LOW LEVEL LASER REDUCES THE SEVERITY OF RADIOTHERAPY INDUCED ORAL MUCOSITIS AND XEROSTOMIA Carlos de Oliveira Lopes, M.D.- University of Vale do Paraiba, Sao Jose dos Campos (SP) - Brasil Josepa Rigau, M.D., PhD.- Rovira i Virgili University –Spain Ana Ortega Lopez, M.D.- University of Hawaii Pathology Residency Program -USA Renato A. Zangaro, PhD.- University of Vale do Paraiba -Brasil Light Activated Tissue Regeneration and Therapy 2004, Kona (Hawaii) -USA 2004, Kona (Hawaii) -USA

BACKGROUND Oral mucositis and xerostomia are frequent complications of cytotoxic treatment Oral mucositis and xerostomia are frequent complications of cytotoxic treatment Threatening the effectiveness of therapy, leading to dose reductions, increased health costs, and impairing patients’ quality of life Threatening the effectiveness of therapy, leading to dose reductions, increased health costs, and impairing patients’ quality of life There are several techniques described in the literature to prevent these complications, but all of them have limitations There are several techniques described in the literature to prevent these complications, but all of them have limitations

OBJECTIVE To verify the utility of soft laser therapy (InGaAlP Diode Laser)to reduce the incidence of xerostomia and oral mucositis, and its associated pain, in patients receiving radiotherapy for head and neck cancer To verify the utility of soft laser therapy (InGaAlP Diode Laser) to reduce the incidence of xerostomia and oral mucositis, and its associated pain, in patients receiving radiotherapy for head and neck cancer

MATERIALS AND METHODS

Patients and methods 60 patients with head and neck cancer 60 patients with head and neck cancer Radiotherapy: Radiotherapy: –Daily dose of 1.8 – 2.0 Gy –Total dose of 45 – 72 Gy Chemotherapy: Chemotherapy: –Cisplatin, weekly dose of 40 mg/m2 29 patients received radiotherapy 29 patients received radiotherapy (control group) (control group) 31 patients received radiotherapy with laser therapy 31 patients received radiotherapy with laser therapy Study performed according to resolution #196/96 of the Health ministry of Brasil, and was approved by the ethics committe for human beings’ reserach of the Universidade do Vale do Paraíba, with affilation to the Conselho Nacional de Pesquisa com Seres Humanos (CONEP) Study performed according to resolution #196/96 of the Health ministry of Brasil, and was approved by the ethics committe for human beings’ reserach of the Universidade do Vale do Paraíba, with affilation to the Conselho Nacional de Pesquisa com Seres Humanos (CONEP)

VariableCategoryLaser YesNo SexMaleFemale 25 (86,2) 4 (13,8) 25 (80,6) 6 (19,4) Tumor localization Inferior lip Tongue Inferior gums Floor of mouth Hard palate Soft palate Jugal mucose Retromolar area Minor salivary gland Parotid gland Submandibular gland AmigdalaOropharynxRinopharynx Piriform sinus HipopharyinxPharynx Maxilar sinus Larynx Auditive conduct - 5 (17,2) - 1 (3,4) 2 (6,9) 1 (3,4) - 2 (6,9) - 3 (10,3) 1 (3,4) 2 (6,9) 1 (3,4) 3 (10,3) - 1 (3,4) 4 (13,8) 1 (3,4) 1 (3,2) (9,7) 1 (3,2) 2 (6,5) 1 (3,2) 3 (9,7) 1 (3,2) - 3 (9,7) 7 (22,6) 2 (6,5) Clinical staging TNMIIIIIIIVUnknown- 1 (3,4) 3 (10,3) 25 (86,2) - 2 (6,5) 1 (3,2) 6 (19,4) 21 (67,7) 1 (3,2) Histologic type Squamous cell carcinoma Adenocarcinoma Basal cell carcinoma Mucoepidermoid Adenoma/Mixed tumor Undifferentiated carcinoma 27 (93,1) 1 (3,4) (77,4) 2 (6,5) 1 (3,2) 2 (6,5) 1 (3,2) SurgeryYesNo 17 (58,6) 12 (41,4) 17 (54,8) 14 (45,2) ChemotherapyYesNo 14 (48,3) 15 (51,7) 17 (54,8) 14 (45,2)

Treatment table Collimate systems delineate the irradiated field Gantry, turns around to be able to treat at different incidences

Parotid gland Submandibular gland Total irradiation field

nm nmPowermW Spot size cm 2 Fibre-% Output OutputPowermwApplicationSize cm 2 Fluence J/cm 2 Times , Laser application Indium-Gallium-Aluminium-Phosphide (InGaAlP) Diode Laser Indium-Gallium-Aluminium-Phosphide (InGaAlP) Diode Laser Laser parameters: Laser parameters: Punctual applications Punctual applications 2 Joules/cm2 in predeterminate points of the oral mucosa, parotid gland, and submandibular gland 2 Joules/cm2 in predeterminate points of the oral mucosa, parotid gland, and submandibular gland

InGaAlP Diode Laser application points

Oral mucositis evaluation Grading of Oral Mucositis, NCI-CTC: Grading of Oral Mucositis, NCI-CTC: Oral mucositis was evaluated weekly Oral mucositis was evaluated weekly 0 (none) No changes 1 (mild) Erythema 2 (moderate) Patchy, non confluent pseudomembranes < 1.5 cm of diameter 3 (severe) Confluent pseudomembranes > 1.5 cm of diameter 4 (life- threatening) Necrosis or deep ulcerations with easy bleeding not induced by minor trauma

Oral Mucositis Pain Score Without pain Moderate pain Strong pain

Xerostomia evaluation Sialometry guidlines, Radiation Therapy Oncology Group RTOG (RTOG, 1999) Sialometry guidlines, Radiation Therapy Oncology Group RTOG (RTOG, 1999) Salivary flow rate: Salivary flow rate: day 1 (basal level determination) day 1 (basal level determination) day 15 day 15 at the end of treatment at the end of treatment at 15 and 30 days after treatment was completed at 15 and 30 days after treatment was completed –Unstimulated salivary production evaluated prior to the stimulated salivary production

Statistical analysis Means and deviations, and frequency distributions for quantitative values Means and deviations, and frequency distributions for quantitative values Chi-square test to verify associations between qualitative values Chi-square test to verify associations between qualitative values Fishers test Fishers test Student’s t test Student’s t test Mann-Whitney test Mann-Whitney test ANOVA ANOVA Friedman test Friedman test Tukey's HSD Tukey's HSD

RESULTS

Variável Sem laser x Com laser p* Parótida D 61,5 (13,2) 57,2 (14,1) 0,081 Parótida E 61,5 (13,2) 57,2 (14,5) 0,090 Submandibular D 61,5 (13,2) 57,2 (14,1) 0,081 Submandibular E 61,5 (13,2) 57,2 (14,5) 0,090 Sublingual D 61,5 (13,2) 57,2 (14,1) 0,081 Sublingual E 61,5 (13,2) 57,2 (14,5) 0,090

Study group Evaluationp* Initial After 4 weeks End of treatment No Laser (NL) 0.3 (0.5) 1.8 (1.0) 1.8 (1.1) I  4w(p<0.001) I  T (p<0.001) 4w = T (p=1.000) With Laser (L) 0.3 (0.5) 0.7 (0.9) 0.8 (0.9) I = 4w (p=0.429) I = T (p=0.229) 4w = T (p=0.999) NL = L (p=1.000) NL  L p<0.001) NL  L (p<0.001) Oral mucositis evaluation : NCI scores, means and deviations

Evaluation Initial End of treatment Second eval. post treatment Study group Without laserWith laser CI 95% Oral mucositis scores Oral mucositis NCI scores means percentages and confidence intervals

Study group Evaluationp* Intial After 4 weeks End of treatment No Laser (NL) 0.0 (0.0) 2.2 (2.6) 2.4 (2.5) I  4w (p<0.001) I  T (p<0.001) 4w = T (p=0.996) With Laser Laser(CL) 0.1 (0.6) 0.9 (1.9) 0.7 (1.5) I = 4w (p=0.348) I = T (p=0.692) 4w= T (p=0.994) SL = CL (p=0.999) SL  CL (p=0.016) SL  CL(p<0.001) Oral mucositis evaluation : Pain scores, means and deviations

CI 95% Pain scores means Study group Without laserWith laser Evaluation Initial End of treatment 2 nd eval. post treatment Oral mucositis pain scores means and confidence intervals

Study group Evaluationp* Initial End of treatment 2 nd eval after treatment NoLaser(NL) 3.5 (1.7) 1.4 (0.5) 1.2 (0.3) I  T (p<0.001) I  PT (p<0.001) T = PT (p=0.985) Laser(L) 3.8 (2.1) 3.8 (1.7) 4.1 (1.8) I = T (p=0.998) I = PT (p=0.878) T = PT (p=0.652) NL =L(p=0.720) NL  L(p<0.001) NL=L(p<0.001) Xerostomia evaluation: Unstimulated saliva production (mL), means and deviations

CI 95% Measurement of non-stimulated salivary flow Study group Without laser With laser Evaluation Initial End of treatment Second eval. post treatment Unstimulated salivary flow rate (mL), means and confidence intervals

Study group Evaluationp* Initial (I) End of treatment (T) Second eval post treatment (PT) No Laser (NL) 4.4 (1.9) 1.5 (0.6) 1.3 (0.4) I  T (p<0.001) I  PT (p<0.001) T = PT (p=0.910) Laser(L) 4.4 (2.2) 4.1 (1.8) 4.5 (1.9) I = T (p=0.965) I = PT (p=0.999) T = PT (p=0.860) SL = L(p=1.000) SL  L (p<0.001) Xerostomia evaluation: Stimulated saliva production (mL), means and deviations

CV 95% Measurement of stimulated salivary flow Study group Without laserWith laser Evaluation Initial End of treatment Second eval. post treatment Stimulated salivary flow rate (mL), means and confidence intervals

RadiotherapyRadiotherapy & Laser

Radiotherapy

Normal salivary gland Radiotherapy Radiotherapy & Laser

Normal gland Radiotherapy Rt & Laser

Normal gland Radiotherapy

Xerostomia: 1 year follow-up Salivary flow rate (stimulated) Evaluation Initial End of tx After 1 year No Laser With laser

CONCLUSIONS

CONCLUSIONS The indicence in xerostomia is significatively reduced in patients treated with radiotherapy with laser The indicence in xerostomia is significatively reduced in patients treated with radiotherapy with laser The use of laser in combination with radiotherapy decreases the severity of oral mucositis The use of laser in combination with radiotherapy decreases the severity of oral mucositis The pain associated with oral mucositis is also reduced significatively in patients treated with radiotherapy with laser The pain associated with oral mucositis is also reduced significatively in patients treated with radiotherapy with laser