Evaluation of Oral Mucositis Occurrence in Oncologic Patients under Antineoplastic Therapy Submitted to the Low–Level Laser Coadjuvant Therapy.
- Programa de Pós-Graduação em Saúde Pública, Universidade Estadual da Paraíba, Avenida das Baraúnas, S/N-Campus Universitário, Bodocongó, Campina Grande 58109-753, Brazil. firstname.lastname@example.org.
- Faculty of Medical Sciences, Campina Grande 58109-753, Brazil. email@example.com.
- School of Dentistry, State University of Paraíba, Campina Grande 58109-753, Brazil. firstname.lastname@example.org.
- School of Dentistry, State University of Paraíba, Campina Grande 58109-753, Brazil. email@example.com.
- School of Dentistry, State University of Paraíba, Campina Grande 58109-753, Brazil. firstname.lastname@example.org.
- Hospital Universitário Alcides Carneiro, Federal University of Campina Grande, Campina Grande 58109-753, Brazil. email@example.com.
- Department of Dentistry, State University of Paraiba, Campina Grande 58109-753, Brazil. firstname.lastname@example.org.
Low–level laser therapy has been widely used in treating many conditions, including oral mucositis. The purpose of this study was to evaluate the occurrence of oral mucositis in patients undergoing antineoplastic therapy submitted to preventive and therapeutic treatment with low–level laser therapy. This cross-sectional study was carried out with 51 children and adolescents of both sexes with malignant neoplasias who developed oral mucositis and underwent low–level laser therapy. Data were collected on sex, age, type and degree of neoplasia, region affected, and remission time. 64.7% of the patients were male and were between 3 and 6 years of age (39.2%). Acute lymphoid leukemia was the most frequent neoplasm (37.3%). Regarding the maximum oral mucositis, grade 2 (41.2%) was predominant, with jugal mucosa (29.9%) and tongue (17.7%) being the most affected regions. The majority of cases presented lesion remission time between 4 and 7 days (44.0%). Most patients were young, male, and diagnosed with acute lymphoid leukemia. Predominance of grade 2 oral mucositis was observed, with jugal mucosa and tongue being the most affected regions, with the majority of cases presenting lesion remission time between 4 and 7 days. Low–level laser therapy has been shown to be an essential therapy in the prevention and treatment of these lesions, since it is a non-invasive and low-cost method.
antineoplastic agents; low–level laser therapy; mucositis
Locally advanced oral squamous cell carcinoma patients treated with photobiomodulation for prevention of oral mucositis: retrospective outcomes and safety analyses.
- Dental Oncology Service, Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
- Oral Diagnosis Department, Piracicaba Dental School, Semiology Area, Piracicaba Dental School, University of Campinas (UNICAMP), Av. Limeira, 901, Bairro Areão, Piracicaba, São Paulo, CEP 13414-903, Brazil.
- Universidade Brasil, Fernandópolis, São Paulo, Brazil.
- Radiotherapy Service, Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
- Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Hospital System, Los Angeles, CA, USA.
- Division of Otolaryngology and Head and Neck Surgery, City of Hope, Duarte, CA, USA.
- Departments of Oral Biology and Biomedical Engineering, Schools of Dental Medicine, Engineering and Applied Sciences, State University of New York at Buffalo, Buffalo, NY, USA.
- Clinical Oncology Service, Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
- College of Dentistry, University of Florida, Gainesville, FL, USA.
- Dental Oncology Service, Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. email@example.com.
- Oral Diagnosis Department, Piracicaba Dental School, Semiology Area, Piracicaba Dental School, University of Campinas (UNICAMP), Av. Limeira, 901, Bairro Areão, Piracicaba, São Paulo, CEP 13414-903, Brazil. firstname.lastname@example.org.
The well-established clinical efficacy of photobiomodulation (PBM) therapy in management of oral mucositis (OM) is leading to increasing use in oncology care. This protection and enhanced repair of damage to mucosal tissue have led to the question of the potential effects of PBM therapy on pre-malignant and malignant cells. The purpose of this study was to examine the outcome of cancer therapy and incidence of tumor recurrence in locally advanced oral squamous cell carcinoma (OSCC) patients treated with PBM therapy for OM.
A retrospective clinical analysis of 152 advanced OSCC patients treated with prophylactic PBM therapy for radiotherapy-induced OM from January 2009 to December 2014 was conducted.
Of the 152 OSCC patients treated with PBM therapy in this study, 19 (12.5%) had stage III and 133 (87.5%) had stage IV tumors. Of these, 52 (34.2%) received initial treatment with surgery followed by adjuvant radiotherapy, 94 (61.8%) with exclusive chemoradiation, and 6 (4%) with induction chemotherapy followed by surgery and radiotherapy. After a mean follow-up of 40.84 (±?11.71) months, the overall survival and disease-free survival rates were 46.7 and 51.8%, respectively. Forty-five (29.6%) patients developed local-regional recurrence, 10 (6.57%) patients developed distant relapse, and 19 (12.5%) developed new (second) primary tumors.
Clinicopathological features and survival outcomes in the PBM-treated patients were similar to previously published data for conventional treatments in patients with advanced OSCC. In this study, prophylactic use of PBM therapy did not impact treatment outcomes of the primary cancer, recurrence or new primary tumors, or survival in advanced OSCC patients.
Cancer; Laser therapy; Mucositis; Photobiomodulation; Radiotherapy
Advances in the understanding and management of mucositis during stem cell transplantation.
- aAdelaide Medical School, University of Adelaide bCentre for Nutrition and Gastrointestinal Disease, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
PURPOSE OF REVIEW:
Mucositis is a severe and common side effect of anticancer treatments, with an incidence of between 40 and 80% depending on the cytotoxic regimen used. The most profound mucositis burden is experienced during conditioning regimens for hematopoietic stem cell transplant (HSCT), where the use of highly mucotoxic agents with or without total body irradiation leads to serious damage throughout the alimentary tract. Currently, the assessment and management of both oral and gastrointestinal mucositis lack authoritative guideline, with recommendations only achieved in narrow clinical scenarios. This review provides a brief overview of current management guidelines for mucositis in both adult and pediatric patients receiving HSCT, highlights recent advances in mucositis prevention and discusses future research avenues.
The Multinational Association of Supportive Care in Cancer and International Society for Oral Oncology (MASCC/ISOO) guidelines for the prevention of mucositis in HSCT are scarce, with low level laser therapy (photobiomodulation) and palifermin only recommended for oral mucositis. Loperamide and octreotide remain gold-standard for the treatment of diarrhea, despite poor efficacy. Although several interventions have been trialled in pediatric cohorts, no recommendations currently exist for children receiving high-dose chemotherapy or total body irradiation for HSCT.
HSCT continues to be associated with mucositis, which impacts on patients’ ability and willingness to receive engraftment, and worsens clinical outcome. Research into the prevention and treatment of mucositis in this setting remains limited, with an overwhelming amount of small, single-center studies that fail to achieve a sufficient level of evidence that warrant recommendation(s). As such, our ability to manage mucotoxic side effects of high-dose chemotherapy and irradiation is limited, particularly in children.
cDNA microarray analysis of human keratinocytes cells of patients submitted to chemoradiotherapy and oral photobiomodulation therapy: pilot study.
- Clinical Research Division, Instituto Nacional de Câncer (INCA), Rua André Cavalcante, n 37, 2 andar, Rio de Janeiro, RJ, 20231-050, Brazil. email@example.com.
- Bioinformatics Unit, Clinical Research Coordination, Instituto Nacional de Câncer (INCA), Rio de Janeiro, RJ, Brazil.
- Head and Neck Oncology Group, Grupo de Oncologia D’Or, Rio de Janeiro, Brazil.
- Radiation Oncology Division, INCA, Rio de Janeiro, Brazil.
- Head and Neck Surgery Division, INCA, Rio de Janeiro, Brazil.
- Program of Cellular Biology, INCA, Rio de Janeiro, Brazil.
- Department of Immunobiology, Universidade Federal Fluminense (UFF), Niterói, Brazil.
- Laboratory of Functional Genomics and Bioinformatics, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil.
- Clinical Research Division, Instituto Nacional de Câncer (INCA), Rua André Cavalcante, n 37, 2 andar, Rio de Janeiro, RJ, 20231-050, Brazil.
- D’Or Institute for Research and Education, Rio de Janeiro, Brazil.
Oral mucositis is an acute toxicity that occurs in patients submitted to chemoradiotherapy to treat head and neck squamous cell carcinoma. In this study, we evaluated differences in gene expression in the keratinocytes of the oral mucosa of patients treated with photobiomodulation therapy and tried to associate the molecular mechanisms with clinical findings. From June 2009 to December 2010, 27 patients were included in a randomized double-blind pilot study. Buccal smears from 13 patients were obtained at days 1 and 10 of chemoradiotherapy, and overall gene expression of samples from both dates were analyzed by complementary DNA (cDNA) microarray. In addition, samples from other 14 patients were also collected at D1 and D10 of chemoradiotherapy for subsequent validation of cDNA microarray findings by qPCR. The expression array analysis identified 105 upregulated and 60 downregulated genes in our post-treatment samples when compared with controls. Among the upregulated genes with the highest fold change, it was interesting to observe the presence of genes related to keratinocyte differentiation. Among downregulated genes were observed genes related to cytotoxicity and immune response. The results indicate that genes known to be induced during differentiation of human epidermal keratinocytes were upregulated while genes associated with cytotoxicity and immune response were downregulated in the laser group. These results support previous clinical findings indicating that the lower incidence of oral mucositis associated with photobiomodulation therapy might be correlated to the activation of genes involved in keratinocyte differentiation.
New photobiomodulation protocol prevents oral mucositis in hematopoietic stem cell transplantation recipients-a retrospective study.
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Av. Limeira, 901, Piracicaba, 13414-903, Brazil.
- Department of Oral Pathology, School of Dentistry, Federal University of Rio Grande do Sul, Rua Ramiro Barcelos, 2492, Porto Alegre, Rio Grande do Sul, 90035-003, Brazil.
- Department of Oral Medicine, Hospital de Clínicas de Porto Alegre (HCPA/UFRGS), Rua Ramiro Barcelos, 2350, Porto Alegre, Rio Grande do Sul, 90035-903, Brazil.
- Pediatric Oncology Service, Clinical Hospital, Federal University of Rio Grande do Sul, Rua Ramiro Barcelos, 2350, Porto Alegre, Rio Grande do Sul, 90035-903, Brazil.
- Hematopoietic Stem Cell Transplantation Service, Federal University of Rio Grande do Sul, Rua Ramiro Barcelos, 2350, Porto Alegre, Rio Grande do Sul, 90035-903, Brazil.
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Av. Limeira, 901, Piracicaba, 13414-903, Brazil. firstname.lastname@example.org.
- Department of Oral Pathology, School of Dentistry, Federal University of Rio Grande do Sul, Rua Ramiro Barcelos, 2492, Porto Alegre, Rio Grande do Sul, 90035-003, Brazil. email@example.com.
- Department of Oral Medicine, Hospital de Clínicas de Porto Alegre (HCPA/UFRGS), Rua Ramiro Barcelos, 2350, Porto Alegre, Rio Grande do Sul, 90035-903, Brazil. firstname.lastname@example.org.
Oral mucositis (OM) is an adverse side effect among hematopoietic stem cell transplantation (HSCT) recipients. The objective of this retrospective study was to evaluate the preventive effect of photobiomodulation (PBM) applied three times per week versus seven times per week in patients undergoing HSCT. The risk factors related to the incidence and severity of OM were also assessed. This was a retrospective study that evaluated 99 HSCT recipients who received different PBM protocols. Group I received three sessions per week, and group II received daily treatment. PBM was applied using a continuous-wave diode laser (InGaAlP; MM Optics, São Carlos, SP, Brazil) at a wavelength of 660 nm (visible-red) and a total radiant energy of 0.24 J per point. The baseline disease, type of transplant, type of conditioning, prophylaxis against graft-versus-host disease, OM grade, absolute leukocyte and platelet counts, and levels of liver and renal function markers were collected from medical records. The patients’ age ranged from 13 to 71 years (mean/SD, 40.54 ± 16.45). No significant difference was observed between groups I and II regarding sex, age, ethnic, diagnosis, donor type, and conditioning treatment. Both PBM protocols were equally efficient in preventing OM (p = 0.34, ANOVA). Independent of the PBM protocol used, patients who received allogeneic transplant (p < 0.01-Fischer’s exact test), total body irradiation (TBI-12Gy) (p = 0.01-chi-square test), busulfan + cyclophosphamide (p < 0.01-chi-square test), or methotrexate-containing regimens (p < 0.01-Fischer’s exact test) demonstrated higher OM incidence and severity. Myelosuppression (p < 0.01-Mann-Whitney test) and impaired renal function (p = 0.02-Mann-Whitney test) were also considered risk factors for OM. Based on this retrospective data, PBM was effective in preventing OM in patients undergoing HSCT even when it was applied three times a week. A prospective study might be necessary to confirm these findings.
Adverse effects; Continuous-wave diode laser; Low-level laser; Oncology; Preventive therapy
Low-level laser therapy/photobiomodulation in the management of side effects of chemoradiation therapy in head and neck cancer: part 2: proposed applications and treatment protocols.
- 1Department of Oral and Maxillofacial Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands.
- 2Department of Medical Dental Interaction and Department of Periodontology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University, P.O. Box 22660 1100 DD, Amsterdam, the Netherlands.
- 3Oral Medicine Oral Pathology and Human Diseases, Menzies Health Institute Queensland and Oral Medicine Consultant, Department of Haematology and Oncology/Cancer Services, Gold Coast University Hospital, Queensland Health, Queensland, Australia.
- 4Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
- 5Division of Otolaryngology and Head and Neck Surgery, City of Hope, Duarte, CA, 91010, USA.
- 6Division of Oral Medicine, Eastman Institute for Oral Health, and Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, 14620, USA.
- 7Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
- 8Department of Dermatology, Harvard Medical School, Boston, MA, 02115, USA.
- 9Harvard-MIT Division of Health Science and Technology, Cambridge, MA, 02139, USA.
- 10Division of Oncology, Weill Cornell Medical Center, New York, NY, USA.
- 11Department of Diagnostic Sciences and Oral Medicine, Director of Oral Medicine, College of Dentistry, University of Tennessee Health Science Center, 875 Union Ave. Suite N231, Memphis, TN, 38163, USA.
- 12Laser Therapy Unit, Institut Jules Bordet, Centre des Tumeurs de l’Université Libre de Bruxelles, Brussels, Belgium.
- 13Antoni van Leeuwenhoek Department of Head and Neck Oncology and Surgery, Netherlands Cancer Institute, Amsterdam, the Netherlands.
- 14Department of Oral Surgery, Faculty of Dentistry, University of Barcelona, Barcelona, Spain.
- 15Antoni van Leeuwenhoek Department of Radiation Oncology, Amsterdam, Netherlands Cancer Institute, Amsterdam, the Netherlands.
- 16Seattle Cancer Care Alliance (SCCA), Oral Medicine, 825 Eastlake Ave E Ste G6900, Seattle, WA, 98109, USA.
- 17World Association for Laser Therapy (WALT) Scientific Secretary, Centre de Haute Energie (CHE), 10 Bd Pasteur, 06000, Nice, France. email@example.com.
There is a large body of evidence supporting the efficacy of low-level laser therapy (LLLT), more recently termed photobiomodulation (PBM) for the management of oral mucositis (OM) in patients undergoing radiotherapy for head and neck cancer (HNC). Recent advances in PBM technology, together with a better understanding of mechanisms involved and dosimetric parameters may lead to the management of a broader range of complications associated with HNC treatment. This could enhance patient adherence to cancer therapy, and improve quality of life and treatment outcomes. The mechanisms of action, dosimetric, and safety considerations for PBM have been reviewed in part 1. Part 2 discusses the head and neck treatment side effects for which PBM may prove to be effective. In addition, PBM parameters for each of these complications are suggested and future research directions are discussed.
Narrative review and presentation of PBM parameters are based on current evidence and expert opinion.
PBM may have potential applications in the management of a broad range of side effects of (chemo)radiation therapy (CRT) in patients being treated for HNC. For OM management, optimal PBM parameters identified were as follows: wavelength, typically between 633 and 685 nm or 780-830 nm; energy density, laser or light-emitting diode (LED) output between 10 and 150 mW; dose, 2-3 J (J/cm2), and no more than 6 J/cm2 on the tissue surface treated; treatment schedule, two to three times a week up to daily; emission type, pulsed (<100 Hz); and route of delivery, intraorally and/or transcutaneously. To facilitate further studies, we propose potentially effective PBM parameters for prophylactic and therapeutic use in supportive care for dermatitis, dysphagia, dry mouth, dysgeusia, trismus, necrosis, lymphedema, and voice/speech alterations.
PBM may have a role in supportive care for a broad range of complications associated with the treatment of HNC with CRT. The suggested PBM irradiation and dosimetric parameters, which are potentially effective for these complications, are intended to provide guidance for well-designed future studies. It is imperative that such studies include elucidating the effects of PBM on oncology treatment outcomes.
Low level laser therapy/photobiomodulation in the management of side effects of chemoradiation therapy in head and neck cancer: part 1: mechanisms of action, dosimetric, and safety considerations.
There is a large body of evidence supporting the efficacy of low level laser therapy (LLLT), more recently termed photobiomodulation (PBM), for the management of oral mucositis (OM) in patients undergoing radiotherapy for head and neck cancer (HNC). Recent advances in PBM technology, together with a better understanding of mechanisms involved, may expand the applications for PBM in the management of other complications associated with HNC treatment. This article (part 1) describes PBM mechanisms of action, dosimetry, and safety aspects and, in doing so, provides a basis for a companion paper (part 2) which describes the potential breadth of potential applications of PBM in the management of side-effects of (chemo)radiation therapy in patients being treated for HNC and proposes PBM parameters.
This study is a narrative non-systematic review.
We review PBM mechanisms of action and dosimetric considerations. Virtually, all conditions modulated by PBM (e.g., ulceration, inflammation, lymphedema, pain, fibrosis, neurological and muscular injury) are thought to be involved in the pathogenesis of (chemo)radiation therapy-induced complications in patients treated for HNC. The impact of PBM on tumor behavior and tumor response to treatment has been insufficiently studied. In vitro studies assessing the effect of PBM on tumor cells report conflicting results, perhaps attributable to inconsistencies of PBM power and dose. Nonetheless, the biological bases for the broad clinical activities ascribed to PBM have also been noted to be similar to those activities and pathways associated with negative tumor behaviors and impeded response to treatment. While there are no anecdotal descriptions of poor tumor outcomes in patients treated with PBM, confirming its neutrality with respect to cancer responsiveness is a critical priority.
Based on its therapeutic effects, PBM may have utility in a broad range of oral, oropharyngeal, facial, and neck complications of HNC treatment. Although evidence suggests that PBM using LLLT is safe in HNC patients, more research is imperative and vigilance remains warranted to detect any potential adverse effects of PBM on cancer treatment outcomes and survival.
Chemotherapy; Head and neck cancer; LLLT and PBM; Low level laser therapy; Low level light therapy; Mucositis; Orofacial complications; Photobiomodulation; Radiation therapy; Safet
Effects of laser irradiation at different wavelengths (660, 810, 980, and 1064 nm) on transient receptor potential melastatin channels in an animal model of wound healing.
The aim of the present study was to compare the effectiveness of four different laser wavelengths used for low-level laser therapy(LLLT) on healing of mucositis in an animal model of wound healing, by investigating expression of transient receptor potential melastatin(TRPM) ion channels. Forty-five rats were intraperitoneally injected with 100 mg/kg 5-fluorouracil on day 1 and 65 mg/kg on day 3. Superficial scratching on left cheek pouch mucosa was performed on days 3 and 5. After ulcerative mucositis was clinically detected, LLLT was started (660 nm, HELBO; 810 nm, Fotona-XD; 980 nm, ARC-Fox; and 1064 nm, Fidelis-Plus3) at 8 J/cm2/day from days 1 to 4. Oval excisional biopsy was performed at the wound site, and expression of TRPM2 to TRPM8 was evaluated. Student’s t test was used for evaluation of significance of TRPM gene expression according to “0” value (??=?0.05). In 980-nm group, TRPM4, TRPM6, and TRPM7 were significantly higher than in the control group (p?<?0.005). In 660, 810, and 1064 nm groups, only TRPM6 was significantly higher than in control group (p?<?0.005). There were no significant differences between control and sham groups (p?>?0.05). These findings suggest that expression of TRPM6 gene was significantly affected by irradiation with lasers at different wavelengths, whereas the TRPM4 and TRPM7 genes were only expressed in the 980-nm diode laser group. TRPM6 gene was highly expressed during LLLT, which may lead to accelerated wound healing and tissue repair. In contrast, there was some evidence that the 980-nm diode laser caused increased expression of TRPM4, TRPM6, and TRPM7 which are responsible for stimulation of Ca2+ and Mg2+ metabolism, as well as apoptotic pathways of controlled cell death.
Lasers Med Sci. 2014 Jul 19. [Epub ahead of print]
Effect of low-level laser therapy on inflammatory mediator release during chemotherapy-induced oral mucositis: a randomized preliminary study.
Silva GB1, Sacono NT, Othon-Leite AF, Mendonça EF, Arantes AM, Bariani C, Duarte LG, Abreu MH, Queiroz-Júnior CM, Silva TA, Batista AC.
Patients undergoing hematopoietic stem cell transplantation (HSCT) are submitted to a conditioning regimen of high-dose chemotherapy, with or without radiation therapy, which usually results in oral ulcerations and mucosal barrier breakdown. Oral mucositis (OM) is a common and debilitating toxicity side effect of autologous and allogeneic HSCT. The aim of this study was to evaluate the effect of low-level laser therapy (LLLT) on the severity of OM and inflammatory mediator (TNF-?, IL-6, IL-1?, IL-10, TGF-?, metalloproteinases, and growth factors) levels in saliva and blood of HSCT patients. Thirty patients were randomly assigned to two groups: control (n?=?15) and laser (n?=?15). LLLT was applied from the first day of the conditioning regimen until day 7 post-HSCT (D?+?7). Saliva and blood were collected from patients on admission (AD), D-1, D?+?3, D?+?7, and on marrow engraftment day (ME). Clinical results showed less severe OM in the laser group (p?<?0.05). The LLLT group showed increased matrix metalloproteinase 2 (MMP-2) levels in saliva on D?+?7 (p?=?0.04). Significant differences were also observed for IL-10 on D?+?7 and on ME in blood plasma, when compared to the control group (p?<?0.05). No significant differences were seen in saliva or blood for the other inflammatory mediators investigated. LLLT was clinically effective in reducing the severity of chemotherapy-induced OM in HSCT patients, and its mechanism of action does not seem to be completely linked to the modulation of pro- or anti-inflammatory cytokines, growth factors or matrix metalloproteinases.
Lasers Med Sci. 2013 May 1. [Epub ahead of print]
Effects of laser irradiation at different wavelengths (660, 810, 980, and 1,064 nm) on mucositis in an animal model of wound healing.
Usumez A, Cengiz B, Oztuzcu S, Demir T, Aras MH, Gutknecht N.
Department of Prosthodontics, Bezmialem Vakif University, Vatan Street, Istanbul, Turkey, firstname.lastname@example.org.
The aim of the present study was to compare the effectiveness of four different laser wavelengths (660, 810, 980, and 1,064 nm) used for low-level laser therapy (LLLT) on the healing of mucositis in an animal model of wound healing by investigating the expression of platelet-derived growth factor (PDGF), transforming growth factor beta (TGF-B), and blood-derived fibroblast growth factor (bFGF). Thirty-five male Wistar albino rats with a weight of 250-300 g body mass and 5 months old were used in the study. All animals were intraperitoneally injected with 100 mg/kg of 5-fluorouracil (5-FU) on the first day and 65 mg/kg of 5-FU on the third day. The tip of an 18-gauge needle was used in order to develop a superficial scratching on the left cheek pouch mucosa by dragging twice in a linear movement on third and fifth days. After ulcerative mucositis were clinically detected on the animals’ left cheek pouch mucosa, the laser therapy was started. Four different laser wavelengths (660 nm, HELBO, Bredent; 810 nm, Fotona XD, Fotona; 980 nm, ARC Fox; and 1,064 nm, Fidelis Plus 3, Fotona) used for LLLT at ED 8 J/cm2 daily from the first to the fourth days. Oval excisional biopsy was taken from the site of the wound, and the expression of PDGF, TGF-B, and bFGF was evaluated. The obtained data were analyzed by one2-way ANOVA, and then Tukey HSD tests were used for pairwise comparisons among groups (??=?0.05). The one-way ANOVA test indicated that expression values of the growth factors, PDGF and bFGF, were significantly affected by irradiation of different wavelengths of lasers (p?<?0.001). However, expression value of the TGF-? was not affected by irradiation of different wavelengths of lasers (p?>?0.05). The highest PDGF expression was detected in neodymium-doped yttrium aluminum garnet (Nd:YAG) laser group (p?<?0.05), and there were no statistically significant differences among the other groups (p?>?0.05). The highest bFGF expression was detected in 980-nm diode and Nd:YAG laser groups (p?<?0.05), and there were no statistically significant differences among the other groups (p?>?0.05). These findings suggest that low-level Nd:YAG and 980-nm diode laser therapy accelerate the wound healing process by changing the expression of PDGF and bFGF genes responsible for the stimulation of the cell proliferation and fibroblast growth.
Support Care Cancer. 2012 Dec 8. [Epub ahead of print]
Effect of low-level laser therapy on patient reported measures of oral mucositis and quality of life in head and neck cancer patients receiving chemoradiotherapy-a randomized controlled trial.
Gautam AP, Fernandes DJ, Vidyasagar MS, Maiya AG, Nigudgi S.
Department of Radiotherapy and Oncology, Kasturba Medical College and Hospital, Manipal University, Manipal, Karnataka 576104, India, email@example.com.
Chemoradiotherapy (CRT)-induced oral mucositis (OM) adversely affects a patient’s oral functions and quality of life (QOL). Low-level laser therapy (LLLT) showed some preventive and curative effects against clinically reported objective measures of OM in few trials including our recently published study. There is dearth of evidence regarding the effects of LLLT on patient’s subjective experience of OM and QOL. Hence, we did this study to evaluate the effects of LLLT on a patient’s reported measures of OM and QOL in head and neck cancer (HNC) patients receiving CRT.
This triple blinded study randomized 220 HNC patients scheduled for CRT (three weekly Cisplatin?+?RT?=?66 Gray (2 Gy/session), five fractions/week for 6.5 weeks, total 33 fractions) into laser (110) and placebo (110) groups. The laser group received LLLT (Technomed Electronics Advanced Laser Therapy 1000, He-Ne, ??=?632.8 nm, power density?=?24 mW/cm(2), dosage?=?3.0 J at each point, total dose/session?=?36-40 J, spot size 1 cm(2), irradiation time/point 125 s) before each radiation session, while the placebo group did not receive laser therapy. Methodology was similar to our recently published study (Gautam et al. Radiother Oncol 104:349-354, 2012). In this part of our study, a blinded assessor collected subjective outcomes of the patient’s reported measures of OM using Oral Mucositis Weekly Questionnaire-Head and Neck (OMWQ-HN) and QOL using Functional Assessment of Cancer Treatment-Head and Neck (FACT-HN) Questionnaire. Data were analyzed using repeated measure ANOVA through general linear model. Statistical significance was kept at p <?0.05.
Results analysis revealed that OMWQ-HN (F?=?12.199, df =?6,1314, p?<?0.001) and FACT-HN (p?<?0.05) scores were significantly lower in LLLT than placebo group patients. Also, a significant reduction (p?<?0.001) in incidence of severe OM, need for opioid analgesics, and total parenteral nutrition was observed.
LLLT was effective in improving the patient’s subjective experience of OM and QOL in HNC patients receiving CRT.
Support Care Cancer. 2012 Jul;20(7):1405-15. doi: 10.1007/s00520-011-1223-8. Epub 2011 Jul 3.
Amelioration of oral mucositis pain by NASA near-infrared light-emitting diodes in bone marrow transplant patients.
Hodgson BD, Margolis DM, Salzman DE, Eastwood D, Tarima S, Williams LD, Sande JE, Vaughan WP, Whelan HT.
Pediatric Dentistry, Marquette University School of Dentistry, 1801 W Wisconsin Ave, Rm 326, Milwaukee, WI 53233, USA. firstname.lastname@example.org
This study seeks to investigate the use of extra-orally applied near-infrared phototherapy for the reduction of oral pain secondary to chemotherapy- and radiation therapy-induced mucositis in adult and pediatric hematopoietic stem cell transplant (HSCT) patients.
Eighty HSCT patients were divided into regular (R) and low (L) risk groups, then to experimental (E) and placebo (P) groups, resulting in four groups (ER, EL, PR, PL). Experimental subjects received 670 (± 10) nm gallium-aluminum-arsinide light-emitting diode device for 80 s at ~50 mW/cm(2) energy density and power exposure of 4 J/cm(2). Placebo patients received the same procedures, but with a placebo phototherapy (identical device but <5 mW/cm(2) energy density). Patients received their respective light therapy once per day starting on the day of the HSCT (day 0) and continued through day +14. Blinded evaluators examined the patients three times per week and scored their oral tissues and patient-reported pain assessments at each evaluation utilizing the WHO, NCI-CTCAE, and OMAS scales.
Analysis of the mean scores at each observation demonstrate that the extra-oral application of phototherapy resulted in a significant reduction in patient-reported pain between the ER and PR patients (p < 0.05) at day +14 when graded via the WHO criteria. The ER and EL patients were improved in almost all other categories and assessment scales, but the differences were not statistically significant.
Phototherapy demonstrated a significant reduction in patient-reported pain as measured by the WHO criteria in this patient population included in this study. Improvement trends were noted in most other assessment measurements.
Eur Arch Paediatr Dent. 2011 Apr;12(2):124-7.
Chemotherapy-induced oral mucositis in a patient with acute lymphoblastic leukaemia.
Rimulo AL, Ferreira MC, Abreu MH, Aguirre-Neto JC, Paiva SM.
School of Dentistry, Itauna University, Minas Gerais, Brazil.
Oral mucositis is the main complication of chemotherapy and radiotherapy used in the treatment of cancer. Phototherapy has proven effective in the treatment of mucositis, as it accelerates the tissue healing process and has both analgesic and anti-inflammatory properties.
This paper reports the case of a paediatric patient with oral mucositis stemming from chemotherapy employed for the treatment of acute lymphoblastic leukaemia.
The lesions were treated daily with a light-emitting diode (LED). FOLLOWUP: Remission of the lesions occurred after 10 days of treatment.
Low level laser therapy in oral mucositis: a pilot study.
Cauwels RG, Martens LC.
Dr Rita Cauwels. Dept Paediatric Dentistry, University Hospital (P8), De Pintelaan 158, B 9000 Ghent, Belgium. Email: email@example.com.
AIM: The goal of this pilot study was to investigate the capacity of pain relief and wound healing of low level laser therapy (LLLT) in chemotherapy-induced oral mucositis (OM) in a paediatric oncology population group.
STUDY DESIGN AND METHODS: 16 children (mean age 9.4 years) from the Gent University Hospital – Department Paediatric Oncology/haematology, suffering from chemotherapy-induced OM were selected. During clinical investigations, the OM grade was assessed using the WHO classification. All children were treated using a GaAlAs diode laser with 830 nm wavelength and a potency of 150 mW. The energy released was adapted according to the severity of the OM lesions. The same protocol was repeated every 48 hrs until healing of each lesion occurred. Subjective pain was monitored before and immediately after treatment by an appropriate pain scale and functional impairment was recorded. At each visit, related blood cell counts were recorded.
RESULTS: After 12 mths, records were evaluated and information about treatment sequence, treatment sessions and frequencies related to the pain sensation and comfort were registered. Immediately after beaming the OM, pain relief was noticed. Depending on the severity of OM, on average, 2.5 treatments per lesion in a period of 1 week were sufficient to heal a mucositis lesion.
CONCLUSIONS: LLLT, one of the most recent and promising treatment therapies, has been shown to reduce the severity and duration of mucositis and to relieve pain significantly. In the present study similar effects were obtained with the GaAlAs 830nm diode laser. It became clear that using the latter diode device, new guidelines could be developed as a function of the WHO-OM grades i.e. the lower the grade, the less energy needed. Immediate pain relief and improved wound healing resolved functional impairment that was obtained in all cases.
Braz Dent J. 2010;21(3):186-92.
Efficacy of low-level laser therapy and aluminum hydroxide in patients with chemotherapy and radiotherapy-induced oral mucositis.
Lima AG, Antequera R, Peres MP, Snitcosky IM, Federico MH, Villar RC.
Clinics Hospital, Medical School, University of São Paulo, São Paulo, SP, Brazil.
This study evaluated the efficacy of low-level laser therapy (LLLT) and aluminum hydroxide (AH) in the prevention of oral mucositis (OM). A prospective, comparative and non-randomized study was conducted with 25 patients with head and neck cancer subjected to radiotherapy (RT) or radiochemotherapy (RCT). Twelve patients received LLLT (830 nm, 15 mW, 12 J/cm²) daily from the 1st day until the end of RT before each sessions during 5 consecutive days, and the other 13 patients received AH 310 mg/5 mL, 4 times/day, also throughout the duration of RT, including weekends. OM was measured using an oral toxicity scale (OTS) and pain was measured using the visual analogue scale (VAS). EORTC questionnaires were administered to the evaluate impact of OM on quality of life. The LLLT group showed lower mean OTS and VAS scores during the course of RT. A significant difference was observed in pain evaluation in the 13th RT session (p=0.036). In both groups, no interruption of RT was needed. The prophylactic use of both treatments proposed in this study seems to reduce the incidence of severe OM lesions. However, the LLLT was more effective in delaying the appearance of severe OM.
Cochrane Database Syst Rev. 2010 Aug 4;8:CD001973.
Interventions for treating oral mucositis for patients with cancer receiving treatment.
Clarkson JE, Worthington HV, Furness S, McCabe M, Khalid T, Meyer S.
Dental Health Services Research Unit, University of Dundee, The Mackenzie Building, Kirsty Semple Way, Dundee, UK, DD2 4BF.
BACKGROUND: Treatment of cancer is increasingly effective but associated with short and long term side effects. Oral side effects, including oral mucositis (mouth ulceration), remain a major source of illness despite the use of a variety of agents to treat them. OBJECTIVES: To assess the effectiveness of interventions for treating oral mucositis or its associated pain in patients with cancer receiving chemotherapy or radiotherapy or both. SEARCH STRATEGY: Electronic searches of Cochrane Oral Health Group and PaPaS Trials Registers (to 1 June 2010), CENTRAL via The Cochrane Library (to Issue 2, 2010), MEDLINE via OVID (1950 to 1 June 2010), EMBASE via OVID (1980 to 1 June 2010), CINAHL via EBSCO (1980 to 1 June 2010), CANCERLIT via PubMed (1950 to 1 June 2010), OpenSIGLE (1980 to 1 June 2010) and LILACS via the Virtual Health Library (1980 to 1 June 2010) were undertaken. Reference lists from relevant articles were searched and the authors of eligible trials were contacted to identify trials and obtain additional information. SELECTION CRITERIA: All randomised controlled trials comparing agents prescribed to treat oral mucositis in people receiving chemotherapy or radiotherapy or both. Outcomes were oral mucositis, time to heal mucositis, oral pain, duration of pain control, dysphagia, systemic infection, amount of analgesia, length of hospitalisation, cost and quality of life. DATA COLLECTION AND ANALYSIS: Data were independently extracted, in duplicate, by two review authors. Authors were contacted for details of randomisation, blindness and withdrawals. Risk of bias assessment was carried out on six domains. The Cochrane Collaboration statistical guidelines were followed and risk ratio (RR) values calculated using fixed-effect models (less than 3 trials in each meta-analysis). MAIN RESULTS: Thirty-two trials involving 1505 patients satisfied the inclusion criteria. Three comparisons for mucositis treatment including two or more trials were: benzydamine HCl versus placebo, sucralfate versus placebo and low level laser versus sham procedure. Only the low level laser showed a reduction in severe mucositis when compared with the sham procedure, RR 5.28 (95% confidence interval (CI) 2.30 to 12.13).Only 3 comparisons included more than one trial for pain control: patient controlled analgesia (PCA) compared to the continuous infusion method, therapist versus control, cognitive behaviour therapy versus control. There was no evidence of a difference in mean pain score between PCA and continuous infusion, however, less opiate was used per hour for PCA, mean difference 0.65 mg/hour (95% CI 0.09 to 1.20), and the duration of pain was less 1.9 days (95% CI 0.3 to 3.5). AUTHORS’ CONCLUSIONS: There is weak and unreliable evidence that low level laser treatment reduces the severity of the mucositis. Less opiate is used for PCA versus continuous infusion. Further, well designed, placebo or no treatment controlled trials assessing the effectiveness of interventions investigated in this review and new interventions for treating mucositis are needed.
Photomed Laser Surg. 2009 Apr;27(2):371-4.
Improvement in quality of life of an oncological patient by laser phototherapy.
Campos L, Simões A, Sá PH, Eduardo Cde P.
Oral Biology Research Center, Department of Biomaterials and Oral Biochemistry, School of Dentistry, University of São Paulo, São Paulo, Brazil.
OBJECTIVE AND BACKGROUND DATA: Common side effects of radiotherapy (RT) to the head and neck include oral mucositis, xerostomia, and severe pain. The aim of this study is to report improvement in the quality of life of an oncological patient by laser phototherapy (LPT). CLINICAL CASE AND LASER
PHOTOTHERAPY PROTOCOL: The patient, a 15-year-old girl diagnosed with mucoepidermoid carcinoma, underwent surgical excision of a tumor of the left palatomaxilla. After that, she was subjected to 35 sessions of RT (2 Gy/d). Clinical examination revealed the spread of severe ulcerations to the jugal mucosa, gums, lips, hard palate, and tongue (WHO mucositis score 3). She had difficulty in moving her tongue and she was unable to eat any solid food. Oral hygiene orientation and LPT were performed throughout all RT sessions. A continuous diode laser, 660 nm, 40 mW, 6 J/cm(2), 0.24 J per point in contact mode, with spot size of 0.04 cm(2) was used in the entire oral cavity. A high-power diode laser at 1 W, 10 sec per cm of mucositis, approximately 10 J/cm(2), was used in defocused mode only on ulcerative lesions. After the first laser irradiation session, decreases in pain and xerostomia were reported; however, a more significant improvement was seen after five sessions. At that point although the mucositis score was still 2, the patient reported that she was free of pain, and consequently a palatine plate could be made to rehabilitate the entire surgical area. Seventeen laser irradiation sessions were necessary to eliminate all oral mucositis lesions.
CONCLUSION: Normal oral function and consequent improvements in the quality of life of this oncologic patient were observed with LPT.
J Pediatr Hematol Oncol. 2009 Jan;31(1):33-7.
Low-level infrared laser therapy in chemotherapy-induced oral mucositis: a randomized placebo-controlled trial in children.
Kuhn A, Porto FA, Miraglia P, Brunetto AL.
Pediatric Oncology Unit, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Brazil. firstname.lastname@example.org
BACKGROUND: Oral mucositis (OM) is one of the most frequent complications of chemotherapy for which there is no standard therapy; treatment is mostly conservative. This study was conducted to determine whether low-intensity laser therapy (LLLT) can reduce the duration of chemotherapy-induced OM. PROCEDURE: A placebo-controlled randomized trial was carried out using LLLT or placebo (sham treatment). Children and adolescents with cancer receiving chemotherapy or hematopoietic stem-cell transplantation between October 2005 and May 2006 were eligible as soon as they developed OM. Patients received intervention for 5 days. The LLLT group was treated with laser GaAlAs, wavelength (lambda): 830 nm (infrared), power: 100 mW, dose: 4 J/cm, and placebo group underwent sham treatment. The grade of OM was clinically assessed by the National Cancer Institute, Common Toxicity Criteria scale. RESULTS: Twenty-one patients developed OM and were evaluable for analysis; 18 (86%) patients had a diagnosis of leukemia or lymphoma and 3(14%) had solid tumors. The mean age was 8.2 (+/-3.1) years. Nine patients were randomized in the laser group and 12 in the placebo-control group. Once OM was diagnosed, the patients had daily OM grading assessments before laser or sham application and thereafter until complete healing of the lesions. On day 7 after OM diagnosis, 1/9 of patients remained with lesions in laser group and 9/12 of patients in the placebo-control group (P=0.029). In the laser group, the mean of OM duration was 5.8+/-2 days and in the placebo group was 8.9+/-2.4 days (P=0.004). CONCLUSIONS: Our study has shown evidence that laser therapy in addition to oral care can decrease the duration of chemotherapy-induced OM. Our results confirm the promising results observed in adult cancer patients and should encourage pediatric oncologists to use laser therapy as first-line option in children with chemotherapy-induced OM.
Braz Dent J. 2009;20(3):215-20.
Use of therapeutci laser for prevention and treatment of oral mucositis.
Khouri VY, Stracieri AB, Rodrigues MC, Moraes DA, Pieroni F, Simões BP, Voltarelli JC.
University Hospital, University of São Paulo, Ribeirão Preto, SP, Brazil. email@example.com
Oral mucositis (OM) affects patients who are submitted to hematopoietic stem cell transplantation (HSCT) due to high doses of chemotherapy and/or radiotherapy. The purpose of this investigation was to perform a comparative study of the frequency and evolution of OM among patients subjected to therapeutic laser and to the conventional therapy (use of mouthwash called ‘Mucositis Formula’). The patients were subjected to a myeloablative conditioning regimen before the allogeneic HSCT. Twenty-two patients were selected and divided into 2 groups: group I was irradiated with InGaAlP laser (660 nm) and GaAlAs laser (780 nm), 25 mW potency, 6.3J/cm(2) dose, in 10-s irradiation time, followed to conventional treatment; group II was subjected only to the conventional treatment. Both World Health Organization (WHO) scale and the Oral Mucositis Assessment Scale (OMAS) were used to evaluate the results. Data were analyzed by the non-parametric Wilcoxon test, with p<0.05 considered as statistically significant. Group I presented a lower frequency of OM (p=0.02) and lower mean scores, according to WHO and OMAS scales (p<0.01 and p=0.01, respectively). In conclusion, laser reduced the frequency and severity of OM, suggesting that therapeutic laser can be used both as a new form of prevention and treatment of OM.
Lasers Surg Med. 2009 Apr;41(4):264-70.
Laser phototherapy as topical prophylaxis against head and neck cancer radiotherapy-induced oral mucositis: comparison between low and high/low power lasers.
Simões A, Eduardo FP, Luiz AC, Campos L, Sá PH, Cristófaro M, Marques MM, Eduardo CP.
Centro de Pesquisa em Biologia Oral, Departamento de Materiais Dentários, Faculdade de Odontologia, Universidade de São Paulo (FOUSP), São Paulo 05508-900, Brazil. firstname.lastname@example.org
BACKGROUND AND OBJECTIVE: Oral mucositis is a dose-limiting and painful side effect of radiotherapy (RT) and/or chemotherapy in cancer patients. The purpose of the present study was to analyze the effect of different protocols of laser phototherapy (LPT) on the grade of mucositis and degree of pain in patients under RT. PATIENTS AND METHODS: Thirty-nine patients were divided into three groups: G1, where the irradiations were done three times a week using low power laser; G2, where combined high and low power lasers were used three time a week; and G3, where patients received low power laser irradiation once a week. The low power LPT was done using an InGaAlP laser (660 nm/40 mW/6 J cm(-2)/0.24 J per point). In the combined protocol, the high power LPT was done using a GaAlAs laser (808 nm, 1 W/cm(2)). Oral mucositis was assessed at each LPT session in accordance to the oral-mucositis scale of the National Institute of the Cancer-Common Toxicity criteria (NIC-CTC). The patient self-assessed pain was measured by means of the visual analogue scale. RESULTS: All protocols of LPT led to the maintenance of oral mucositis scores in the same levels until the last RT session. Moreover, LPT three times a week also maintained the pain levels. However, the patients submitted to the once a week LPT had significant pain increase; and the association of low/high LPT led to increased healing time. CONCLUSIONS: These findings are desired when dealing with oncologic patients under RT avoiding unplanned radiation treatment breaks and additional hospital costs.
Photomed Laser Surg. 2008 Aug;26(4):393-400.
Low-level laser therapy in the prevention and treatment of chemotherapy-induced oral mucositis in young patients.
Abramoff MM, Lopes NN, Lopes LA, Dib LL, Guilherme A, Caran EM, Barreto AD, Lee ML, Petrilli AS.
Private practice, São Paulo, Brazil.
Abstract Objective: A pilot clinical study was conducted to evaluate the efficacy and feasibility of low-level laser therapy (LLLT) in the prevention and treatment of chemotherapy (CT)-induced oral mucositis (OM) in young patients. Background Data: Besides compromising the patient’s nutrition and well-being, oral mucositis represents a portal of entry into the body for microorganisms present in the mouth, which may lead to sepsis if there is hematological involvement. Oncologic treatment tolerance decreases and systemic complications may arise that interfere with the success of cancer treatment. LLLT appears to be an interesting alternative to other approaches to treating OM, due to its trophic, anti-inflammatory, and analgesic properties. Materials and Methods: Patients undergoing chemotherapy (22 cycles) without mucositis were randomized into a group receiving prophylactic laser-irradiation (group 1), and a group receiving placebo light treatment (group 2). Patients who had already presented with mucositis were placed in a group receiving irradiation for therapeutic purposes (group 3, with 10 cycles of CT). Serum granulocyte levels were taken and compared to the progression of mucositis. Results: In group 1, most patients (73%) presented with mucositis of grade 0 (p = 0.03 when compared with the placebo group), and 18% presented with grade 1. In group 2, 27% had no OM and did not require therapy. In group 3, the patients had marked pain relief (as assessed by a visual analogue scale), and a decrease in the severity of OM, even when they had severe granulocytopenia. Conclusion: The ease of use of LLLT, high patient acceptance, and the positive results achieved, make this therapy feasible for the prevention and treatment of OM in young patients.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008 Feb;105(2):180-6, 186.e1.
Efficacy of He-Ne Laser in the prevention and treatment of radiotherapy-induced oral mucositis in oral cancer patients.
Arora H, Pai KM, Maiya A, Vidyasagar MS, Rajeev A.
Department of Oral Medicine and Radiology, Manipal College of Dental Sciences, Manipal, Karnatka, India. email@example.com
OBJECTIVE: The objective of this study was to evaluate the efficacy of low-level lasers for the prevention and treatment of radiotherapy-induced oral mucositis in oral cancer patients. MATERIAL AND METHODS: Twenty-four hospitalized patients with oral cancer, scheduled to undergo radiotherapy at KMC, Manipal, were enrolled in the present study and assigned to laser (Group I)/control group (Group II). They were treated using He-Ne laser (lambda = 632.8nm, output = 10 mW and energy density = 1.8 J/cm(2)). Patients were subjected to treatment using laser scanner for 8 days and subsequently were treated using laser probe at 6 anatomic sites in the oral cavity for 5 minutes each. The patients were evaluated on each day of treatment for pain severity (NRS), functional impairment (FIS), and oral mucositis (RTOG) and were followed until the end of cancer treatment. Statistical analysis was done using SPSS version 10. RESULTS: Laser therapy applied prophylactically during radiotherapy can reduce the severity of oral mucositis, severity of pain, and functional impairment.
Oral Dis. 2007 Nov;13(6):538-43.
Low-energy laser therapy for prevention of oral mucositis in hematopoietic stem cell transplantation.
Jaguar GC, Prado JD, Nishimoto IN, Pinheiro MC, de Castro DO Jr, da Cruz Perez DE, Alves FA.
Department of Stomatology, Cancer Hospital A.C. Camargo, São Paulo, Brazil.
AIM: To evaluate the clinical effects of laser therapy on the prevention and reduction of oral mucositis in patients who underwent hematopoietic stem cell transplantation (HSCT). PATIENTS AND METHODS: From January 2003 to September 2004, 24 patients received prophylactic laser therapy (L+ group). The applications started from the beginning of the conditioning regimen up to day +2. The oral assessment was performed daily until day +30. This group was compared with historical controls, namely 25 patients, who did not receive laser therapy (L- group). RESULTS: All patients developed some grade of mucositis. However, the L- group presented initial mucositis by 4.36 days, whereas the L+ group presented it in 6.12 days (P = 0.01). The maximum mucositis occurred between day +2 and day +6 with healing by day +25 in the L- group and between day +2 and day +7 with healing by day +14 for the L+ group (P = 0.84). Laser therapy also reduced the time of oral pain from 5.64 to 2.45 days (P = 0.04), and decreased the consumption of morphine (P = 0.07). CONCLUSION: This study suggests that laser therapy can be useful in oral mucositis to HSCT patients and improve the patient’s quality of life. However, controlled randomized trials should be performed to confirm the real efficacy of laser therapy.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007 Jun;103(6):764-73. Epub 2006 Nov 7.
A preliminary study of healing of diode laser versus scalpel incisions in rat oral tissue: a comparison of clinical, histological and immunohistochemical results.
D’Arcangelo C, Di Nardo Di Maio F, Prosperi GD, Conte E, Baldi M, Caputi S.
University G. D’Annunzio, Faculty of Medicine, Department of Oral Science, Unit of Restorative Dentistry, Chieti, Italy.
OBJECTIVE: The aim of this preliminary study was to compare wound healing of rat oral tissues after surgical procedure with diode laser or scalpel. Healing was evaluated histologically, immunohistochemically, and by measurement of 2 nitric oxide synthase isoforms (eNOS and iNOS) as intracellular messenger molecules with important immune functions. The instruments were also evaluated for performance and ease of use. STUDY DESIGN: Twenty-four standardized incisions were performed in the hard palate of 12 male Wistar rats. Each rat received 2 incisions on the opposite sides of the palate by using a steel scalpel (control group) and a diode laser (808 nm) at a power output of 4 W and 6 W (test group). Histological and immunohistochemical analyses were performed on tissue samples after 7 and 14 days. The expression of eNOS and iNOS was confirmed by RT-PCR (reverse transcriptase-polymerase chain reaction) and Western blot analysis. RESULTS: Scalpel repair was found to be equivalent to or better than laser repair at the intervals measured. Histological analysis showed that incision wound repair after laser surgical procedure was related to parameters and beam characteristics. Diode laser at a power output of 6 W showed the worst results of tissue repair, especially after 7 days. On the contrary, the extent of epithelial damage lateral to the wound edge and the extent of collagen denaturation were near equal with scalpel incision and laser irradiation at 4 W after 14 days. Biochemical analysis of RT-PCR and Western blots also confirmed histological results with a greater concentration of eNOS and iNOS after 7 days of laser surgical procedure. CONCLUSIONS: Clinical and histological findings change over time for different treatments. Diode laser tends to produce more pronounced changes than conventional scalpel surgical procedure (due to tissue thermal damage), with corresponding greater inflammatory reaction and delay in tissue organization only at the initial stage. Thus, long-term histology is critical for predicting treatment results. The clinical use of low-level diode laser for tissue welding of oral mucosa should be investigated further, since it appears to be a good alternative to scalpel incision and suture repair.
Indian J Med Res. 2006 Oct;124(4):399-402.
Effect of low level helium-neon (He-Ne) laser therapy in the prevention & treatment of radiation induced mucositis in head & neck cancer patients.
Arun Maiya G, Sagar MS, Fernandes D.
Departments of Physiotherapy , Manipal College of Allied Health Sciences, Kasturba Medical College, MAHE University, Manipal, India. firstname.lastname@example.org
BACKGROUND & OBJECTIVES: Oral mucositis is a common debilitating complication of radiotherapy occurring in about 60 per cent of cancer patients. Considerable buccal toxicity of radiotherapy or chemotherapy in cancer patients to become discouraged and can affect their quality of life. In addition, such toxicity can alter the treatment plan. At present, there is no clinically appropriate prophylaxis efficacious antidote for mucositis. The low level laser (LEL) appears to be a simple, non-traumatic technique for the prevention and treatment of radiation induced mucositis. Therefore the present study was carried out to find out the effect of low-level helium-neon (He-Ne) laser in the prevention and treatment of radiation induced mucositis in head and neck cancer patients. METHODS: The patients with carcinoma of oral cavity with stages II-IV a being uniformly treated with curative total tumour dose of 66 Gy in 33 fractions over 6 wk were selected for the study. The patients were divided based on computer generated randamosization into laser (study group) and control groups with 25 patients in each group. Both study and control groups were comparable in terms of site of the lesion, stage of the cancer and histology. The study group patients were treated with He-Ne laser (wavelength 632.8 nm and output of 10mW) and control group patients were given oral analgesics, local application of anaesthetics, 0.9 per cent saline and povidine wash during the course of radiotherapy. RESULTS: All patients tolerated the laser treatment without any adverse effect or reactions. The result showed a significant difference in pain and mucositis (P<0.001) between the two groups. At the end of radiotherapy (after 6 wk) mean pain sure and mucositis grade were significantly lower (P<0.001) in the study group compared to control. INTERPRETATION & CONCLUSION: The low-level He-Ne laser therapy during the radiotherapy treatment was found to be effective in preventing and treating the mucositis in head and neck cancer patients. Further studies need to be done on a larger sample to find the mechanism.
Int Nurs Rev. 2005 Mar;52(1):68-72
Patients with moderate chemotherapy-induced mucositis: pain therapy using low intensity lasers.
Nes AG, Posso MB.
Buskerud University, Drammen, Norway. email@example.com
BACKGROUND: Intensive cancer therapy normally affects malignant and normal cells with high replication rates. Cells in the gastrointestinal tract are therefore commonly affected by cytotoxins. This often results in the development of chemotherapy-induced oral mucositis (COM). COM is the inflammatory response of the oral mucous membrane to the chemotherapy drugs. Low level laser therapy (LLLT) has proved to be effective in treating and repairing biologically damaged tissue and to reduce pain. LLLT has also proven to be an efficient method for the prevention of oral mucositis. OBJECTIVE: To investigate the effect of LLLT on pain relief among patients who have developed COM. METHOD: The study was performed as a clinical test with a sample consisting of 13 adult patients receiving oncology treatment. The patients were treated during a 5-day period, and the pain was measured before and after each laser application. The laser used was an AsGaAl, with a wavelength of 830 nm and a potency of 250 mW. The energy given was 35 J cm(-2). ANALYSIS: The results were analysed using the Wilcoxon test. RESULTS: There was a significant (P = 0.007) 67% decrease in the daily average experience of pain felt before and after each treatment, confirming that LLLT can relieve pain among patients who have developed COM. STUDY LIMITATIONS: The low number of COM patients at the hospital did not allow a control group to be included in the study, and therefore the results contain a potential placebo effect. IMPLICATIONS FOR NURSING CARE: The most important benefit the authors consider to be the value for the patients of better and quicker treatment with a drastic reduction in painful mucositis..
Cancer J. 2002 May-Jun;8(3):247-54.
Pilot study of laser effects on oral mucositis in patients receiving chemotherapy.
Wong SF, Wilder-Smith P.
Western University of Health Sciences, College of Pharmacy, Division of Hematology/Oncology, Pomona, California 91766, USA.
PURPOSE: The purpose of this study was to examine the effectiveness of laser therapy in the prevention and/or healing of chemotherapy-induced oral mucositis lesions. This study also evaluated the ease and feasibility of the laser therapy and the impact of the treatment on improving the patient’s quality of life. PATIENTS AND METHODS: Fifteen patients with an episode of prior chemotherapy-induced grade 3 or 4 mucositis with 5-fluorouracil continuous infusion consented to participate in this study. All patients were provided with standardized mouth care instructions at the initiation of chemotherapy treatments. Enrolled patients received laser therapy treatments 24 hours before the chemotherapy and then recommenced weekly with evenly distributed exposure to the standardized designated areas by one operator during the entire cycle of chemotherapy at the same doses until the mucositis resolved or the chemotherapy cycle was completed. lntraoral perfusion was measured by laser Doppler technology. Patients were assessed for response to laser therapy according to standardized mucositis grading criteria by evaluating development of lesions, extent and duration of lesions, and time to healing. The effect of laser therapy on ability to continue planned chemotherapy, the reduction in dose, delays, and ability to maintain planned dose intensity were assessed. The impact of laser therapy on pain control was evaluated using the visual analogue score. A quality-of-life survey was completed by each patient at the initiation of chemotherapy and then weekly throughout the chemotherapy. RESULTS: Eleven of 15 patients experienced grade 0 mucositis, three patients experienced grade 1 to 2 mucositis, and one patient experienced grade 3 to 4 mucositis. Fourteen patients completed the lasertherapy as planned, and none of the patients withdrew from the laser therapy treatments because of noncompliance. One patient continued to experience grade 4 mucositis that necessitated an interruption in the planned chemotherapy regimen and, consequently, the laser treatment. Patients tolerated the laser therapy very well and did not report any increased discomfort. No significant changes in perfusion were observed as a result of laser therapy. DISCUSSION: In this pilot study, laser therapy significantly reduced the incidence and the severity of mucositis in chemotherapy patients. The laser therapy does not appear to promote wound healing by affecting the intraoral perfusion, as assessed by Doppler measurements. The mechanisms involved in the mediating of the observed effects remain unknown at this time. Continued research is warranted to determine the optimal laser wavelength and parameters.
Support Care Cancer. 1999 Jul;7(4):244-52.
Low-energy He/Ne laser in the prevention of radiation-induced mucositis. A multicenter phase III randomized study in patients with head and neck cancer.
Bensadoun RJ, Franquin JC, Ciais G, Darcourt V, Schubert MM, Viot M, Dejou J, Tardieu C, Benezery K, Nguyen TD, Laudoyer Y, Dassonville O, Poissonnet G, Vallicioni J, Thyss A, Hamdi M, Chauvel P, Demard F.
External Radiotherapy Unit, Centre Antoine-Lacassagne, Nice, France. firstname.lastname@example.org
Use of the low-energy helium-neon laser (LEL) appears to be a simple atraumatic technique for the prevention and treatment of mucositis of various origins. Preliminary findings, and significant results obtained for chemotherapy-induced mucositis in a previous phase III study, prompted a randomized multicenter double-blind trial to evaluate LEL in the prevention of acute radiation-induced stomatitis. Irradiation by LEL corresponds to local application of a high-photon-density monochromatic light source. Activation of epithelial healing for LEL-treated surfaces, the most commonly recognized effect, has been confirmed by numerous in vitro studies. The mechanism of action at a molecular and enzymatic level is presently being studied. From September 1994 to March 1998, 30 patients were randomized. Technical specification: 60 mW (25 mW at Reims, 1 patient), He-Ne, wavelength 632.8 nm. The trial was open to patients with carcinoma of the oropharynx, hypopharynx and oral cavity, treated by radiotherapy alone (65 Gy at a rate of 2 Gy/fraction, 5 fractions per week) without prior surgery or concomitant chemotherapy. The malignant tumor had to be located outside the tested laser application areas (9 points): posterior third of the internal surfaces of the cheeks, soft palate and anterior tonsillar pillars. Patients were randomized to LEL or placebo light treatment, starting on the first day of radiotherapy and before each session. The treatment time (t) for each application point was given by the equation : t(s)= energy (J/cm2) x surface (cm2)/Power (W). Objective assessment of the degree of mucositis was recorded weekly by a physician blinded to the type of treatment, using the WHO scale for grading of mucositis and a segmented visual analogue scale for pain evaluation. Protocol feasibility and compliance were excellent. Grade 3 mucositis occured with a frequency of 35.2% without LEL and of 7.6% with LEL (P<0.01). The frequency of “severe pain” (grade 3) was 23.8% without LEL, falling to 1.9% with LEL (P<0.05). Pain relief was significantly reduced throughout the treatment period (weeks 2-7). LEL therapy is capable of reducing the severity and duration of oral mucositis associated with radiation therapy. In addition, there is a tremendous potential for using LEL in combined treatment protocols utilizing concomitant chemotherapy and radiotherapy.
Int J Radiat Oncol Biol Phys. 1997 Jul 1;38(4):697-703.
Low energy Helium-Neon laser in the prevention of oral mucositis in patients undergoing bone marrow transplant: results of a double blind randomized trial.
Cowen D, Tardieu C, Schubert M, Peterson D, Resbeut M, Faucher C, Franquin JC.
Department of Radiotherapy, Institut Paoli-Calmettes, Cancer Center, Marseilles, France.
PURPOSE: To evaluate the efficiency of Helium-Neon (He-Ne) laser in the prevention of oral mucositis induced by high dose chemoradiotherapy before autologous bone marrow transplantation (BMT). METHODS AND MATERIALS: Between 1993 and 1995, 30 consecutive patients receiving an autologous peripheral stem-cell or bone marrow transplant (BMT) after high dose chemoradiotherapy were randomized to possibly receive prophylactic laser to the oral mucosa after giving informed consent. Chemotherapy consisted of cyclophosphamide, 60 mg/kg intravenously (I.V.) on day (d)-5 and d-4 in 27 cases, or melphalan 140 mg/kg I.V. on d-4 in three cases. Total body irradiation (TBI) consisted of 12 Gy midplane dose in six fractions (4 Gy/day for three days). He-Ne laser (632.8 nm wavelength, power 60 mW) applications were performed daily from d-5 to d-1 on five anatomic sites of the oral mucosa. Oral examination was performed daily from d0 to d + 20. Mucositis was scored according to an oral exam guide with a 16 item scale of which four were assessed by the patients themselves. Mean daily self assessment scores for oral pain, ability to swallow and oral dryness were measured. A daily mucositis index (DMI) and a cumulative oral mucositis score (COMS) were established. Requirement for narcotics and parenteral nutrition was recorded. RESULTS: The COMS was significantly reduced among laser treated (L+) patients (p = 0.04). The improvement of DMI in L+ patients was also statistically significant (p < 0.05) from d + 2 to d + 7. Occurrence and duration of grade III oral mucositis were reduced in L+ patients (p = 0.01). Laser applications reduced oral pain as assessed by patients (p = 0.05) and L+ patients required less morphine (p = 0.05). Xerostomia and ability to swallow were improved among the L+ patients (p = 0.005 and p = 0.01, respectively). Requirement for parenteral nutrition was not reduced (p = NS). CONCLUSION: Helium-Neon laser treatment was well tolerated, feasible in all cases, and reduced high dose chemoradiotherapy-induced oral mucositis. Optimal laser treatment schedules still needs to be defined.
HeNe laser reduces mucositis
a) Barasch B et al. Helium-neon laser effects on conditioning-induced mucositis in bone marrow transplantation patients. Cancer. 1995; 76 (12): 2550-2556.
Oral mucositis is a common complication of bone marrow transplantation conditioning therapy. Different drugs are given in order to reduce rejection of the implant. These drugs induce an oral mucosits. The mucositis is painful and complicates nutrition. Sometimes the intake of the drug has to be stopped due to complications. In the study above 20 patients received HeNe to their oral mucosa, either right or left of midline. One side was sham irradiated. Laser treatment was well-tolerated and reduced the severity of oral mucositis.
b) Cowen D et al. Low energy helium-neon laser in the prevention of oral mucositis in patients undergoing bone marrow transplant: results of a double blind randomized trial. Int J Radiat Oncol Biol Phys. 1997; 38 (4): 697-707. Significant reduction of oral mucositis using a 60 mW HeNe laser.
|Eur Arch Otorhinolaryngol. 2001 Nov;258(9):481-Che.|
Chemotherapy- and radiotherapy-induced mucositis in head and neck cancer patients: new trends in pathophysiology, prevention and treatment.
Bensadoun RJ, Magne N, Marcy PY, Demard F.
Department of Radiation Oncology, Centre Antoine Lacassagne, Nice, France. email@example.com
Mucositis is the intensity-limiting toxicity in the management of locally advanced non-resectable head and neck cancer with radiotherapy and chemotherapy. New radiation modalities (hyperfractionation and/or acceleration) as well as combined modality regimens in this situation induce higher rates of acute toxicity. Hyperfractionation, for example, allows higher control rates, with few late toxicities, but it slightly increases acute mucositis. The addition of chemotherapy introduces systemic toxicity and can exacerbate local tissue reactions when used concurrently with radiotherapy. Mucositis is recognized as the principal limiting factor to further treatment intensification. As local regional control and overall survival are related to dose-intensity in this case, further research into the assessment, analysis, prevention and treatment of mucosal toxicity is not only crucial to improvement in quality of life, but certainly also to improved rates of disease control. Several topical and systemic treatments are directed to the decrease and the acceptance of this acute toxicity, but few have shown a significant preventive effect. The efficacy of low-level laser therapy in the management of such toxicity could hence yield important developments with this method in the field of oncology.
CHEMO-AND RADIATION-INDUCED MUCOSITIS: RESULTS OF MULTICENTER PHASE III STUDIES.
Rene Jean Bensadoun Centre Antoine-Lacassagne, Nice, France
Considerable buccal toxicity of radiotherapy and/or chemotherapy in patients with cancer can cause patients to become discouraged and can alter their quality of life. In addition, such toxicity often necessitates alterations of treatment planning, with grave consequences in term of tumor response and even survival (concept of dose-intensity). With 5-fluorouracil and head and neck radiotherapy for example, acute mucosal toxic effect is the main limiting factor for which no clinically appropriate prophylaxis or efficacious antidote has been found to date. Management of oral mucositis is currently primarily directed at palliation of the symptoms, and prevention of infections. Low Level Laser Therapy (LLLT) has been reported effective in reducing the severity of oral mucositis lesions in a non-randomized trial, initiated in Nice (France) by Ciais et al. (1). The efficacy of this method in the prevention of chemotherapy induced oral mucositis has been subsequently confirmed in two prospective, double-blind randomized trials, in patients undergoing bone marrow transplant (2 ; 3). These initial findings and the high incidence of radiation-induced mucositis prompted a randomized multicenter trial to evaluate LLLT for the prevention of acute radiation-induced oropharyngeal mucosal lesions. The trial was open to patients with carcinoma of the oropharynx, hypopharynx and oral cavity being treated by external radiotherapy, with a total dose of 65 Gy at a rate of 1 fraction of 2 Gy/day, 5 days a week, from cobalt-60 or linear accelerator photons, without prior surgery or concomitant chemotherapy. Between September 1994 and March 1998, thirty patients entered this double-blind randomized study conforming to the Huriet law. The goal was to determine whether preventive HeNe laser beam applications could reduce or prevent oropharyngeal mucositis caused by radiotherapy.
Patients characteristics: There were 26 men and 4 women. Mean age was 60.4 years (range 36 – 78). Oral examination and preventive dental management were performed prior to radiotherapy. Daily oral hygiene (cleaning of the teeth and dental prosthesis) during treatment was recommended. Patients were assigned to either laser treatment (L+) or sham-treatment (L-) by computer blocked randomization. The protocol called for the inclusion of 30 patients, 15 in each arm. No associated anti-inflammatory or other treatment was authorized. Analgesics could be prescribed, but not during the 2 days preceding each week evaluation. Patients received HeNe laser applications daily for five consecutive days (Monday to Friday) each week, during the seven weeks of radiotherapy. The malignant tumor had to be located outside the areas selected for randomized preventive LLL application. Laser was delivered to the tissues by a straight optical fiber with a 1.2 mm spot size. The 9 treatment areas included : posterior third of buccal mucosa, soft palate and anterior tonsillar pillars. Laser illumination consisted of a continuous beam (wavelength: 632.8 nm; power: 60 mW), calibrated at the end of the optical fiber every day. The treatment time (t) for each application point was given by the equation : t (sec) = energy (J/cm2) x surface (cm2)/ Power (W). The average energy density delivered to the treatment areas was 2 J/cm2, and was applied on these nine points, equally distributed on the treated surfaces, for 33 s per point (each specific LLL session lasted approximately 5 minutes). The 60 mW lasers were designed and produced by Fradama S.A. (Geneva, Switzerland). All laser illuminations were performed by the same individual in each center. This operator was the only person to know whether or not the patient was sham-treated, and did not participate in the evaluation and scoring mucositis. During the sessions, patients wore wavelength-specific dark glasses and were instructed to keep their eyes closed, to assure that they did not know whether they were sham-treated or whether they received laser applications. The laser made the same noises, and the probe was held in the mouth exactly the same way, when treating control subjects and when treating laser patients. The whole irradiation field, the oral cavity and the visible oropharynx were inspected weekly during seven weeks by the same physician (head and neck surgeon, or radiation oncologist), blinded to the result of randomization. The evaluation of mucositis and pain was performed on the oropharyngeal areas (9 points). Criteria for evaluation were the standard WHO scale for mucositis in the oropharynx; and a segmented visual analogic scale for pain (patient self evaluation). In this phase III study, no adverse effect was noted with the use of a 60-mW HeNe laser, though it is important to emphasize the importance of preventing retinal damage by the use of wavelength-specific goggles. This is consistent with previous reports. Laser applications delayed time of onset, attenuated the peak severity and shortened the duration of oral mucositis. The difference between L+ and L- patients was statistically significant from week 4 to week 7. With the total delivered dose of 65Gy, conventionally fractionated, all L- patients developed mucositis at week 2, with a peak at week 5 (13 with grade 3 mucositis, and 2 with grade 2 mucositis). All L+ patients also had mucositis at week 2, with a peak at week 5 (5 with grade 3 mucositis, 9 with grade 2, 1 with grade 1). During the 7 weeks of treatment, the mean grade of mucositis in L+ patients was significantly lower (p=0.01) than the mean grade in L- patients. Results on decrease in pain intensity were also quite convincing. Laser applications reduced the incidence and duration of morphine administration. Ability to swallow was also improved. These results confirm previous data collected with this method, especially for patients undergoing bone marrow transplant (BMT). In a prospective study, Barasch et al. (2) used a 25- mW laser on one side of the mouth only and reported a statistically significant reduction in oral mucositis on that side, according to the scoring system they used. In the Barasch study, each patient was his or her own control, which could be of importance, since mucosal damage on the sham-treated side could have benefited also from a distant systemic laser effect. Cowen et al. (3), using a 60 mW HeNe laser, performed a double-blind randomized phase III trial, in which laser was administered to the treatment group during conditioning, prior to the day of transplant. This study showed a 33% reduction of grades 3 and 4 mucositis in L+ patients. In this trial, mucositis was scored according to an oral examination guide, with a 16 items scale, of which 4 were assessed by the patients themselves. Daily mucositis index was significantly lower in L+ patients (p < 0.05) from d+2 to d+7 after BMT. The duration of grade 3 stomatitis was also reduced in L+ patients (p = 0.01). Oral pain was lower (p = 0.05), and L+ patients required less morphinomimetics (p = 0.05). Finally, xerostomia and ability to swallow were improved among L+ patients (p = 0.05, and p = 0.01, respectively). All these results were in keeping with previous observations, suggesting the efficacy of the method (1, 4). Schubert et al. for example (4), identified a trend towards lower oral mucositis scores, on all examination days, in an interim results report of a phase I/II study, in which laser application was performed prophylactically during conditioning before BMT.
In conclusion, LLLT seems to be a safe and efficient method for the prevention of chemo- and radiation-induced mucositis, with a tremendous potential interest for combined modality treatment. The concomitant use of chemo- and radiotherapy is becoming the new standard of care in advanced head and neck cancer, with very encouraging results, even in nonresectable cases. Since the main limiting factor of these combined protocols is the acute mucositis, this complementary treatment option with low level HeNe laser could be important in enhancing the feasibility of such regimens, and especially in the conservation of dose-intensity effect. At Nice, where the method is now used routinely during head and neck radiation, we project a new study testing LLL in patients being treated with concomitant chemo- and radiotherapy for advanced head and neck cancer. Even more than the improvement of patient comfort, the therapeutic index of combined specific treatment should be increased by the use of LLLT, besides standard supportive care, oral care and enteral nutrition (5). During this study, other laser wavelengths and powers could be tested, and compared to 60-mW HeNe laser.
1. CIAIS G., NAMER M., SCHNEIDER M., DEMARD F., POURREAU-SCHNEIDER N., MARTIN P.M., SOUDRY M., FRANQUIN J.C., ZATTARA H. La laserthérapie dans la prévention et le traitement des mucites liées à la chimiothérapie anticancéreuse. Bull. Cancer 79 : 183-191, 1992.
2. BARASCH A., PETERSON D., TANZER J.M., D’AMBROSIO J.A., NUKI K., SCHUBERT M., FRANQUIN J.C., CLIVE J., TUTSCHKA P. Helium-Neon laser effects on conditioning-induced oral mucositis in bone marrow transplantation patients. Cancer 76:2550-2556, 1995.
3. COWEN D., TARDIEU C., SCHUBERT M., PETERSON D., RESBEUT M., FAUCHER C., FRANQUIN J.C. Low energy helium-neon laser in the prevention of oral mucositis in patients undergoing bone marrow transplant : results of a double blind randomized trial. Int. J. Radiat Oncology Biol. Phys. 38 (4):697-703, 1997.
4 . SCHUBERT M.M., FRANQUIN J.C., NICCOLI-FILHO F., MARCIAL F., LLOID M., KELLY J. Effects of low-energy laser on oral mucositis : a phase I/II pilot study. Cancer Researcher Weekly 7:14, 1997.
5 . R. J. BENSADOUN, J. C. FRANQUIN, G. CIAIS, V. DARCOURT, M. M. SCHUBERT, M. VIOT, J. DEJOU, C. TARDIEU, K. BENEZERY, T. D. NGUYEN, Y. LAUDOYER, O. DASSONVILLE, G. POISSONNET, J. VALLICIONI, A. THYSS, M. HAMDI, P. CHAUVEL, F. DEMARD. Low-energy He/Ne laser in the prevention of radiation-induced mucositis. A multicenter phase III randomized study in patients with head and neck cancer. Support Care Cancer 7(4):244-252, 1999.