A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: management strategies and economic impact
University of Copenhagen1, University Medical Center Groningen2, University of Delaware3, The Royal Marsden NHS Foundation Trust4, Indiana University5, University of Belgrade6, Federal University of São Paulo7, University of Michigan8, Griffith University9, Carolinas Medical Center10, University of Gothenburg11, University of Maryland, Baltimore12, University of Texas MD Anderson Cancer Center13
TL;DR: 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.
Abstract: 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. 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. 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. 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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University of Copenhagen1, University Medical Center Groningen2, College of Health Sciences, Bahrain3, The Royal Marsden NHS Foundation Trust4, Indiana University5, University of Belgrade6, Federal University of São Paulo7, University of Michigan8, Griffith University9, Carolinas Medical Center10, University of Gothenburg11, University of Maryland, Baltimore12, University of Texas MD Anderson Cancer Center13
TL;DR: Salivary gland hypofunction and xerostomia are induced by radiotherapy in the head and neck region depending on the cumulative radiation dose to the gland tissue, and treatment focus should be on optimized/new approaches to further reduce the doses to the parotids.
Abstract: This systematic review aimed to assess the literature for prevalence, severity, and impact on quality of life of salivary gland hypofunction and xerostomia induced by cancer therapies. 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. Two independent reviewers extracted information regarding study design, study population, interventions, outcome measures, results and conclusions for each article. The inclusion criteria were met by 184 articles covering salivary gland hypofunction and xerostomia induced by conventional, 3D conformal radiotherapy or intensity-modulated radiotherapy in head and neck cancer patients, cancer chemotherapy, total body irradiation/hematopoietic stem cell transplantation, radioactive iodine treatment, and immunotherapy. Salivary gland hypofunction and xerostomia are induced by radiotherapy in the head and neck region depending on the cumulative radiation dose to the gland tissue. Treatment focus should be on optimized/new approaches to further reduce the dose to the parotids, and particularly submandibular and minor salivary glands, as these glands are major contributors to moistening of oral tissues. Other cancer treatments also induce salivary gland hypofunction, although to a lesser severity, and in the case of chemotherapy and immunotherapy, the adverse effect is temporary. Fields of sparse literature included pediatric cancer populations, cancer chemotherapy, radioactive iodine treatment, total body irradiation/hematopoietic stem cell transplantation, and immunotherapy.
343 citations
TL;DR: 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.
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.
290 citations
TL;DR: There is no strong evidence from this review that any topical therapy is effective for relieving the symptom of dry mouth, and both integrated mouthcare systems and oral reservoir devices show promising results but there is insufficient evidence at present to recommend their use.
Abstract: Background
Xerostomia (the feeling of dry mouth) is a common symptom especially in older adults. Causes of dry mouth include medications, autoimmune disease (Sjogren's Syndrome), radiotherapy or chemotherapy for cancer, hormone disorders and infections.
Objectives
To determine which topical treatments for dry mouth are effective in reducing this symptom.
Search methods
We searched the following electronic databases: the Cochrane Oral Health Group Trials Register (28 October 2011), The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 4 2011), MEDLINE via OVID (1950 to 28 October 2011), EMBASE via OVID (1980 to 28 October 2011), CINAHL via EBSCO (1980 to 28 October 2011), AMED via OVID (1985 to 28 October 2011), CANCERLIT via PubMed (1950 to 28 October 2011).
Selection criteria
We included randomised controlled trials of topical interventions such as lozenges, sprays, mouthrinses, gels, oils, chewing gum or toothpastes for the treatment of dry mouth symptom. We classified interventions into two broad categories, saliva stimulants and saliva substitutes, and these were compared with either placebo or another intervention. We included both parallel group and crossover trials.
Data collection and analysis
Two or more review authors independently carried out data extraction and assessed risk of bias. Trial authors were contacted for additional information as required.
Main results
Thirty-six randomised controlled trials involving 1597 participants met the inclusion criteria. Two trials compared saliva stimulants to placebo, nine trials compared saliva substitutes to placebo, five trials compared saliva stimulants directly with saliva substitutes, 18 trials directly compared two or more saliva substitutes, and two trials directly compared two or more saliva stimulants. Only one trial was at low risk of bias and 17 were at high risk of bias. Due to the range of interventions, comparisons and outcome measures in the trials, meta-analysis was possible for only a few comparisons. Oxygenated glycerol triester (OGT) saliva substitute spray shows evidence of effectiveness compared to an electrolyte spray (standardised mean difference (SMD) 0.77, 95% confidence interval (CI) 0.38 to 1.15) which corresponds to approximately a mean difference of 2 points on a 10-point visual analogue scale (VAS) for mouth dryness. Both integrated mouthcare systems (toothpaste + gel + mouthwash) and oral reservoir devices show promising results but there is insufficient evidence at present to recommend their use. Although chewing gum is associated with increased saliva production in the majority of those with residual capacity, there is no evidence that gum is more or less effective than saliva substitutes.
Authors' conclusions
There is no strong evidence from this review that any topical therapy is effective for relieving the symptom of dry mouth. OGT spray is more effective than an aqueous electrolyte spray (SMD 0.77, 95% CI 0.38 to 1.15) which is approximately equivalent to a mean difference of 2 points on a 10-point VAS scale for mouth dryness. Chewing gums appear to increase saliva production in those with residual secretory capacity and may be preferred by patients, but there is no evidence that gum is better or worse than saliva substitutes. Integrated mouthcare systems and oral reservoir devices may be helpful but further research is required to confirm this. Well designed, adequately powered randomised controlled trials of topical interventions for dry mouth, which are designed and reported according to CONSORT guidelines, are required to provide evidence to guide clinical care. For many people the symptom of dry mouth is a chronic problem and trials should evaluate whether treatments are palatable, effective in reducing xerostomia, as well as the long-term effects of treatments on quality of life of those with chronic dry mouth symptoms.
222 citations
Sheba Medical Center1, Tel Aviv University2, Icahn School of Medicine at Mount Sinai3, University of Connecticut Health Center4, University of Michigan5, American Society of Clinical Oncology6, Stony Brook University7, Hofstra University8, University of Florida9, McMaster University10, Queen Elizabeth II Health Sciences Centre11, Dalhousie University12, University of Rochester13, Vanderbilt University14, University of North Carolina at Chapel Hill15, Case Western Reserve University16, Stanford University17, Aarhus University18, Northern Ontario School of Medicine19
TL;DR: In this paper, the authors provide guidance regarding best practices in the prevention and management of medication-related osteonecrosis of the jaw (MRONJ) in patients with cancer.
Abstract: PURPOSETo provide guidance regarding best practices in the prevention and management of medication-related osteonecrosis of the jaw (MRONJ) in patients with cancer.METHODSMultinational Association ...
186 citations
Cites background from "A systematic review of salivary gla..."
...Use of both fluoridated and remineralizing toothpaste is recommended tomaintain dental health in the presence of altered oral flora from the impact of cancer treatment–induced salivary hypofunction.(162,163)...
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TL;DR: The available evidence on the use of different therapeutic strategies to alleviate common late sequelae of RT in head and neck cancer patients is reviewed, with a focus on the critical assessment of the treatment options for xerostomia, dysphagia, mandibular osteoradionecrosis, trismus, and hearing loss.
179 citations
Cites background from "A systematic review of salivary gla..."
...In general, gustatory and masticatory stimulation by acidic substances showed some increase in whole saliva secretion and amelioration of oral dryness; oral lubricants and saliva substitutes usually exert a short-term effect over the placebo effect [63]....
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References
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TL;DR: Dose/volume/function relationships in the parotid glands are characterized by dose and volume thresholds, steep dose/response relationships when the thresholds are reached, and a maximal volume dependence parameter in the NTCP model.
Abstract: Purpose: To determine the relationships between the three-dimensional dose distributions in parotid glands and their saliva production, and to find the doses and irradiated volumes that permit preservation of the salivary flow following irradiation (RT). Methods and Materials: Eighty-eight patients with head and neck cancer irradiated with parotid-sparing conformal and multisegmental intensity modulation techniques between March 1994 and August 1997 participated in the study. The mean dose and the partial volumes receiving specified doses were determined for each gland from dose–volume histograms (DVHs). Nonstimulated and stimulated saliva flow rates were selectively measured from each parotid gland before RT and at 1, 3, 6, and 12 months after the completion of RT. The data were fit using a generalized linear model and the normal tissue complication probability (NTCP) model of Lyman-Kutcher. In the latter model, a "severe complication" was defined as salivary flow rate reduced to ≤25% pre-RT flow at 12 months. Results: Saliva flow rates data were available for 152 parotid glands. Glands receiving a mean dose below or equal to a threshold (24 Gy for the unstimulated and 26 Gy for the stimulated saliva) showed substantial preservation of the flow rates following RT and continued to improve over time (to median 76% and 114% of pre-RT for the unstimulated and stimulated flow rates, respectively, at 12 months). In contrast, most glands receiving a mean dose higher than the threshold produced little saliva with no recovery over time. The output was not found to decrease as mean dose increased, as long as the threshold dose was not reached. Similarly, partial volume thresholds were found: 67%, 45%, and 24% gland volumes receiving more than 15 Gy, 30 Gy, and 45 Gy, respectively. The partial volume thresholds correlated highly with the mean dose and did not add significantly to a model predicting the saliva flow rate from the mean dose and the time since RT. The NTCP model parameters were found to be TD 50 (the tolerance dose for 50% complications rate for whole organ irradiated uniformly) = 28.4 Gy, n (volume dependence parameter) = 1, and m (the slope of the dose/response relationship) = 0.18. Clinical factors including age, gender, pre-RT surgery, chemotherapy, and certain medical conditions were not found to be significantly associated with the salivary flow rates. Medications (diuretics, antidepressants, and narcotics) were found to adversely affect the unstimulated but not the stimulated flow rates. Conclusions: Dose/volume/function relationships in the parotid glands are characterized by dose and volume thresholds, steep dose/response relationships when the thresholds are reached, and a maximal volume dependence parameter in the NTCP model. A parotid gland mean dose of ≤26 Gy should be a planning goal if substantial sparing of the gland function is desired.
864 citations
"A systematic review of salivary gla..." refers background in this paper
...To preserve salivary gland function, mean radiation doses ≤26–30 Gy [25, 57, 59, 60, 64, 67], <38 Gy [62], or <40 Gy [70] to the parotid glands have been suggested as well as submandibular/sublingual-sparing IMRT can be of relevance in selected patients [71] with a mean dose of ≤39 Gy to the submandibular/sublingual glands for potential recovery of gland function over time [72]....
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TL;DR: With and without amifostine, 2-year local-regional control, disease-free survival, and overall survival were 58% versus 63, 53% versus 57%, and 71% versus 66%, respectively, while Antitumor treatment efficacy was preserved.
Abstract: PURPOSE: Radiotherapy for head and neck cancer causes acute and chronic xerostomia and acute mucositis. Amifositine and its active metabolite, WR-1065, accumulate with high concentrations in the salivary glands. This randomized trial evaluated whether amifostine could ameliorate these side effects without compromising the effectiveness of radiotherapy in these patients. PATIENTS AND METHODS: Patients with previously untreated head and neck squamous cell carcinoma were eligible. Primary end points included the incidence of grade ≥ 2 acute xerostomia, grade ≥ 3 acute mucositis, and grade ≥ 2 late xerostomia and were based on the worst toxicity reported. Amifostine was administered (200 mg/m2 intravenous) daily 15 to 30 minutes before irradiation. Radiotherapy was given once daily (1.8 to 2.0 Gy) to doses of 50 to 70 Gy. Whole saliva production was quantitated preradiotherapy and regularly during follow-up. Patients evaluated their symptoms through a questionnaire during and after treatment. Local-regional c...
731 citations
TL;DR: An improvement over time in xerostomia, occurring in tandem with rising salivary production from the spared major Salivary glands, suggests a long-term clinical benefit from their sparing.
Abstract: Purpose: To assess long-term xerostomia in patients receiving parotid-sparing radiation therapy (RT) for head-and-neck cancer, and to find the patient and therapy-related factors that affect its severity. Patients and Methods: From March 1994 through January 2000, 84 patients received comprehensive bilateral neck RT using conformal and multisegmental intensity-modulated RT (IMRT) aiming to spare the major salivary glands. Before RT and periodically through 2 years after the completion of RT, salivary flow rates from each of the major salivary glands were selectively measured. At the same time intervals, each patient completed an 8-item self-reported xerostomia-specific questionnaire (XQ). To gain a relative measure of the effect of RT on the minor salivary glands, whose output could not be measured, the surfaces of the oral cavity (extending to include the surface of the base of tongue) were outlined in the planning CT scans. The mean doses to the new organ (“oral cavity”) were recorded. Forty-eight patients receiving unilateral neck RT were similarly studied and served as a benchmark for comparison. Factors predicting the XQ scores were analyzed using a random-effects model. Results: The XQ was found to be reliable and valid in measuring patient-reported xerostomia. The spared salivary glands which had received moderate doses in the bilateral RT group recovered to their baseline salivary flow rates during the second year after RT, and the spared glands in the unilateral RT group, which had received very low doses, demonstrated increased salivary production beyond their pre-RT levels. The increase in the salivary flow rates during the second year after RT paralleled an improvement in xerostomia in both patient groups. The improvement in xerostomia was faster in the unilateral compared with the bilateral RT group, but the difference narrowed at 2 years. The major salivary gland flow rates had only a weak correlation with the xerostomia scores. Factors found to be independently associated with the xerostomia scores were the pre-RT baseline scores, the time since RT, and the mean doses to the major salivary glands (notably to the submandibular glands) and to the oral cavity. Conclusion: An improvement over time in xerostomia, occurring in tandem with rising salivary production from the spared major salivary glands, suggests a long-term clinical benefit from their sparing. The oral cavity mean dose, representing RT effect on the minor salivary glands, was found to be a significant, independent predictor of xerostomia. Thus, in addition to the major salivary glands, sparing the noninvolved oral cavity should be considered as a planning objective to further reduce xerostomia.
699 citations
"A systematic review of salivary gla..." refers background in this paper
...If oncologically feasible, IMRT is recommended as a standard approach in head and neck cancer to limit the cumulated radiation dose to critical normal tissues....
[...]
...IMRT can reduce the dose to parotid, submandibular/sublingual, and minor salivary glands while helping maintain adequate whole saliva flow rates and reducing xerostomia....
[...]
...In addition, 49 intensity-modulated radiation therapy (IMRT) studies were included as a management strategy aiming for less salivary gland damage....
[...]
...Historical summary of the literature before 1990 on management of salivary gland hypofunction and xerostomia as oral complications of cancer therapies Before 1990, radiation techniques such as 3D-conformal radiotherapy and intensity-modified radiotherapy (IMRT) that currently are applied in head and neck cancer to reduce radiation damage to normal tissues (including salivary glands) were in development....
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...Eleven studies specifically assessed the impact of xerostomia or salivary gland hypofunction on QoL aspects in relation to IMRT [25, 27, 31, 32, 34, 40, 44, 56, 58, 59, 73]....
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TL;DR: IMRT was significantly better than CRT in terms of parotid sparing and improved QoL for early-stage disease and support the case for assessment of health-relatedQoL in relation to head-and-neck cancer using a site-specific approach.
Abstract: Purpose: To compare directly the effect of intensity-modulated radiotherapy (IMRT) vs. conventional radiotherapy (CRT) on salivary flow and quality of life (QoL) in patients with early-stage nasopharyngeal carcinoma (NPC). Methods and Materials: Fifty-one patients with T2, N0/N1, M0 NPC took part in a randomized controlled clinical study and received IMRT or CRT. Stimulated whole (SWS) and parotid (SPS) saliva flow were measured and Medical Outcomes Short Form 36 (SF-36), European Organization for Research and Treatment of Cancer (EORTC) core quetionnaire, and EORTC head-and-neck module (QLQ-H&N35) were completed at baseline and 2, 6, and 12 months after radiotherapy. Results: Forty-six patients (88%) were in disease remission 12 months after radiotherapy. At 12 months postradiotherapy, 12 (50.0%) and 20 patients (83.3%) in the IMRT group had recovered at least 25% of preradiotherapy SWS and SPS flow respectively, compared with 1 (4.8%) and 2 patients (9.5%), respectively, in the CRT group. Global health scores showed continuous improvement in QoL after both treatments ( p p Conclusions: IMRT was significantly better than CRT in terms of parotid sparing and improved QoL for early-stage disease. The findings support the case for assessment of health-related QoL in relation to head-and-neck cancer using a site-specific approach.
652 citations
"A systematic review of salivary gla..." refers background in this paper
...If oncologically feasible, IMRT is recommended as a standard approach in head and neck cancer to limit the cumulated radiation dose to critical normal tissues....
[...]
...IMRT can reduce the dose to parotid, submandibular/sublingual, and minor salivary glands while helping maintain adequate whole saliva flow rates and reducing xerostomia....
[...]
...In addition, 49 intensity-modulated radiation therapy (IMRT) studies were included as a management strategy aiming for less salivary gland damage....
[...]
...Historical summary of the literature before 1990 on management of salivary gland hypofunction and xerostomia as oral complications of cancer therapies Before 1990, radiation techniques such as 3D-conformal radiotherapy and intensity-modified radiotherapy (IMRT) that currently are applied in head and neck cancer to reduce radiation damage to normal tissues (including salivary glands) were in development....
[...]
...Eleven studies specifically assessed the impact of xerostomia or salivary gland hypofunction on QoL aspects in relation to IMRT [25, 27, 31, 32, 34, 40, 44, 56, 58, 59, 73]....
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TL;DR: IMRT is superior to 2DRT in preserving parotid function and results in less severe delayed xerostomia in the treatment of early-stage NPC, which reflects the need to enhance protection of other salivary glands.
Abstract: Purpose This randomized trial compared the rates of delayed xerostomia between two-dimensional radiation therapy (2DRT) and intensity-modulated radiation therapy (IMRT) in the treatment of early-stage nasopharyngeal carcinoma (NPC). Patients and Methods Between November 2001 and December 2003, 60 patients with T1-2bN0-1M0 NPC were randomly assigned to receive either IMRT or 2DRT. Primary end point was incidence of observer-rated severe xerostomia at 1 year after treatment based on Radiotherapy Oncology Group /European Organisation for the Research and Treatment of Cancer late radiation morbidity scoring criteria. Parallel assessment with patient-reported outcome, stimulated parotid flow rate (SPFR), and stimulated whole saliva flow rate (SWSFR) were also made. Results At 1 year after treatment, patients in IMRT arm had lower incidence of observer-rated severe xerostomia than patients in the 2DRT arm (39.3% v 82.1%; P = .001), parallel with a higher fractional SPFR (0.90 v 0.05; P < .0001), and higher frac...
629 citations