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

Transcription

1 Orphan Symptoms: XEROSTOMIA Paolo Bossi Head and Neck Medical Oncology Unit Istituto Nazionale Tumori Milan, Italy

2 Conflict of Interest Participation in Advisory Boards: Roche, Merck, Mundipharma, Astrazeneca, BMS

3 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

4 ORPHAN SYMPTOMS What is an orphan symptom? Difficult to be defined!

5 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.

6 ORPHAN SYMPTOMS What is an orphan symptom? A neglected symptom? A symptom not assessed in any classification? A rare adverse event? Toxicity without effective treatment?

7 WHY XEROSTOMIA SHOULD BE AN ORPHAN SYMPTOMS? x A neglected symptom?

8 WHY XEROSTOMIA SHOULD BE AN ORPHAN SYMPTOMS? x A symptom not assessed in any classification? 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)

9 WHY XEROSTOMIA SHOULD BE AN ORPHAN SYMPTOMS? C H A M P I O N S O R P H A N

10 WHY XEROSTOMIA SHOULD BE AN ORPHAN SYMPTOMS? x A rare adverse event?

11 WHY XEROSTOMIA SHOULD BE AN ORPHAN SYMPTOMS? Toxicity without effective treatment?

12 ORPHAN SYMPTOMS What is an orphan symptom? I have no drug to treat it! It is rare! A symptom nobody would like to identify and to treat? I do not know how to classify!

13 WHICH GRADING OF XEROSTOMIA? CTCAE V 4.0 Another physician s interpretation of subjective symptom? Do the objective assessment of CTCAE really measure the impact on everyday life?

14 SYMPTOM ASSESSMENT WITH RT Comparison between observer s (physician) way to assess toxicity and patient evaluation with EORTC Quality of Life questionnaires

15 SYMPTOM ASSESSMENT WITH RT Sensitivity of observer = 74%; specificity = 90%

16 PRO-CISION IN SYMPTOM ASSESSMENT?

17 PRO-CTCAE LIBRARY

18 PRO-CTCAE LIBRARY

19 XEROSTOMIA: the burden of the problem cancer polipharmacy XEROSTOMIA cancer treatments mucositis Tooth decay Reduced QoL Dysphagia Oral cavity infection Taste alterations Difficulty in chewing malnourishment

20 TREATMENT-RELATED CAUSES Radiation Radioiodine therapy Chemotherapy Targeted therapies Immunotherapy

21 RADIATION-INDUCED XEROSTOMIA: Head & Neck Ca 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

22 RADIATION-INDUCED XEROSTOMIA: PREVENTION Lancet Oncology 2011 Decrease the exposure of salivary gland tissues from excessively high RT doses

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24 XEROSTOMIA Dirix, Lancet Oncol, 2010

25 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 Kam JCO 2017 Naso D-RT vs IMRT no Naso D-RT vs IMRT 66+/-BT 66+/-BT no Nutting LO 2011 Oro- Hypo D-RT vs IMRT (postop) Neo (40%) Gupta R&O 2014 Oro- Hypo Lar D-RT vs IMRT Conc Peng R&O 2012 Naso D-RT vs IMRT 74+/-BT 74+/-BT Neo/con c/adj 25

26 Xerostomia scores grades 2-4 A significant overall benefit in favor of IMRT HR of 0.76 (p< ) Locoregional control and OS Not significant benefit in favour of IMRT both for LRC and OS 26

27 RADIOIODINE TX- INDUCED XEROSTOMIA Before and 5 mo after radioiodine treatment: Reduction in salivary flow rate Change in composition (less protein and amylase) Worse subjective xerostomia inventory score J Nucl Med 2016

28 TARGETED TX- AND IMMUNOTX- INDUCED XEROSTOMIA DRUG INCIDENCE Everolimus 6% Dacomitinib 8-14% Multitargeted angiogenesis inh Nivolumab/ Pembrolizumab Ipilimumab 4-12% 4-8% negligible

29 MANY DRUGS CAUSES XEROSTOMIA! List of medications affecting salivary gland function and inducing xerostomia

30 MANY DRUGS CAUSES XEROSTOMIA! Consider, among all, the frequently prescribed opioids: morphine, fentanyl, tapentadol, tramadol

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

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

33 1) Cholinergic agonists: pilocarpin, cevimeline 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 Topical administration??

34 1) Cholinergic agonists: pilocarpin, cevimeline Oral Oncology, 2017

35 2) Gustatory and masticatory stimulants Acidic substances Purely symptomatic measures Limited studies

36 3) Lubrificants, saliva substitutes Widely used No need of residual salivary function Weak evidences Enzyme-enriched could be better High viscosity is better

37 4) Acupuncture Stimulation possible only with residual salivary function Weak or no evidence

38 5) Hyperbaric Oxygen Therapy Some studies suggest possible long-term benefit However: low number of patients, heterogeneous pt population, no risk-assessment on possible procancerogen effect

39 6) Gene Therapy Viral vector injection of gene able to partially restore salivary tissue Human aquaporin-1 gene transfer Preliminary data, phase I-II trial

40 Practically speaking suggestions First step: symptomatic measures Test 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!

41 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!

42 Thanks for your attention!