radiation induced xerostomia & pilocarpine
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RADIATION INDUCED XEROSTOMIA
& ORAL PILOCARPINE
Dr. V. Lokesh M.D
Radiation Oncologist
Kidwai memorial Institute of Oncology, Bangalore, India.
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Physiology of Salivary Secreation
• Surface Epithelial – Mucous Glands
• Compound Glands – Salivary Glands
• Daily Secreation : 800 to 1500ml/day
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» w.r.t Plasma Level
• Na & Cl – 15 mEq/L ½ to 1/10
• K - 30 mEq/L > 7 times
• HCO3 - 50-70 mEq/L > 2-3 times
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Mechanism of Stimulus
• Local Epithelial Stimulation (Enteric)
• Autonomic : Parasympathetic (glossopharyngeal & vagus) > Superior salivary nucleus – Brain Stem.
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Functions of Saliva
• Maintanance of Oral Heygine– Wash : Pathogens and Food particles– Antimicrobial agents :
• Thiocyanate ions
• Porteolytic enzymes{lysozymes}
• antibodies
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RADIATION INDUCED XEROSTOMIA
• Related to changes in salivary components
• Salivary function is extremely sensitive to irradiation
• Acute Change in salivary flow : Water content
• Principle Damage to Acinar & Duct system
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XEROSTOMIA DURING RADIATION THERAPY
• 30 Patients
• Dose to S-Glands > 50 Gy
• Salivary Flow Rate– Pre RT : 1.32 ml/min– End of RT : 0.22 ml/min
• Reduction in flow - 83.3%
• Reduction in Buffering Capacity – 44.3%
Samuel Dreizen 38: 273-278, 1976
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Salivary Electrolytes in Radiation Xerostomia
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• Overall in total Salt content
• Pronounced in Water content
• Post RT at 3 months: mean decline in out put is 93.4 %
• Clinicall > 3 months Dental caries
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• 32 patients
• RT all major S-glands
– Dryness : 81%– Thickened Saliva : 16%– Observed Dryness : 53%– Taste Impairment: 62%– Dysphagia : 59%– Soreness : 37%– Coated tongue : 64%
Abraham Kuten Int Jr Rad Oncol Biol Phys Vol:12,401-405,1985
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Feeling of Dryness of Mouth
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Salivary flow rates during RT
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Na + concentration during RT
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Deterioration in Taste acuity
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Dysphagia during RT
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Candida during RT
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1000-2000cGy
• Sharp decline in S-Secreation : 50 – 75%• Sharp rise in Na+ : 50%
– Lekage via damaged mucosa– Augumented transduction in the duct system– Impaired reabsorption in the duct
• > 20Gy Subjective feeling of dryness– I : 100%– II : 80%– III: 55%
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Salivary Flow rate after RT K.Mossman et al
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XEROSTOMIA RELATED MORBIDITY
• Oral discomfort • Pain• Difficulty in
– Mastication– Swallowing– Speech– Sleep
• Dental Caries• Peridontal disease
•Severe oral disease
•Nutritional deficency
•Decline in QOL
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Most effective intervention for Xerostomia
• Prevention : – Meticulous Planning – Beam arrangement to spare salivary glands– Sparing > 50% of S-gland
• WR 2721
• Pilocarpine Hydrochloride
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ORAL PILOCARPINE
• Leaves of South american plant: Genus : Pilocarcus• Parasympathomimmetic – Colinergic agonist• Predominantly Muscarnic in action• Broad spectrum of pharmological effect:
– Secreation of Exocrine glands (sweat , salivary, lacrimal, gastric, pancreatic, intestinal)
– Smooth muscle tone
– Motility tone ( Intestine , U-tract, G- bladder, bronchus)
Ferguon et al , 1890. Recognised use of pilocarpine for Xerostomia
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Oral Pilocarpine in Salivary DysfunctionStimulated & Unstimulated : Significant Increase in Secreation
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POST RT - XEROSTOMIA
• Prospective Randomised, Double Blind, Placebo Controlled , 3arm study
• 204 patients (166 as per protocol)• > 40Gy to S-gland• 41 withdrawal• Post RT xerostomia = at 6months• Placebo v/s 4 mg t.I.d v/s 10 mg t.I.d
x 12 weeks
Jona T. Johnson, The NEJM Aug 05, 1993
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• Improvement in Oral Dryness– 5mg : 45%– Placebo : 25% (p= 0.027)
• Patients recall : – sense of improvement :
• 5mg v/s placebo (p=0.003) Significant
• 19 mg v/s placebo (p= 0.052) not significant
• Improvement in values– At visit 2 and 3 & nil at visit 4
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Effect of Oral Pilocarpine on Symptom of Post RT Xerostomia
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Improvement in salivary function
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Effect of Oral Pilocarpine production of whole saliva and unstimulated Parotid Saliva
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Incidence of Adverse events
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• Responses generally seen at 12 weeks– Reasons – unknown (probably related to oral mucosal
changes with improvement in saliva production)
• Subjective Improvement – Consistant• Objective , Sialometric findings – less production
(Reason: inadequate technique to detect small increase in flow and small minor increase may be sufficient for major clinical benifits)
• Minor salivary glands contribute to > 70% mucin content
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French Co-operative Study
• Prospective study
• 156 patients
• 145 evaluable
• Compliance 75
• To evaluate the Dose and volume parameters
J.C.Horiot . Radiotherapy and Oncology, 55 , 233-239, 2000
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SALIVARY UNFAVOURABLE FAVOURABLEGLAND > 50Gy < 50GyExpected response30% 75%Patients 49 107
XerostomiaImprovement 29(62%) 68(69%)
*** no difference regardless the Dose and Volume parameters
*** action of pilocarpin on minor salivary glands are widely under-estimated
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• At 12 weeks : relief of symptom – 67%
• Normal food intake doubled < 12 wks
• Impact on QOL – 75%
• Drop in difficulty for solid food ingestion- 50%
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CONCURRENT AND ADJUVANT ORAL
PILOCARPINE
Ingrid H. Valdez, Cancer Medicine, 1993, Vol 71, No:5
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Double Blind, Placebo controlled
• N = 10• 5mg t.I.d v/s Placebo• Subjective:
– Does UR mouth feel dry when UR eating 84 v/s 27% – Do U sip Liquids+meal to aid swallowing 78 v/s 37%
» p < 0.0001
• Objective : better stimulated salivary secreation
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Retospective Analysis• Pilo 5mg q.i.d(n=17) v/s RT alone (n=18)
• Parotid Dose > 45Gy
• Visual Anolog Scale
Robert P. Zimmerman, Int Jr Rad Oncolo, Bio Phy, Vol 37, No:3, 1996
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Randomised, Double Blind, Placebo Controlled Trial
• 60 patients• 39 evaluable (Pilo - 18 v/s Placebo - 21)• Xerostomia evaluation 6mths after EORT• Mean Subjective Xerostomia Score
– ( 40.3 v/s 57 p=0.02,95%CI, Difference 3-32)
• Mean Xerostomia Grade– ( 2.2 v/s 2.6 , p=0.01, 95% CI, Diiference 0.1 – 0.7)
Pieman Haddad, Radiotherapy & Oncology, 64, (2002)
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Use of Pilocarpine During RT• Mechanism of sparing salivary function – not fully
understood.• Valdez et al: action on salivary tissue outside RT field • Protective effect: Pharmocologically
mediated– Animal Models:
• By depletion of secretory granules in Serous Cells» Secretory Granules contain proteolytic enzymes which can cause
membrane damage if there is intercellular leakage due to irradiation
• Causes Depletion of Heavy Metals (Zn, Mn, Fe) in Secretory Granulesleads to mreduction in Metal Catlyzed Lipid Peroxidation of Lysozomal Membrane and Subsequent Serous Cell autolysis seen following irradiation
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Maximun Tolerance Dose TD 50/5
• 50% complication rate , 5years after treatment : 40 to 65Gy
Mossman Int J Rad Oncol Biol & Phy Vol:8,991-997,1982
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CONCLUSIONS
• Subjective and objective assesment sujjests oral pilocarpine given during and after RT has Clincal benefit.
• Clinical Advantage in improved oral intake, mastication, deglution, Physical Cleansing and Chemical Buffering of Upper GI .
• Sequlae of Dental Caries may be ameliorated by maintaining better Salivary function.
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THANK YOU