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RADIATION INDUCED XEROSTOMIA
& ORAL PILOCARPINE
Dr. V. Lokesh M.D
Radiation Oncologist
Kidwai memorial Institute of Oncology, Bangalore, India.
Physiology of Salivary Secreation
• Surface Epithelial – Mucous Glands
• Compound Glands – Salivary Glands
• Daily Secreation : 800 to 1500ml/day
» 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
Mechanism of Stimulus
• Local Epithelial Stimulation (Enteric)
• Autonomic : Parasympathetic (glossopharyngeal & vagus) > Superior salivary nucleus – Brain Stem.
Functions of Saliva
• Maintanance of Oral Heygine– Wash : Pathogens and Food particles– Antimicrobial agents :
• Thiocyanate ions
• Porteolytic enzymes{lysozymes}
• antibodies
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
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
Salivary Electrolytes in Radiation Xerostomia
• 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
• 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
Feeling of Dryness of Mouth
Salivary flow rates during RT
Na + concentration during RT
Deterioration in Taste acuity
Dysphagia during RT
Candida during RT
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%
Salivary Flow rate after RT K.Mossman et al
XEROSTOMIA RELATED MORBIDITY
• Oral discomfort • Pain• Difficulty in
– Mastication– Swallowing– Speech– Sleep
• Dental Caries• Peridontal disease
•Severe oral disease
•Nutritional deficency
•Decline in QOL
Most effective intervention for Xerostomia
• Prevention : – Meticulous Planning – Beam arrangement to spare salivary glands– Sparing > 50% of S-gland
• WR 2721
• Pilocarpine Hydrochloride
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
Oral Pilocarpine in Salivary DysfunctionStimulated & Unstimulated : Significant Increase in Secreation
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
• 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
Effect of Oral Pilocarpine on Symptom of Post RT Xerostomia
Improvement in salivary function
Effect of Oral Pilocarpine production of whole saliva and unstimulated Parotid Saliva
Incidence of Adverse events
• 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
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
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
• 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%
CONCURRENT AND ADJUVANT ORAL
PILOCARPINE
Ingrid H. Valdez, Cancer Medicine, 1993, Vol 71, No:5
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
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
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)
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
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
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.
THANK YOU