radiation induced xerostomia & pilocarpine

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