Raj G. Nair

A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: prevalence, severity and impact on quality of life

PurposeThis 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.MethodsThe 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.ResultsThe 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.ConclusionsSalivary 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.

A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: management strategies and economic impact

PurposeThis 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.MethodsThe 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.ResultsSeventy-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.ConclusionsThere 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.

Emerging evidence on the pathobiology of mucositis

BackgroundConsiderable progress has been made in our understanding of the biological basis for cancer therapy-induced mucosal barrier injury (mucositis). The last formal review of the subject by MASCC/ISOO was published in 2007; consequently, an update is timely.MethodsPanel members reviewed the biomedical literature on mucositis pathobiology published between January 2005 and December 2011.ResultsRecent research has provided data on the contribution of tissue structure changes, inflammation and microbiome changes to the development of mucositis. Additional research has focused on targeted therapy-induced toxicity, toxicity clustering and the investigation of genetic polymorphisms in toxicity prediction. This review paper summarizes the recent evidence on these aspects of mucositis pathobiology.ConclusionThe ultimate goal of mucositis researchers is to identify the most appropriate targets for therapeutic interventions and to be able to predict toxicity risk and personalize interventions to genetically suitable patients. Continuing research efforts are needed to further our understanding of mucositis pathobiology and the pharmacogenomics of toxicity.

Low-level laser therapy in the prevention and treatment of cancer therapy-induced mucositis: 2012 state of the art based on literature review and meta-analysis.

Purpose of review To discuss the promising state of the art low-level laser therapy (LLLT) for preventive and therapeutic usage in oral mucositis due to cancer therapy. Recent findings Photomedicine using LLLT is very effective with intraoral and extraoral devices in the management of oral mucositis, based on several studies including randomized control studies. A systematic review identified 33 relevant articles that were subjected to meta-analysis based on which laser parameters in routine practice are being defined. Meta-analysis showed that LLLT reduced risk of oral mucositis with relative risk (RR) 2.45 [confidence interval (CI) 1.85–3.18], reduced duration, severity of oral mucositis and reduced number of days with oral mucositis (4.38 days, Pu200a=u200a0.0009). RR was similar between the red (630–670u200anm) and infrared (780–830u200anm) LLLT. Pain-relieving effect based on the Cohen scale was at 1.22 (CI 0.19–2.25). Summary No adverse side effects of LLLT were reported; hence, we recommend red or infrared LLLT with diode output between 10–100u200amW, dose of 2–3u200aJ/cm2/cm2 for prophylaxis and 4u200aJ/cm2 (maximum limit) for therapeutic effect, application on single spot rather than scanning motion. Lesions must be evaluated by a trained clinician and therapy should be repeated daily or every other day or a minimum of three times per week until resolution. There is moderate-to-strong evidence in favor of LLLT at optimal doses as a well tolerated, relatively inexpensive intervention for cancer therapy-induced oral mucositis. It is envisaged that LLLT will soon become part of routine oral supportive care in cancer.

The effect of oral commensal bacteria on candidal adhesion to denture acrylic surfaces - An in vitro study

The effect of four different species of oral bacteria (Streptococci (X2); Escherichia; Porphyromonas) on the adhesion of Candida albicans and Candida krusei to denture acrylic surfaces was studied using a previously described in vitro adhesion assay. Clear acrylic strips immersed in known concentrations of bacterial suspensions and incubated for 45 min to 1 h, at 37°C, were transferred to yeast suspensions of known concentrations and incubated for a similar period, and the adherent yeasts were quantified using an image analysis system. Pre‐exposure to different bacterial concentrations resulted in suppression of candidal adhesion to varying degrees. Of three selected concentrations, exposure to the highest bacterial concentration (106 organisms/ml) resulted in a consistent reduction in candidal adhesion, except for E. coli‐C. albicans and S. salivarius‐C. albicans combinations. Candidal adhesion was significantly reduced on pre‐exposure to S. sanguis and P. gingivalis, but not E. coli. There were also significant differences in relative adhesion between C. albicans and C. krusei. Taken together, these results indicate that the adhesion of yeasts to acrylic strips is modulated both by the quantity and the quality of pre‐existing bacterial flora on acrylic surfaces.

Could the biological robustness of low level laser therapy (Photobiomodulation) impact its use in the management of mucositis in head and neck cancer patients

Low level laser therapy (LLLT) has been noted to be effective in mitigating the development of oral mucositis among patients being treated with chemoradiation for cancers of the head and neck. To explain the biological basis for this observation we performed a comprehensive literature search. Our investigation identified a substantial number of LLLT-activated pathways that have been strongly associated with negative tumor outcomes including proliferation, invasion, angiogenesis, metastases and cancer-treatment resistance. In light of these findings, we suggest an investigational strategy to assure that LLLTs anti-mucositis efficacy is independent of its possible potential to enhance threatening tumor behaviors. Included are appropriate pre-clinical modeling, short- and long-term follow-up of LLLT-treated patients, and the requirement for consistency of LLLT parameters.

The effect of oral bacteria on Candida albicans germ-tube formation

Abstract: A total of eight bacterial isolates belonging to six species, and a select group of 12 oral Candida albicans isolates, were used to study the effect of bacteria on germ‐tube formation. Briefly, each bacterial suspension (105–6 cells/ml) was mixed with a C. albicans suspension (107 cells/ml) and incubated at 37u2003°C for 90 min with bovine serum, and the percentage germ‐tube‐positive Candida cells was quantified using a haemocytometer, under light microscopy. In general, out of eight bacteria, Streptococcus sanguis SK21A, Streptococcus salivarius SK56, Escherichia coli ATCC 25922, and S. salivarius OBU3 suppressed germ‐tube formation to varying degrees, with different C. albicans isolates. Porphyromonas gingivalis Pg 50, Lactobacillus casei ATCC 7469 and Prevotella intermedia OBU4 elicited significant enhancement of germ‐tube formation, whereas S. sanguis OBU 2 had no effect. E. coli ATCC 25922 was the only organism to show statistically significant suppression of germ‐tube formation (p=0.0312). A significant increase in the germ tube production of C. albicans isolated from HIV‐infected compared with HIV‐free individuals was also noted. The current results tend to suggest that commensal and transient oral bacterial populations may selectively influence the differential expression of germ‐tube‐forming ability of C. albicans isolates.

Comparison between self-formulation and compounded-formulation dexamethasone mouth rinse for oral lichen planus: a pilot, randomized, cross-over trial.

AIMnThere is a lack of appropriate, commercially-available topical corticosteroid formulations for use in oral lichen planus (OLP) and oral lichenoid reaction. Current therapy includes crushing a dexamethasone tablet and mixing it with water for use as a mouth rinse. This formulation is unpleasant esthetically and to use in the mouth, as it is a bitter and gritty suspension, resulting in poor compliance. Thus, the present study was designed to formulate and pilot an effective, esthetically-pleasing formulation.nnnMETHODSnA single-blinded, cross-over trial was designed with two treatment arms. Patients were monitored for 7 weeks. Quantitative and qualitative data was assessed using VAS, numeric pain scales, the Treatment Satisfaction Questionnaire for Medication-9, and thematic analysis to determine primary patient-reported outcomes, including satisfaction, compliance, quality of life, and symptom relief.nnnRESULTSnNine patients completed the pilot trial. Data analysis revealed the new compounded formulation to be superior to existing therapy due to its convenience, positive contribution to compliance, patient-perceived faster onset of action, and improved symptom relief.nnnCONCLUSIONnTopical dexamethasone is useful in the treatment of OLP. When carefully formulated into a compounded mouth rinse, it improves patient outcomes.

Efficacy of Low-Level Laser Therapy (LLLT) in Oral Mucositis: What Have We Learned from Randomized Studies and Meta-Analyses?

Oral mucositis (OM) is an inevitable complication of radiation therapy (RT) of the head and neck region, as part of gastrointestinal toxicity in chemotherapy and hematopoietic stem cell transplantation (HSCT), causing severe morbidity and affecting the patient’s quality of life. Duration and severity of OM, especially in higher grades, are critical, as it hampers the cancer treatment, affects duration of hospital stay, and to a certain extent, predicts success of treatment and complications such as graft-versus-host disease (GVHD) in transplantation patients. There is no consensus on a single agent or agents that can be used either prophylactically or therapeutically in OM. The frequency of OM varies from 12% in patients receiving adjuvant chemotherapy to 80% and 100% in patients undergoing HSCT and RT of the orofacial region, respectively. The art and science of photomedicine or phototherapy involving low-level laser therapy (LLLT) or near-infrared light-emitting diodes (NIR-LED) have become promising and effective tools in prophylactic and therapeutic interventions for OM and associated orofacial pain. First reports on LLLT on OM originated from Nice, France in 1992, and since then there have been reports of several randomized control studies with promising outcome. In 2007, Multinational Association of Supportive Care in Cancer/ International Society of Oral Oncology (MASCC-ISOO) Mucositis Guidelines have upgraded LLLT as a ‘‘recommended’’ method for the prevention of OM during HSCT. LLLT of an output power range from 5 to 200 mW with helium/neon (He/Ne) laser of wavelength 632.8 nm or diode lasers of various wavelengths ranging from 630 to 680 nm, 700 to 830 nm, and 900nm is an efficacious, simple, and atraumatic technique in the treatment of OM, with no known toxicity in clinical setting. In addition, LLLT has been found to reduce the total duration and severity of OM in all the studies, with a few exceptions in which the laser parameters were, perhaps, inadequate. Another debilitating effect of OM is orofacial pain, which often depends upon existing oral health; underlying disease, type of treatment, severity of OM, and pain threshold. It has been shown that there is considerable reduction in orofacial pain in those patients who underwent LLLT. Although side effects were reported, none of them was different from those experienced by the control group, which is a clear indication of how well LLLT was tolerated by cancer patients, irrespective of their mode of cancer treatment. Perhaps one of the main pitfalls in past reports of studies with LLLT is the inconsistency in the parameters used, the calibration of the laser device, and the manner in which LLLT was delivered to the site. It is vital to formulate a protocol on parameters from the existing data on what is best for both a prophylactic dose and therapeutic effect. Briefly, we recommend a fairly simple regimen as follows, when considering a commercially available device: wavelength for a red light source at 633– 685 nm, infrared 780–830 nm; output of diode between 10 and 150 mW; dose in the range of 2–3 J/cm for prophylaxis, and not less than 4 J/cm for therapeutic effect; application on single spot on a lesion rather than a scanning motion over the entire lesion. Also one should follow a simple formula such as

Low-Level Laser Therapy in the Management of Mucositis and Dermatitis Induced by Cancer Therapy.

Low-level laser therapy (LLLT)/photobiomodulation (PBM) has been consistently shown in laboratory studies to have distinct biological effects, and has a dosedependent mechanism of action at the cellular level. Since the introduction of LLLT/PBM in 1967, >400 randomized, double-blinded (some placebo-controlled) clinical trials have been published for multiple applications. Although the complex biological mechanisms underlying the therapeutic effects of LLLT/PBM have not been completely elucidated, and may vary among different cell types and tissue states (healthy versus stressed or hypoxic), laboratory and clinical studies suggest that LLLT/PBM significantly reduces inflammation and prevents fibrosis. Moreover, LLLT/PBM, when delivered appropriately, reduces pain and improves optimal function of the whole organism. In addition, in vivo studies show that LLLT/PBM is neuroprotective and may benefit neurodegenerative diseases and neurotrauma. Current data suggest that LLLT/PBM acts predominantly on cytochrome C oxidase (CcO) in the mitochondrial respiratory chain by facilitating electron transport, resulting in an increased transmembrane proton gradient that drives adenosine triphosphate (ATP) production. ATP is the universal energy source in living cells essential for all biologic reactions, and even a small increase in ATP levels can enhance bioavailability to power the functions of cellular metabolism. In addition, the absorption of red or near-infrared (NIR) light may cause a short, transient burst of reactive oxygen species (ROS) that is followed by an adaptive reduction in oxidative stress. A low concentration of ROS activates many cellular processes, because ROS activates transcription factors, including nuclear factor kappa B (NF-jB), resulting in the upregulation of stimulatory and protective genes. These genes generate growth factors belonging to the fibroblast growth factor family, cytokines, and chemokines that are involved in tissue repair. In hypoxic or otherwise stressed cells, mitochondria produce nitric oxide (mtNO), which binds to CcO and displaces oxygen. This binding results in the inhibition of cellular respiration, decreased ATP production, and increased oxidative stress (a state that develops when the levels of ROS exceed the defense mechanisms), leading to the activation of intracellular signaling pathways, including several transcription factors. These include redox factor-1 (Ref-1), activator protein-1 (AP-1), NF-jB, p53, activating transcription factor/ cyclic adenosine monophosphate (cAMP)-response element– binding protein (ATF/CREB), hypoxia-inducible factor (HIF)-1, and HIF-like factor, These transcription factors induce downstream production of both inflammatory mediators, such as tumor necrosis factor-alpha (TNF-a), interleukin [IL]-1 and IL-6, cyclooxygenase (COX)-2, and prostaglandin E2 (PGE-2), and anti-inflammatory mediators (transforming growth factor-beta [TGF-b] IL10). There is evidence suggesting that when LLLT/PBM is administered with appropriate parameters to stressed cells, NO is dissociated from its competitive binding to CcO, ATP production is increased, and the balance between proand antioxidant mediators is restored, resulting in a reduction of oxidative stress. For example, LLLT/PBM has been shown to attenuate the production of ROS by human neutrophils. Silveira et al.23 reported that LLLT/PBM reduced ROS in an animal model of traumatic tissue injury; whereas a study in a model of acute lung inflammation found LLLT/PBM to reduce the generation of TNF-a and to increase IL-10, an anti-inflammatory cytokine. In addition, NO is a potent vasodilator and can increase the blood supply to the illuminated tissue. LLLTmediated vascular regulation increases tissue oxygenation and also allows for greater traffic of immune cells. These two effects may contribute to the promotion of wound repair and regeneration. Analgesic effects are probably induced by additional mechanisms rather than by the increased ATP/reduced oxidative stress model. LLLT/PBM with a relatively high power density (>300 mW/cm), when absorbed by nociceptors, has an inhibitory effect on A and C neuronal pain fibers. This slows neural conduction velocity, reduces amplitude of compound action potentials, and suppresses neurogenic inflammation. Virtually all conditions modulated by LLLT/PBM (e.g., ulceration, inflammation, edema, pain, fibrosis, and neurological and muscular injury) are thought to be involved in the pathogenesis of chemotherapy (CT) or radiotherapy (RT)-induced complications in patients treated for head and neck cancer (HNC). For example, in an animal model of oral mucositis (OM), it was demonstrated that LLLT/PBM