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.