Saliva and Taste in Cancer Survivors · Saliva and Taste in Cancer Survivors Joel Epstein DMD, MSD,...

Saliva and Taste in Cancer Survivors

Joel Epstein DMD, MSD, FRCD(C), FDS RCS(E), Dip ABOM

Professor

Samuel Oschin Comprehensive Cancer Institute

Cedars-Sinai Health System

Los Angeles, CA

Consulting staff

Division of Otolaryngology and Head and Neck Surgery

City of Hope National Medical Center

Duarte, CA

Oralmedicinepacific.com

DisclosuresAdvisory Boards/Speakers Bureau:

– Dara Biosciences

– Galera Pharmaceuticals

– Insys Therapeutics

– Onxeo SA

– Sucampo USA Inc

Funded Research:

– Amgen Inc

– Arphion Inc

– Medactive Biopharma

– Vigilant Biosciences

– Synedgen Inc

Importance of Oral Health Outcomes:� Oral health conditions result in:

» Altered function

» ↑ Symptom burden

» ↓ quality of life

» ↑ costs

� Oral health influences general health:

» Pain, taste, dysphagia; nutritional deficits

» Aspiration may cause pulmonary disease

» Periodontitis associated with CAD

» Psychosocial impact: pain, esthetics, social function

� Changing Expectations:

» ↑ HNC in younger adults

» Retention & esthetics of dentition is important

The Role of Saliva:

� Lubrication, dilution, clearance� Anti-microbial

– Lysozyme, lactoferrin, peroxidase, defensins, histatins, IgA

� Dental integrity – Maintaining oral pH– Constituents for remineralization

� Mucous membrane integrity� Normal voice� Support taste� Food bolus formation, swallowing

Mucosal Integrity

� Saliva (volume): Lubrication, diluting, washing, removal

� Cell turnover: loss of epithelial cells (E-cadherin)

� Cytokine profile, growth factors

� IgA, peroxidase, histatins, defensins

� Reduced microbial adhesion: IgA

� T-cell function (CD8); IL-17?

� Inflammation

Saliva in Cancer Patients: More than a dry mouth

Quantity, Quality and Management

� Xerostomia

� Hyposalivation

� Saliva consistency and constituents

� Sialorrhea

� Saliva Control

RT induced Salivary dysfunction

� low proliferative index tissue

� vascular supply, neural changes & apoptosis

� end result: loss of acinar cells; atrophic, fibrotic connective tissue with minimal secretory capacity

� ROS, DNA damage, P53 ~ apoptosis of salivary epithelium

� IGF-1 prior to RT: ↓ salivary apoptosis, ↓ cell cycling, blocking P53, ↑cells in G2, ↓ PCNA

� Grundman et al 2009

� Limesand KH. 2006, 2009

� Michell GG 2010

Chronic complications of hyposalivation

�Mucosal dryness, sensitivity; altered healing

�Increased oral infections, increased risk of mucosal trauma

�Risk of dental demineralization, caries; gingivitis, periodontitis

�Altered & reduced taste

�Halitosis

�Chewing & swallowing difficulties

�Dysphonia

�Denture use & function

�Nutritional compromise

Vanderbilt HNSSVHNSS v 2.0; 70 HNC pts > 3mos post-tx; 48 > 6mos post-tx

60% mod/sev xerostomia

52% difficulty chewing/swallowing

40% difficulty sleeping

36% mod/sev thick saliva; causing:

Difficulties speaking 36%

choking/gagging 16%

dysphagia 18%

33% mod/sev taste change

41% mod/sev mucosal sensitivity to spicy, acidic & dry food; altered food choice 26%

34% limited jaw movement; 28% neck/shoulder function

21% Dental complaints: tooth sensitivity 21%; tooth damage 19%; denture problems 6%

Murphy B, Epstein J et al. Head Neck 2010

Vanderbilt Head and Neck Survey:Viscous Secretions

Question Number ≥ 1 ≥ 4

• Thick mucus/phlegm 67 82.1 47.8• Choking/gagging results 67 58.2 28.4• Swallowing difficult 67 61.2 25.4• Sleep effected 67 49.3 20.9

Cooperstein E, Gilbert J, Epstein JB, et al. Head Neck 2011

Oral health & QOL in cancer patients in hospice

� 104 terminally-ill CA pts (2.5-3 wk life expectancy); median age 66.0; M 40.8%, F 59.2%

� Oral Problems Scale (OPS): xerostomia, oral pain, taste change & functional/social impact on QOL; oral exam

� Hyposalivation (98.1%), erythema (50%), ulceration (20.2%), fungal infection (35.6%), other oral problems (44.2%).

� Xerostomia, taste change & oral pain impact QOL (p

Hyposalivation Affects Mastication and Bolus Formation:

� 15 HNC with xerostomia v 20 controls� Methods:

– Saliva volume & scintigraphy

� Results:– No difference with liquids or paste– Xerostomia patients

» 46% longer masticating shortbread» Initiation & duration of pharyngeal swallow: no change» Larger oral & pharyngeal residues

Hamlet, Int J Rad Oncol Biol

Hyposalivation and Voice:

� 20 patients early glottic lesions; 20 controls� Treatment: RT including salivary glands� Results:

– No change in acoustic or aerodynamic profiles– Subjective vocal & stroboscopic dysfunction

(p

Sialorrhea

� Less common than hyposalivation

� More commonly dysphagia or anatomical/functional disturbance

– Lip incompetence, tumor mass, post-treatment dysfunction of larynx, oropharynx, fibrosis, injury to motor nerves

� Brosky ME. J Support Oncol 2007;5:215-25

� Bomeli ST, Desai S, Johnson JT. Oral Oncol 2008;44:1000-8

Measures to control saliva

� Surgical reconstruction: redirect salivary gland ducts, controlled fistula

� Prostheses

� Speech therapy

� Suction

� Avoid medications with sialogogue effect

� Reduce saliva volume (local, systemic meds, RT)

� Chorda tympani section (PSNS innervation)� Bomeli S, Desai SC. Oral Oncol 2008;44:1000-8

Clinical interventions

Excessive saliva:

� Anticholinergics: banthane, probanthane,

� Others: tricyclic antidepressants (eg: amitriptyline), scopolamine, octreotide, atropine

� Botulinumtoxin(10-50 u): blocks local release of acetycholine

� Radiation therapy12Gy 2 fn/1/wk� Bomeli S, Desai SC. Oral Oncol 2008;44:1000-8

Excessive Saliva Viscosity:

� Viscosity is a considerable problem for cancer patients during & following treatment

� Limited research to date in epidemiology and management

� Possible interventions: systemic sialogogues; mucolytic agents (n-acetyl-cysteine, guaifenesin)

Systemic sialogogues

� Pilocarpine

� Civemiline

� Bethanechol

� Anetholetrithione

� (Niacin)

Symptom Burden HNC Following CT/RTSymptom Burden HNC Following CT/RT

� late toxicities often underreported.

� Symptom burden into the late stage of recovery:

– Xerostomia

– Taste alterations

– Mucosal sensitivity to dryness, spice, temperature & acidity

� Clinicians should identify & manage oral symptom burden

� Ganzer H, Touger-Decker R, Parrott JS, Murphy BA, Epstein JB.

Taste function following HNC: qualitative research

� “Eating is more than nutrition…it’s also a very pleasurable experience…it is like an activity for us more than just eating food for nutrition, it’s something that we do for fun.” (GS=1.54)

� “Having gone through a couple of months of only drinking liquids…it means a lot. I like to eat.” (GS=0.15)

� “Before cancer I ate to live, and now I live to eat. Because after you go for so long and not be able to savor the food and enjoy it…I never really appreciated food in the way that I do now that I can eat again.” (GS=0.21)

� “The taste of food is of significant importance…it’s almost up there with sex in terms of you know, what it brings from a list of things you couldn’t live without…” (GS=0.02)

� Ganzer H, et al. Oral Oncol 2015

Taste change in cancer patients

Under-reportedInfluence of xerostomia: correlations possible

Mossman et al Int J Radiat Oncol Biol Phys 1982 8: 991-7Inokuchi et al, Practica Oto-Rhino-Laryngologica 2002 95: 1091-6

Zheng et al, Fukuoka Igaku Zasski 2002 93: 64-76

Tongue volume: Correlations suggestedFernando et al, Clin Oncol (R Coll Radiol) 1995 7: 173-8

Yamashita et al, Head and Neck 2006 June 508-516

Variability: unusual report of long term complete loss despite ½ tongue being spared

Saito et al, Radiation Medicine 2002 20: 257-60

Taste

Evaluates nutritious content of food and prevents ingestion of toxic substances; associated with fluid balance (thirst)

� Bitter: detect submicromolar levels of toxic/noxious compounds

� Sour: warns of toxic/ noxious compounds

� Sweet: identifies energy-rich nutrients

� Salt: ensures intake for electrolyte balance

� Umami: recognizes amino acids (glutamate, aspartate)(savory/pleasure); MSG

� Fatty acid: energy dense foodsChandrashekar et al, Nature 2006 444:288-94

Taste Receptors

GustationSpecialised epithelial cells:

TongueSoft palatePharynxLarynxUpper 1/3 of oesophagus

Each taste bud: 50-100 taste-receptor cells; lifespan of ~10-14 days

No segregation of taste qualities in the human tongue

Scott, Curr Opin Neurobiol 2004 14:423-7Scott, Neuron 2005 48:455-64Chandrashekar et al, Nature 2006 444:288-94

Sugar/amino acid receptorsSweet and amino acids – determined by T1R genes (T1R1,

T1R2 and T1R3)

� T1R receptors function as dimers

� T1R1+3 – amino acids (MSG & aspartate; “umami”)

� T1R2+3 – sugars (including saccharin)

Function as G protein coupled receptors (GCPCR)

Tuned to individual compounds (site of ligand binding determines recognition of quality)

Knock out of T1R2+T1R3 causes loss of sweet

Sweet preference may be determined by T1R

Scott, Curr Opin Neurobiol 2004 14:423-7Scott, Neuron 2005 48:455-64

Chandrashekar et al, Nature 2006 444:288-94

Bitter receptors

Bitter – determined by T2R genes (~25)

Different T2R receptors recognise different compounds e.g.

hT2R14 – picrotoxininhT2R28 – phenylthiocarbamide

Most T2Rs expressed on the same TCR- the cells are broadly tuned high affinity bitter receptors on a single cell

Scott, Curr Opin Neurobiol 2004 14:423-7Scott, Neuron 2005 48:455-64

Chandrashekar et al, Nature 2006 444:288-94

Salt and sourSalt: sodium channels? (receptor unknown)

Sour: Acid sensing proton channels?Calcium channels?Chloride channels?Potassium channels?PKD2L1 (involved)

Umami

� Savory, desirable, enjoyable, good taste

� intensifies other taste sensations

� Amino acid rich foods, free glutamate

� Glutamate receptors: – T1R1/T1R3; mGluR4, mGluR1

Free Fatty Acid Receptors (FFAR)

� FFAR: may be CD-36 or G protein coupled receptors (GPCR) in the oral cavity & GIT

� May have role in taste/texture preferences

� Role in energy regulation & appetite via secretion of insulin & incretin & sympathetic nerves

� Hara T, Kimura I et al. Reve Physiol Biochem Pharmacol2013;Apr 30

Other tastes� Spicy taste: capsaicin, gingerzone; menthol; c-

fibers

� Metallic taste ?

� Water?

Taste evaluationSubjective

PRO (Questionnaires)Chemical gustometry

Tastants applied via rinses, drops, paper disks, taste strips, swabsDetection of lowest concentration (threshold)Supra-threshold concentrations

ElectrogustometryRecognition of electrical change – but does not define taste quality

Objectivee.g. PET, Functional MRI

Ruo Redda and Allis, Cancer Treat rev 2006 32: 541-7Epstein JB, BaraschA. Oral Oncol2010

rr

Altered taste and head and neck malignancy

Common – up to 100% - before treatment due to tumor. Up to 89% of patients prior to RT have some taste disturbance

Ruo Redda and Allis Canc Treat Rev 2006 32:541-7

Subjective assessment prior to RT partial loss of bitter (35%), salt (18%) and/or sweet (6%)

Maes et al, Radiother Oncol 2002 63: 195-201

Taste change begins ~3 weeks of RT; some studies improves by 8 weeks of TX

Yamashita H, Nakagawa K et al Int J Radiat Oncol Biol Phys 2006;66:1422-9

Yamashita H, Nakagawa K. Et al. 2008

Second most common complaint in patients after 3 & 6 months post-RT HNC

Murphy BA, Epstein JB 2011

Radiotherapy-associated taste changeEffects on taste quality variable

Loss of sweet firstBitter and salt>sweet4 “conventional” qualities equally affectedUmami affected

Mossman et al, 1979 5:521-8Maes et al, Radiother and Oncol 2002 63:195-2001Zheng et al, Fukuoka Igaku Zasski 2002 93: 64-76

Shi et al, Auris Nasus Larynx 2004 31: 401-6Yamashita et al, Head and Neck 2006 June 508-16

Ruo Redda and Allis Canc Treat Rev 2006 32:541-7Yamashita H, Nakagawa K et al. 2008

Possibly reflecting:Methods

Radiotherapy dose & technique

Loss of umami may have the strongest correlation with QoLShi et al, Auris Nasus Larynx 2004 31: 401-6

Altered taste: HNCRadiotherapy taste changes highly variable:

“Soapy”

“Burning”

“Oily”

“Powdery”

“Chemical”

“Awful”

Impact of taste change:

Reduced dietary intake

Weight loss

Reduced QoL

Poor(er) outcomes

Sandow et al, 2006 J Dent Res 2006 85: 608-611

Vanderbilt Head and Neck Survey:Smell and Taste

Taste change Number ≥ 1 ≥ 4

• Taste altered 68 80.9 47.1• Decreased desire to eat 68 61.8 38.2• Altered food choices 66 68.2 42.4• Decreased food eaten 66 59.1 33.3

Smell change Number ≥ 1 ≥ 4• Sense of smell changed 69 43.5 30.4• Altered food choices 67 37.3 19.4

Cooperstein E, Gilbert J, Epstein JB, et al. Head Neck 2011

Post-irradiation gustatory dysfunction

Loss of taste receptor cells (as part of mucositis)Synaptic uncouplingPossible neurological damage (unlikely)

Nelson Anat Rec 1998 253:70-8

taste buds lost by day 6-7 after 15Gy (rats), return of taste buds by ~day 19. No change in nerve distribution

Yamashita et al, Head Neck 2006; 508-516

Taste/Flavor Alterations:• Flavor: a combination of sensory mechanisms:

• Taste, texture, temperature & smell • Basic qualities:

• Sweet, bitter, salty, sour & umami (others?)• Umami associated with pleasure or desirable flavor

may have strongest correlation with QOL

• Impact:

– Reduced interest in food

– Reduced or altered food intake leading to dietary deficiencies or weight loss

– Impaired quality of lifeChandrashekar J, Hoon MA, Ryba NJ. Nature. 2006Yamashita H, Nakagawa K et al. Oral Oncol. 2008

Shi HB, Masuda M, et al. Auris Nasus Larynx 2004Murphy BA, Epstein JB. Head Neck 2011

Dietary Adaptations/maladaptations

� Smaller meals ↓ intake

� ↓high fiber foods

� ↓ vitamin, mineral, protein & energy

� ↓ or ↑fat content

� ↑caffeine & sugar

� ↑caries risk

Impact:

– ↓ interest in food

– dietary deficiencies, weight loss

PreventionTreatment modification: IMRT, tissue sparing fieldsRadioprotectants: Amifostine suggested

Buntzel et al, Semin Radiat Oncol 2002 12 (Suppl 1): 4-13

Prevention/management of hyposalivation

Antonadou et al, Int J Radiation Oncol Biol Phys 2002 52: 739-47;

Lin et al, Int J Radiation Oncol Biol Phys 2003 57: 61-70;

Wasserman et al, Int J Radiation Oncol Biol Phys 2005 63:985-90)

Variable benefit

Buentzel et al, Int J Radiation Oncol Biol Phys 2006 64: 684-91)

Management of taste changeDietary counselling/modification

Seasoning, avoid unpleasant foods, extend dietary choice (pleasing color, form, smell etc) Peregrin J Am Diet Assoc 2006 106: 1536-40

Food preparation: spice/flavoring, increase Umami flavor

Manage xerostomia

Manage oral disease

Zinc sulphate: may promote taste bud proliferation

Reduced severity & duration of taste dysfunction (18 patients)Ripamonti et al, Cancer 1998 82: 1938-45

But benefit (NS) observed in larger study (169 patients; lower dose)Halyard et al, Int Radiation Oncology Biol Phys 2007 67: 1318-22

Centrally acting medications: clonazepam, gabapentin, Marinol(THC), megestrol Thorne T, Olson K, Wismer W. JSCC 2015;23:284

The Critical Role of Oral Care in Cancer Therapy

� The mouth is a part of the body

� Commonest infections affecting mankind:

– caries, periodontal disease

� Oral complications and toxicities are common

� Dental & medical communities are poorly prepared

� Timely & appropriate treatment is needed

� Integrated teams for best care:

– Oral/dental knowledge, medical knowledge

– communication

Resources: � MASCC.com

� NCI-PDQ: oral care, mucositis

� Epstein JB, Barasch A. Taste disorders in cancer patients: Pathogenesis, and approach to assessment and management. Oral Oncol 2010;46(2):77-81.

� Epstein JB, Murphy BE. Oral health and survivorship: Late effects of cancer and cancer therapy. In: The MASCC Textbook of Cancer Supportive Care and Survivorship. Oliver IN (Ed). Springer, New York, ISBN 978-1-4419-1224-4 2010; pp 399-406.

� Davies AN, Epstein JB (Eds). Oral Complications of Cancer and its Management. Oxford University Press Inc, Great Clarendon Street, Oxford OX2 6DP; Oxford University Press Inc, New York, 2010; ISBN 978-0-19-954358-8.