicity was evaluated according to the RTOG/EORTC score. Results. Xerostomia was the most common related complication (98.7%). Neoadjuvant chemotherapy and hyperfractionated radiotherapy did not increase late toxicities. Multivariate analyses showed that radiation dose was a significant factor for hearing impairment, younger age for trismus, initial node status for neck fibrosis, and initial dental hygiene for dental complications. Female gender was associated with significantly higher incidence of trismus and hearing impairment. Conclusion. Conventional radiotherapy was associated with a high rate of late toxicities which affect patients’ quality of life. With the development of three-dimensional conformal radiotherapy and intensity modulated radiotherapy, a reduced incidence of radiation related complications could be expected.
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Sood AJ, Fox NF, O’Connell BP, Lovelace TL, Nguyen SA, Sharma AK, Hornig JD, Day TA. Salivary gland transfer to prevent radiation-induced xerostomia: A systematic review and meta-analysis. Oral Oncol 2014; 50:77-83. [DOI: 10.1016/j.oraloncology.2013.10.010] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2013] [Revised: 10/08/2013] [Accepted: 10/10/2013] [Indexed: 12/14/2022]
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Kałużny J, Wierzbicka M, Nogala H, Milecki P, Kopeć T. Radiotherapy induced xerostomia: Mechanisms, diagnostics, prevention and treatment – Evidence based up to 2013. Otolaryngol Pol 2014; 68:1-14. [DOI: 10.1016/j.otpol.2013.09.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2013] [Accepted: 09/12/2013] [Indexed: 11/28/2022]
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Sasportas LS, Hosford DN, Sodini MA, Waters DJ, Zambricki EA, Barral JK, Graves EE, Brinton TJ, Yock PG, Le QT, Sirjani D. Cost-effectiveness landscape analysis of treatments addressing xerostomia in patients receiving head and neck radiation therapy. Oral Surg Oral Med Oral Pathol Oral Radiol 2013; 116:e37-51. [PMID: 23643579 PMCID: PMC4018820 DOI: 10.1016/j.oooo.2013.02.017] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2012] [Revised: 11/30/2012] [Accepted: 02/20/2013] [Indexed: 12/11/2022]
Abstract
Head and neck (H&N) radiation therapy (RT) can induce irreversible damage to the salivary glands thereby causing long-term xerostomia or dry mouth in 68%-85% of the patients. Not only does xerostomia significantly impair patients' quality-of-life (QOL) but it also has important medical sequelae, incurring high medical and dental costs. In this article, we review various measures to assess xerostomia and evaluate current and emerging solutions to address this condition in H&N cancer patients. These solutions typically seek to accomplish 1 of the 4 objectives: (1) to protect the salivary glands during RT, (2) to stimulate the remaining gland function, (3) to treat the symptoms of xerostomia, or (4) to regenerate the salivary glands. For each treatment, we assess its mechanisms of action, efficacy, safety, clinical utilization, and cost. We conclude that intensity-modulated radiation therapy is both the most widely used prevention approach and the most cost-effective existing solution and we highlight novel and promising techniques on the cost-effectiveness landscape.
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Affiliation(s)
- Laura S Sasportas
- Department of Bioengineering, Biodesign Innovation Program, Stanford University, Stanford, CA 94305, USA.
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Dijkema T, Raaijmakers CPJ, Braam PM, Roesink JM, Monninkhof EM, Terhaard CHJ. Xerostomia: a day and night difference. Radiother Oncol 2012; 104:219-23. [PMID: 22809589 DOI: 10.1016/j.radonc.2012.06.004] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2011] [Revised: 05/18/2012] [Accepted: 06/07/2012] [Indexed: 10/28/2022]
Abstract
PURPOSE To compare patient-reported xerostomia during daytime and during nighttime with objectively measured parotid and submandibular gland function in a cohort of head-and-neck cancer (HNC) patients treated with RT. MATERIALS AND METHODS A cohort of 138 HNC patients underwent objective measurements of parotid (PF) and submandibular (SMF) gland function and completed a xerostomia questionnaire (XQ) before RT, at 6 weeks, 6 months and 1 year after RT. No attempt was made to spare the submandibular gland(s). The XQ contained specific questions concerning the sensation of dry mouth during day- (XD) and nighttime (XN), scored on a 5-point Likert scale. Patients with no or mild (grade 1-3) xerostomia and patients with more severe (grade 4-5) complaints were grouped together. RESULTS Before RT, no association existed between dry mouth complaints and PF or SMF. At 6 weeks, 6 months and 1 year after RT; 37%, 51% and 36% had grade 4-5 XD and 65%, 64% and 56% had grade 4-5 XN, respectively. Patients with grade 4-5 XD and XN had significantly worse SMF at all time points after RT compared to patients with grade 1-3 XD and XN, while PF was significantly worse only at 6 weeks after RT. In multivariate analyses, SMF was consistently the most important factor related to XN after treatment. PF significantly influenced XD at 6 weeks and 1 year after RT. CONCLUSIONS Differentiating between complaints during day- and nighttime in xerostomia research is necessary. Dry mouth at night is a frequent problem after (parotid-sparing) RT for HNC and is explained by submandibular gland dysfunction. Sparing of the contralateral submandibular gland, in addition to parotid gland sparing, may result in improved patient-reported xerostomia.
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Affiliation(s)
- Tim Dijkema
- Department of Radiotherapy, University Medical Center Utrecht, The Netherlands.
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Radioprotective Effect of Lidocaine on Function and Ultrastructure of Salivary Glands Receiving Fractionated Radiation. Int J Radiat Oncol Biol Phys 2012; 82:e623-30. [DOI: 10.1016/j.ijrobp.2011.09.017] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2011] [Revised: 08/29/2011] [Accepted: 09/12/2011] [Indexed: 11/23/2022]
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Scrimger R. Salivary gland sparing in the treatment of head and neck cancer. Expert Rev Anticancer Ther 2012; 11:1437-48. [PMID: 21929317 DOI: 10.1586/era.11.101] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Radiotherapy is an important component of the multimodality treatment of head and neck cancer. Although an effective treatment for many patients, it can have significant long-term sequelae. In particular, xerostomia - or dry mouth - caused by salivary gland injury is a serious problem suffered by most patients and leads to problems with oral comfort, dental health, speech and swallowing. This article explores the mechanisms behind radiation injury to the major salivary glands, as well as different strategies to minimize and alleviate xerostomia. This includes technical approaches to minimize radiation dose to salivary tissue, such as intensity-modulated radiotherapy and surgical transfer of salivary glands, as well as pharmacologic approaches to stimulate or protect the salivary tissue. The scientific literature will be critically examined to see what works and what strategies have been less effective in attempting to minimize xerostomia in head and neck cancer patients.
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Affiliation(s)
- Rufus Scrimger
- Department of Oncology, University of Alberta, 11560 University Ave NW, Edmonton, AB, T6G 1Z2, Canada.
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Histamine modulates salivary secretion and diminishes the progression of periodontal disease in rat experimental periodontitis. Inflamm Res 2012; 61:455-64. [DOI: 10.1007/s00011-011-0432-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2011] [Accepted: 12/26/2011] [Indexed: 12/20/2022] Open
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Medina VA, Prestifilippo JP, Croci M, Carabajal E, Bergoc RM, Elverdin JC, Rivera ES. Histamine prevents functional and morphological alterations of submandibular glands induced by ionising radiation. Int J Radiat Biol 2010; 87:284-92. [DOI: 10.3109/09553002.2010.533247] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Conservation of salivary function and new external head and neck radiation techniques. Eur Ann Otorhinolaryngol Head Neck Dis 2010; 127:197-203. [PMID: 21123132 DOI: 10.1016/j.anorl.2010.09.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2010] [Revised: 09/10/2010] [Accepted: 09/10/2010] [Indexed: 12/17/2022]
Abstract
INTRODUCTION New radiation therapy techniques seek to adapt dose distribution to three-dimensional tumor geometry, so as to deliver the lowest possible dose to normal tissue and at-risk organs. This is expected to enhance locoregional control and survival and to reduce complications and thereby improve quality of life. Post-radiation xerostomia significantly deteriorates quality of life. MATERIAL AND METHODS New external radiation techniques (such as intensity-modulated conformal radiation therapy, RapidArc VMAT arc therapy, tomotherapy, CyberKnife(®), protontherapy, use of carbon ions) applicable in ENT are reviewed. RESULTS Preliminary data show interesting results in terms of salivary function with highly conformal techniques. CONCLUSION In France, assessment is ongoing, financed under the Health Ministry's "Support for Expensive Innovatory Techniques" scheme (STIC [Soutien aux techniques innovantes coûteuses]), as routine use is growing rapidly.
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Vissink A, Mitchell JB, Baum BJ, Limesand KH, Jensen SB, Fox PC, Elting LS, Langendijk JA, Coppes RP, Reyland ME. Clinical management of salivary gland hypofunction and xerostomia in head-and-neck cancer patients: successes and barriers. Int J Radiat Oncol Biol Phys 2010; 78:983-91. [PMID: 20970030 PMCID: PMC2964345 DOI: 10.1016/j.ijrobp.2010.06.052] [Citation(s) in RCA: 232] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2010] [Revised: 06/12/2010] [Accepted: 06/20/2010] [Indexed: 12/22/2022]
Abstract
The most significant long-term complication of radiotherapy in the head-and-neck region is hyposalivation and its related complaints, particularily xerostomia. This review addresses the pathophysiology underlying irradiation damage to salivary gland tissue, the consequences of radiation injury, and issues contributing to the clinical management of salivary gland hypofunction and xerostomia. These include ways to (1) prevent or minimize radiation injury of salivary gland tissue, (2) manage radiation-induced hyposalivation and xerostomia, and (3) restore the function of salivary gland tissue damaged by radiotherapy.
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Affiliation(s)
- Arjan Vissink
- Department of Oral and Maxillofacial Surgery, University Medical Center Groningen, University of Groningen, Grongingen, The Netherlands
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Ho KF, Farnell DJJ, Routledge JA, Burns MP, Sykes AJ, Slevin NJ, Davidson SE. Comparison of patient-reported late treatment toxicity (LENT-SOMA) with quality of life (EORTC QLQ-C30 and QLQ-H&N35) assessment after head and neck radiotherapy. Radiother Oncol 2010; 97:270-5. [PMID: 20554338 DOI: 10.1016/j.radonc.2010.01.017] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2009] [Revised: 12/09/2009] [Accepted: 01/29/2010] [Indexed: 01/23/2023]
Abstract
PURPOSE The patient's role in toxicity reporting is increasingly acknowledged but requires the adaptation and validation of toxicity reporting instruments for patient use as most toxicity scales are designed for physician use. Recording of radiotherapy related late toxicity is important and needs to be improved. A patient-scored symptom questionnaire of late treatment effects using LENT-SOMA was compared with a recognised quality of life tool (EORTC QLQ-C30/H&N35). MATERIALS/METHODS LENT-SOMA and EORTC QLQ-C30 patient questionnaires were prospectively completed by 220 head and neck cancer patients over 3 years and 72 completed EORTC QLQ-H&N35 questionnaires at 2 years post-radiotherapy. RESULTS Endpoints common to both questionnaires (pain, swallowing, dental pain, dry mouth, opening mouth, analgesics) were matched. Spearman rank correlation coefficients with ρ>0.6 (P<0.001) were obtained for all "matched" scales except for analgesics scale, ρ=0.267 (P<0.05). There was good agreement between LENT-SOMA and EORTC QLQ-H&N35 except for analgesic endpoints. Global quality of life scores correlated negatively with average LENT-SOMA scores (P<0.001). Significant differences in average LENT-SOMA scores between treatment modalities were found. The LENT-SOMA questionnaire has demonstrated a high Cronbach's α value (0.786) indicating good reliability. CONCLUSIONS LENT-SOMA patient questionnaire results agreed well with those from the EORTC QLQ-H&N35 questionnaire for toxicity items where they could be compared explicitly, particularly for subjective endpoints. Patient-reported late toxicity had a negative impact on quality of life. The LENT-SOMA patient questionnaire is both reliable and sensitive to differences between patients treated with different modalities. A patient-based questionnaire is an important contributor to capturing late radiotherapy effects.
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Affiliation(s)
- Kean Fatt Ho
- Academic Radiation Oncology, University of Manchester, The Christie NHS Foundation Trust, Manchester, UK.
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Jensen SB, Pedersen AML, Vissink A, Andersen E, Brown CG, Davies AN, Dutilh J, Fulton JS, Jankovic L, Lopes NNF, Mello ALS, Muniz LV, Murdoch-Kinch CA, Nair RG, Napeñas JJ, Nogueira-Rodrigues A, Saunders D, Stirling B, von Bültzingslöwen I, Weikel DS, Elting LS, Spijkervet FKL, Brennan MT. A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: management strategies and economic impact. Support Care Cancer 2010; 18:1061-79. [PMID: 20333412 DOI: 10.1007/s00520-010-0837-6] [Citation(s) in RCA: 178] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2009] [Accepted: 02/08/2010] [Indexed: 12/12/2022]
Abstract
PURPOSE This systematic review aimed to assess the literature for management strategies and economic impact of salivary gland hypofunction and xerostomia induced by cancer therapies and to determine the quality of evidence-based management recommendations. METHODS The electronic databases of MEDLINE/PubMed and EMBASE were searched for articles published in English since the 1989 NIH Development Consensus Conference on the Oral Complications of Cancer Therapies until 2008 inclusive. For each article, two independent reviewers extracted information regarding study design, study population, interventions, outcome measures, results, and conclusions. RESULTS Seventy-two interventional studies met the inclusion criteria. In addition, 49 intensity-modulated radiation therapy (IMRT) studies were included as a management strategy aiming for less salivary gland damage. Management guideline recommendations were drawn up for IMRT, amifostine, muscarinic agonist stimulation, oral mucosal lubricants, acupuncture, and submandibular gland transfer. CONCLUSIONS There is evidence that salivary gland hypofunction and xerostomia induced by cancer therapies can be prevented or symptoms be minimized to some degree, depending on the type of cancer treatment. Management guideline recommendations are provided for IMRT, amifostine, muscarinic agonist stimulation, oral mucosal lubricants, acupuncture, and submandibular gland transfer. Fields of sparse literature identified included effects of gustatory and masticatory stimulation, specific oral mucosal lubricant formulas, submandibular gland transfer, acupuncture, hyperbaric oxygen treatment, management strategies in pediatric cancer populations, and the economic consequences of salivary gland hypofunction and xerostomia.
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Affiliation(s)
- S B Jensen
- Department of Oral Medicine, University of Copenhagen, Copenhagen N, Denmark.
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