Support Care Cancer. 2016 Mar 17. [Epub ahead of print]
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.
Zecha JA1, Raber-Durlacher JE1,2, Nair RG3, Epstein JB4,5, Elad S6, Hamblin MR7,8,9, Barasch A10, Migliorati CA11, Milstein DM1, Genot MT12, Lansaat L13,van der Brink R5, Arnabat-Dominguez J14, van der Molen L13, Jacobi I13, van Diessen J15, de Lange J1, Smeele LE1,13, Schubert MM16, Bensadoun RJ17.
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.
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.
Photomed Laser Surg. 2011 Apr;29(4):233-7. Epub 2010 Dec 23.
Effect of photobiomodulation on vinblastine-poisoned murine HERS cells.
Hodgson BD, Pyszka B, Henry MM, Buchmann E, Whelan HT.
Marquette University, Milwaukee, Wisconsin, USA. firstname.lastname@example.org
The aim of this study was to investigate the effect of near-infrared (NIR) photobiomodulation on the proliferation and glutathione levels in murine Hertwig’s epithelial root sheath (HERS) cells after poisoning with vinblastine.
Photobiomodulation has been shown to improve wound healing in a number of animal models. There have been no studies on the effect of photobiomodulation on cancer-related chemotherapy injury to the cells that initiate tooth root growth.
MATERIALS AND METHODS:
Control groups consisted of murine HERS cells without vinblastine (VB-) and cells with vinblastine at 10, 20, and 30?ng/mL (VB10, VB20, and VB30). Experimental groups consisted of these same groups with light therapy (VB-L, VB10L, VB20L, and VB30L). The cells were exposed to vinblastine for 1?h. Photobiomodulation consisted of a 75-cm(2) gallium-aluminum-arsenide light-emitting diode (LED) array at an energy density of 12.8?J/cm(2), delivered with 50?mW/cm(2) power over 256?s.
Vinblastine alone significantly decreased HERS cell proliferation and glutathione levels at all concentrations (VB10 [-55%, p?
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.
LED was effective in the treatment of mucositis, as it diminished pain symptoms and accelerated the tissue repair process.
Vopr Kurortol Fizioter Lech Fiz Kult. 2010 Jul-Aug;(4):3-6.
The use of drinking sulfate mineral water in combination with laser and magnetic-laser irradiation for primary prophylaxis of post-radiation disorders(experimental study).
[Article in Russian]
Korolev IuN, Mikha?lik LV, Geniatulina MS, Nikulina LA.
Experiments on laboratory rats have demonstrated that prophylactic use of drinkable sulfate mineral water in combination with laser and magnetolaser irradiation of adrenal glands produces a radioprotecive effect that was especially well apparent in the liver and less so in the testes. Simultaneously, the functional activity of the thymus decreased. Protection of the liver by the combination of the above factors was more pronounced than the effect of each of them applied separately.
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.
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. email@example.com
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 therapeutic 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. firstname.lastname@example.org
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. email@example.com
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 firstname.lastname@example.org
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.
Photomed Laser Surg. 2007 Jun;25(3):197-204.
Effect of laser therapy on bone tissue submitted to radiotherapy: experimental study in rats.
Da Cunha SS, Sarmento V, Ramalho LM, De Almeida D, Veeck EB, Da Costa NP, Mattos A, Marques AM, Gerbi M, Freitas AC.
Federal University of Bahia, Salvador, Bahia, Brazil. email@example.com
OBJECTIVE: The aim of this study was to investigate the effect of laser therapy (lambda = 780 nm) on bone tissue submitted to ionizing radiation.
BACKGROUND DATA: The biostimulation effect of laser in normal bone tissue has already been demonstrated successfully; however its effect on bone tissue submitted to radiotherapy has not yet been studied.
METHODS: Twenty-two Wistar rats were randomly divided into four groups: group I, control (n = 4), submitted only to radiotherapy; group II, laser starting 1 day prior to radiotherapy (n = 6); group III, laser started immediately after radiotherapy (n = 6); group IV, laser 4 weeks after radiotherapy (n = 6). The source of ionizing radiation used was Cobalt 60, which was applied in a single dose of 3000 cGy on the femur. The laser groups received seven applications with a 48-h interval in four points per session of DE = 4 J/cm(2), P = 40 mW, t = 100 sec, and beam diameter of 0.04 cm(2). All animals were killed 6 weeks after radiotherapy.
RESULTS: Clinical examination revealed cutaneous erosions on experimental groups (II, III, and IV) starting at the 6th week after radiotherapy. The radiographic findings showed higher bone density in groups II and IV (p < 0.05) compared to the control group. The results further showed an increase of bone marrow cells, and number of osteocytes and Haversian canals in experimental groups II and IV (p < 0.05). It was also found an increase of osteoblastic activity, in groups II, III, and IV (p < 0.05).
CONCLUSION: Laser therapy on bone tissue in rats presented a positive biostimulative effect, especially when applied before or 4 weeks after radiotherapy. However, the use of laser in the parameters above should be used with caution due to epithelial erosions.
Oral Surg Ora l 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 immunological 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.
J Photochem Photobiol B. 2000 Dec;59(1-3):1-8.
Magnetic resonance imaging (MRI) controlled outcome of side effects caused by ionizing radiation, treated with 780 nm-diode laser — preliminary results.
Schaffer M, Bonel H, Sroka R, Schaffer PM, Busch M, Sittek H, Reiser M, Duhmke E. Department of Radiation Therapy, University of Munich, Germany. firstname.lastname@example.org
BACKGROUND and OBJECTIVE: Ionizing radiation therapy by way of various beams such as electron, photon and neutron is an established method in tumor treatment. The side effects caused by this treatment such as ulcer, painful mastitis and delay of wound healing are well known, too. Biomodulation by low level laser therapy (LLLT) has become popular as a therapeutic modality for the acceleration of wound healing and the treatment of inflammation. Evidence for this kind of application, however, is not fully understood yet. This study intends to demonstrate the response of biomodulative laser treatment on the side effects caused by ionizing radiation by means of magnetic resonance imaging (MRI). STUDY DESIGN/PATIENTS and METHODS: Six female patients suffering from painful mastitis after breast ionizing irradiation and one man suffering from radiogenic ulcer were treated with lambda=780 nm diode laser irradiation at a fluence rate of 5 J/cm2. LLLT was performed for a period of 4-6 weeks (mean sessions: 25 per patient, range 19-35). The tissue response was determined by means of MRI after laser treatment in comparison to MRI prior to the beginning of the LLLT. RESULTS: All patients showed complete clinical remission. The time-dependent contrast enhancement curve obtained by the evaluation of MR images demonstrated a significant decrease of enhancement features typical for inflammation in the affected area. CONCLUSION: Biomodulation by LLLT seems to be a promising treatment modality for side effects induced by ionizing radiation.
Voprosy onkologii. 2000; 46 (4): 459-461.
Nizkointensivnaia lasernaia terapiia v detskoi onkologii
Balakirev S A, Gusev L I, Kazanova M B et al.
The study by Balakirev suggests that the application of laser therapy makes it possible to reduce the time needed for the management of radiation injury and chemotherapy complications in pediatric patients 1.5-2-fold. It was shown that exposure to laser caused mononuclear levels of donors’ blood to rise, which in turn led to release, in higher concentrations, of IL-1 and FNO cytokins, major factors of immune response development.
Vestn Ross Akad Med Nauk. 2000; (6): 24-27.
Low-intensity lasers in pediatric oncology.
Durnov L A, Gusev L I, Balakirev S A et al
The study by Durnov outlines the outcomes of treatment for complications associated with chemo- and radiation therapy in children with malignant neoplasms by using low-intensity laser radiation. The use of this therapy may reduce the duration of treatment of these complications by 1.5-2 times. The use of low-intensity laser radiation in the treatment of other complications that are common in pediatric oncological care is briefly described.
Vopr Kurortol Fizioter Lech Fiz Kult. 2000; (3): 3-4.
The correction of the subcellular postradiation changes in the hypothalamus and parathyroid gland by using low-intensity laser radiation; An experimental study.
Korolev Iu N, Panova L N, Geniatulina M S
The study by Korolev showed that exposure of the rat adrenals 30 days after radiation (1 Gy) to infrared laser radiation arrested the development of ultrastructural disorders in the cells of the hypothalamus and the parathyroid gland and enhanced subcellular manifestations of adaptation and rehabilitation processes.
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. email@example.com
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
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.