Orphan Symptoms: XEROSTOMIA Paolo Bossi Head and Neck Medical - - PowerPoint PPT Presentation

Orphan Symptoms: XEROSTOMIA

Paolo Bossi

Head and Neck Medical Oncology Unit Istituto Nazionale Tumori Milan, Italy

Conflict of Interest

Participation in Advisory Boards: Roche, Merck, Mundipharma, Astrazeneca, BMS

AGENDA

• Again an orphan symptom.. What is it?
• Who decides the intensity of xerostomia?
• The burden of the symptom(s)
• Causes: RT – radioiodine Tx – systemic Tx

(chemo - targeted agents- immune) – other drugs

• Possible treatments

ORPHAN SYMPTOMS

What is an orphan symptom?… Difficult to be defined!

ORPHAN SYMPTOMS

What is an orphan disease? A disease that has not been “adopted” by the pharmaceutical industry because it provides little financial incentive to make and market new medications to treat or prevent it. An orphan disease may be a rare disease or a common disease that has been ignored because it is far more prevalent in areas without market.

ORPHAN SYMPTOMS

What is an orphan symptom?…

A neglected symptom?  A symptom not assessed in any classification? A rare adverse event?  T

• xicity without effective treatment?

WHY XEROSTOMIA SHOULD BE AN ORPHAN SYMPTOMS?

A neglected symptom?

x

WHY XEROSTOMIA SHOULD BE AN ORPHAN SYMPTOMS?

A symptom not assessed in any classification?

x

Evaluation of symptoms reported by 6 PRO measures:

• 1. ESAS 2. SDS 3. MDASI 4. EORTC QLQ-C30

V.3

• 5. Rotterdam Symptom Checklist (RSCL)
• 6. Memorial Symptom Assessment Scale (MSAS)

WHY XEROSTOMIA SHOULD BE AN ORPHAN SYMPTOMS?

C H A M P I O N S O R P H A N

WHY XEROSTOMIA SHOULD BE AN ORPHAN SYMPTOMS?

A rare adverse event?

x

WHY XEROSTOMIA SHOULD BE AN ORPHAN SYMPTOMS?

T

• xicity without effective treatment?

ORPHAN SYMPTOMS

What is an orphan symptom?… A symptom nobody would like to identify and to treat?

It is rare! I have no drug to treat it! I do not know how to classify!

WHICH GRADING OF XEROSTOMIA?

• Another physician’s interpretation of subjective

symptom?

• Do the objective assessment of CTCAE really

measure the impact on everyday life?

CTCAE V 4.0

SYMPTOM ASSESSMENT WITH RT

Comparison between observer’s (physician) way to assess toxicity and patient evaluation with EORTC Quality of Life questionnaires

SYMPTOM ASSESSMENT WITH RT

• Sensitivity of observer = 74%; specificity = 90%

PRO-CISION IN SYMPTOM ASSESSMENT?

PRO-CTCAE LIBRARY

PRO-CTCAE LIBRARY

XEROSTOMIA: the burden of the problem

polipharmacy XEROSTOMIA

malnourishment

Difficulty in chewing Taste alterations Dysphagia T

• oth

decay cancer cancer treatments mucositis Reduced QoL Oral cavity infection

Radiation

Radioiodine therapy Chemotherapy Targeted therapies Immunotherapy

TREATMENT

• RELATED CAUSES

 Serous acinar cells seem especially susceptible

to radiation damage  change in saliva composition (“sticky saliva”)

 One week post-radiation loss of 60-90% of

salivary output has been documented.

 Late symptoms (>3 months): moderate-severe

xerostomia in 60-75% with 2DRT and 40% with modern techniques

RADIATION-INDUCED XEROSTOMIA: Head & Neck Ca

RADIATION-INDUCED XEROSTOMIA: PREVENTION

Decrease the exposure of salivary gland tissues from excessively high RT doses Lancet Oncology 2011

XEROSTOMIA

Dirix , Lancet Oncol, 2010

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FIVE PHASE III TRIALS COMPARING 2D/3DRT VS IMRT

Site Stage I/II III/IV Overall Npts RT technique RT dose, Gy (tumor) 2D/RT IMRT CHT

Pow IJROBP 20106 Naso 45 - 45 2D-RT vs IMRT 68 66-68 no Kam JCO 2017 Naso 56 - 56 2D-RT vs IMRT 66+/-BT 66+/-BT no Nutting LO 2011 Oro- Hypo 23 71 80 14 2D-RT vs IMRT (postop) 65 65 Neo (40%) Gupta R&O 2014 Oro- Hypo Lar 12 48 32 17 11 3D-RT vs IMRT 70 66 Conc Peng R&O 2012 Naso 194 422 616 2D-RT vs IMRT 74+/-BT 74+/-BT Neo/con c/adj

26

Xerostomia scores grades 2-4

A significant overall benefit in favor of IMRT HR of 0.76 (p< 0.0001)

Locoregional control and OS

Not significant benefit in favour of IMRT both for LRC and OS

Before and 5 mo after radioiodine treatment:  Reduction in salivary flow rate  Change in composition (less protein and amylase)  Worse subjective xerostomia inventory score

RADIOIODINE TX- INDUCED XEROSTOMIA

J Nucl Med 2016

TARGETED TX- AND IMMUNOTX- INDUCED XEROSTOMIA

DRUG INCIDENCE Everolimus 6% Dacomitinib 8-14% Multitargeted angiogenesis inh 4-12% Nivolumab/ Pembrolizumab 4-8% Ipilimumab negligible

MANY DRUGS CAUSES XEROSTOMIA!

List of medications affecting salivary gland function and inducing xerostomia

Consider, among all, the frequently prescribed

• pioids: morphine, fentanyl, tapentadol, tramadol…

MANY DRUGS CAUSES XEROSTOMIA!

AN ORPHAN SYMPTOM: NEEDS TO BE ADOPTED BY A THERAPY!

1) Cholinergic agonists: pilocarpin, cevimeline 2) Gustatory and masticatory stimulants 3) Lubrificants, saliva substitutes 4) Acupuncture 5) Hyperbaric Oxygen Therapy 6) Gene therapy

TREATMENT: mainstays

 Stimulate muscarinic receptors on the surface of

(residual) salivary gland cells

 Benefits: active both during and after RT; increase

in unstimulated saliva; benefit on subj xerostomia

 Drawbacks: toxicities (bronchospasm,

bradycardia, vasodilatation, diarrhea); short-lived efficacy

 T

• pical administration??

1) Cholinergic agonists: pilocarpin, cevimeline

1) Cholinergic agonists: pilocarpin, cevimeline

Oral Oncology, 2017

 Acidic substances  Purely symptomatic measures  Limited studies

2) Gustatory and masticatory stimulants

 Widely used  No need of residual salivary function  Weak evidences  Enzyme-enriched could be better  High viscosity is better

3) Lubrificants, saliva substitutes

 Stimulation possible only with residual salivary

function

 Weak or no evidence

4) Acupuncture

 Some studies suggest possible long-term benefit  However: low number of patients, heterogeneous

pt population, no risk-assessment on possible procancerogen effect

5) Hyperbaric Oxygen Therapy

 Viral vector injection of gene able to partially

restore salivary tissue

 Human aquaporin-1 gene transfer  Preliminary data, phase I-II trial

6) Gene Therapy

 First step: symptomatic measures  T

est different saliva substitutes by individual patients to select the most effective one

 If not efficacious: in patients without risk factors

try pilocarpine 5 mg t.i.d (10 mg if no adv events)

 Clinical trials on supportive care!

Practically speaking…suggestions

Conclusions

 An orphan symptom due to lack of

treatments…

 Again, ask the patient what does it mean  Burden of consequences  Radiation is the main cause  Treatment: salivary substitutes – cholinergic

drugs

 Push to clinical trials in supportive care!

Thanks for your attention!

paolo.bossi@istitutotumori.mi.it