Paris, HEGP

- 20 Novembre 2014 -

TAO 2014

Soins de Support en cours de Radiothérapie

Gestion de la Toxicité aiguë de la Radiothérapie

Exemple des K des Voies Aéro-Digestives Supérieures

--------------------------

- René-Jean Bensadoun -

OPTIMISATION DE LA RADIOTHERAPIEDES CANCERS des VADS

BALISTIQUE : RCMI (IMRT) ++++

CHIMIOTHERAPIE CONCOMITANTE

ASSOCIATION AUX THERAPIES CIBLEES

SOINS DE SUPPORT : Place du Laser de Basse Energie; Nutrition Entérale; «S.O.T» (soins d’optimisation thérapeutique)

REFERENTIELS (contourage, dose

intensité…)

1

2

34

5

IMRT 3D CONFORMAL TRADITIONAL 2D

45 54 70 84 Gy PTV BRAINSTEM/SPINAL CORD

D’’’’après Clifton Ling , Memorial SK, New York

Radiothérapie de l’’’’oropharynx et du cavum(RT2D, RC3D, IMRT)

3 mois p=0,00412 mois p=0,0518 mois p=0,04

Fonction Salivaire avec stimulation(RCMI vs RC3D)

BASE DU CRANE

Radiochimiothérapie

Concomitante

Radiochimiothérapie

Concomitante

(et/ou association aux thérapies

ciblées (anti REGF): cetuximab)

BiRCF phase III : Toxicité précoce

Mucite Grade 3 et 4 Bras A : 69,5 % (57/82) dont 91,2% grade 3 (52), 8, 8 % grade 4 (5)Bras B : 76,5 % (62/81) dont 91,9% grade 3 (57), 8, 1% grade 4 (5)(119/163 : 73% pour les 2 bras)

Epithélite Grade 3 (4 : 1 bras B)Bras A : 27 % (22/82)Bras B : 38% (30/81)(53/163 : 32,5% pour les 2 bras)

Neutropénie G 3 et 4Bras A : 2% (2/82)Bras B : 33% (27/81) dont 74,1% grade 3 (20/27), 25, 9% grade 4 (7/27)(29/163 = 29% pour les 2 bras)

Tox digestive (nausées, vomissements, diarrhée) grade 3Bras A : 0Bras B : 5/81 (6%)(5/163 = 3% pour les 2 bras)

NOTION DE«QUALITE de SOINS» :

� OBTENIR UNE EFFICACITE MAXIMALE (DOSE, ADMINISTRATION, et CHOIX du TRAITEMENT), avec :

– une BONNE COMPLIANCE du PATIENT au traitement ;

– le MOINS POSSIBLE D’’’’EFFETS SECONDAIRES.

«Doing the right thing right»

MISE EN OEUVRE des protocoles de RADIO-CHIMIOTHERAPIE (K ORL)

� Notion d'intensité de dose optimale .� Prise en charge des effets secondaires

précoces, � Support nutritionnel :

("Supportive care")

=> Notion de rapport "coût fonctionnel"/efficacité,

=> et FAISABILITE ou non du protocole.

TRAITEMENTS ASSOCIES

� SUPPORT NUTRITIONNEL ++

� ANTALGIQUES (et AINS)

� ANTIBIOTIQUES

� ANTINAUSEEUX

� SOINS LOCAUX / LASER DE BASSE ÉNERGIE

� FACTEURS DE CROISSANCE HEMATOPOIETIQUES

� RADIOPROTECTEURS, CHIMIOPROTECTEURS ??

LIMITES

� HOSPITALISATION ? Alternatives ++� Compliance au traitement?� Support logistique ++� Qualité de vie ?� Séquelles des réactions locales

précoces ?� Efficacité à long terme ?� Coût …

Exemple de la Radio -chimiothérapie des Cancers ORL:

EFFETS SECONDAIRES PRECOCES

� Perte de poids� Mucite� Epithélite� Neutropénie fébrile� Surinfections� Insuffisance rénale et troubles

métaboliques� Troubles digestifs� Oedème laryngé.

A différencier des EFFETS SECONDAIRES TARDIFS :

� atteintes muqueuses� atteintes cutanées, sous-cutanées, et

musculaires� atteintes neurologiques� atteintes osseuses� fonctions de déglutition, de phonation

=> qualité de vie=> vie de relation=> réinsertion sociale .

Optimisation de la Prise en Charge Globale

du patient traité pour cancer ORL :

� Prise en charge de la Mucite, et de l’Epithélite, notamment par Laser de basse énergie (essais de phase III concluants)

� Soins locaux, antalgiques opiacés de niveau III, AINS, anti-fongiques locaux

� Renutrition entérale par Gastrostomie

(essais de phase II et phase III).

Mucite Chimio-Induite de grade 3:

Mucite Radio-Induite de grade 3:

HealingUlcerationSignaling andAmplificationUpregulationInitiation

Apoptosis

FibronectinBreaks Up

ActivatesMacrophages MMP

IL -1ββββ

TNF-ααααIL -6Gene

Upregulation

NF-κκκκB

Cell Membrane

Epithelium

Endothelium

ConnectiveTissue

Macrophages

SphingomyelinaseCeramidePathwayCeramide Synthase

ClonogenicCell Death

ROS

MUCOSITIS Today’s Pathobiology Perspective :

“A Multiple Mechanism Model” (d’après S. SONIS et al)

MUCOSITIS Today’s Pathobiology Perspective :

“A Multiple Mechanism Model” (d’après S. SONIS et al)

CT

RT

Tissue Injury

AngiogenesisExpressionof AdhesionMolecules

COX-2

DNA Injury

Le Laser de basse énergie (LLLT) dans la prise en charge des Mucites et Epithélites

radio- et chimio-induites

A - MUCITES

•Lasers les plus étudiés : (puissance de 10 à 150 mW max)

-> Laser Hélium-Néon (He-Ne, λλλλ=632,8 nm)

-> Lasers à diode ( λλλλ=de 650 à 905 nm)

•Aucune toxicité précoce ou tardive (application préventive de lunettes opaques pour protection de la rétine)

•Très bonne Observance du traitement par les patients.

•3 effets reconnus: - Antalgique

- Anti-inflammatoire- Accélération de la cicatrisation :

-> par action directe sur le système énergétique mitochondrial(« Biostimulation »)

-> par activation de la transformation des fibroblastes en myofibroblastes.

+ réduction de la production de radicaux libres par Chimio- ou Radiothérapie.

Laser de Basse Energie (ou «Soft-Laser» ou «LLLT»)Laser de Basse Energie (ou «Soft-Laser» ou «LLLT»)

Laser trans-cutané 830 nm traitant la muqueuse buccale (face int. Joue G)

Penetration of laser lightPenetration of laser lightPenetration of laser lightPenetration of laser light

http://www.walt.nu

Wavelength630-660 nm Wavelength

750-830 nm

B - Epithélites

Laser cutané

Oral Mucositis

Joel Epstein DMD, MSD, FRCD(C), FDS RCS(Ed)Diplomate American Board of Oral Medicine

Samuel Oschin Comprehensive Cancer InstituteCedars-Sinai Medical Center, Los Angeles, CA

Department of SurgeryCity of Hope National Medical Center,Duarte, CA

Oralmedicinepacific.com

Oral/Dental Complications � Oral and dental care:

– prevention and intervention – before, during and following cancer therapy:

� Acute complications: – mucositis, stomatitis, saliva (quantity, quality), taste, pain,

infection

� Chronic complications: – Mucositis/stomatitis, pain, saliva (quantity, quali ty),

infection, taste, tissue necrosis, caries, periodon tal disease, oral function, rehabilitation

� Impact: cost of care, hospitalization, diet/nutriti on, speech, esthetics, infection risk, pain, systemic health, activity of daily living, quality of life

Why does mucositis matter in the treatment of potentially fatal disease:

� Common & debilitating� Pain, functional impact:

� Oral intake, dysphagia, dehydration, weight loss, ( need for nutritional support), speech, infection risk

� Impact on cancer therapy: � Dose delay, dose reduction, change in CT, treatment breaks, hospitalization,

discontinuing treatment

� Increased costs.

Barasch A, Epstein JB. Dermatol Ther 2011;24:424-31Murphy BA, Beaumont JL, Isitt J,et al.. J Pain Symp Ma nage 2009; 38:522-32.Scully C, Epstein JB, Sonis S. Head Neck 2003;25:105 7-70.; Head Neck 2004;26:77-84Gabriel DA, Shea T, Olajida O, Serody JS, Comeau T. Sem in Oncol 2003;30:76-83Rose-Ped AM, Bellm LA, Epstein JB, et al. Cancer Nurs ing 2002:25:461-467Bellm LA, Epstein JB, Rose-Ped A, et al. Supp Care Ca ncer. 2000; 8:33-39. 59

Impact of Mucositis

� Impact QOL & completion of Cancer TX� Symptom clusters: shared pathobiology 1,2

� True incidence under-estimated� Most clinical trials toxicity not primary endpoint� Most clinical trails report based on PRO, NCI CTCAE 3

� Health professionals assessment of incidence & seve rity less than patient report 4

� Pain, swallowing, speech, eating, feeling ill, wght loss, overall QoL (all p<0.01) 5

� ↑ toxicity in elderly (p=0.04) 5

1 Aprile G, Ramoni M, Keefe D. Curr Opin Supp Palliat Ca re 2009;3:50-42 Nishimura N, , Nakano K, Ueda K. Support Care Can cer 2011

3. Saed ED. Ind J Med Res 2011;134:413-84. Bateman E, Keefe D. Semin Oncol 2011;38:358-61

5.Liu Y, Guan X, Zhu G. Oral Oncol 2012

61

Outcomes of Oral Mucositis in HNC

� 103 consecutive HNC, chart review� 81% males; 80% Caucasian; average 66 Gy� Mucosal ulcers associated with:

• ↑↑↑↑ topical & opioid analgesics (p<0.001) •↑ weight loss (p=0.02) •↑ feeding tubes (p=0.07) • RT delay 6% vs 0% without ulcers

Elting L, Cookelsy C, Garden A. Supp care Cancer 2005; 13:443

Outcomes of Oral Mucositis in HNC

� Retrospective review 204 consecutive pts treated 20 02, single center

� Mucositis 91% � 66% severe (gr 3-4); severity & duration ↑ with RT+CT

� OM more common: � combined CT/RT (OR 7.8) p=0.02), � altered fractionation RT (OR 6.3, p=0.03)

� Severe mucositis:� associated with severe pain (54% v 6%, p<0.001) � weight loss >5% (60% v 17%, P<0.001)

� OM associated with ↑cost: $1,700 (mild mucositis) to $6,000 (severe mucositis)

Elting LS, Cooksley CD, Chambers MS, Garden AS. Int J Radiat Oncol Biol Phys 2007;68:1110-20

62

Mucositis in HNC: morbidity & resource utilization

� 75 pts, 6 centers; RT+CT 67%, 33% RT alone� 76% mouth/throat soreness, opioids in 85%� Mucositis pain affects function despite opioids� Resource utilization:

� tube feeding 51% � hospitalization 31% (30% recorded due to mucositis), average LOS 4.9 days

Murphy BA, Beaumont JL, Isitt J, Garden AS, Gwede CK, et aly. J Pain Symp Manage 2009;38(4):522-32.

63

Oral Mucositis: Resource utilization in HNC

� Prospective study: 69 pts; 75% OSCC or OPC; 49% IMRT with chemo; 72% male

� 90% mouth & throat soreness (MTS) > 2; only 6% no MTS

� Patients with MTS: – non-prophylactic G-tubes 25% – unplanned office visits 37%– hospitalization 18%

Keefe D et al. Supp Care Cancer 2007:395

64

Survey of Professional Burden of Mucositis in HNSCC

• 50 Rad Onc & 51 Oncol Nurses, tx average of 6-12 HNC pts/mo

• Mean target RT 72 Gy; 92% developing mucositis, 71% Gr 2 or 3 (WHO), 16% Gr 4

• Rad Onc spend 7.2hrs, nurses 12.1 hrs managing mucositis, increasing time as mucositis increased

Xiao X, Barron RL, Mautner B et al. J Support Care C ancer 2010

Targeted Agents, immunotherapy & oral complications

� EGFRi (cetuximab): erythema , pain; ↑mucositis with cytotoxicTX, anterior mucositis, in field/ out of field muco sitis/dermatitis; taste change

� Anti-VEGF (bevacizumab): bleeding, delayed healing, osteonecrosis; taste

� Tki (sunitinib/sorafinib): osteonecrosis, lichenoid m ucositis; taste

� mTORi (tacro-, siro-, evero-, ridaforo-limus): stoma titis (aphthous-like), pain; lichenoid; taste

� Immunotherapy� Different pathobiology, different management

MASCC/ISOO Evidence -Based Clinical Practice Guidelines for Oral Mucositis (2014)

� Recommend for prevention:– Cryotherapy 30 mins bolus 5-FU CT (level evidence II ) – KGF-1-palifermin for high-dose CT + TBI in auto-HSC T (level evidence II)– LLLT (2J/cm 2; 2 secs/point) for HSCT with high dose CT, with or without TBI

(level evidence II)– Benzydamine HNC for standard dose RT (level evidence I)

� Recommend for Treatment: – PCA for oral pain in HSCT (level evidence II)

MASCC/ISOO Evidence -Based Clinical Practice Guidelines for Oral Mucositis (2014)

� Suggestions in favor: Prevention: – Oral care protocols (level of evidence III)– Oral cryotherapy high dose melphalan HSCT with/witho ut TBI (level of evidence

III)– LLLT (wavelength ~633nm) HNSCC Tx RT with/without CT (level of evidence III)

� Suggestions for Pain– Transdermal fentanyl conventional & high dose CT in HSCT with/without TBI

(level of evidence III)– 2% morphine mouthrinse HNSCC RT (level of evidence I II– 0.5% doxepin mouthrinse for mucositis pain (level of evidence IV)

MASCC/ISOO Evidence -Based Clinical Practice Guidelines for Oral Mucositis (2014)

� Recommendations against (prevention): – Antimicrobials: BCoG, PTA, chlorhexidine [HNSCC],

chlorhexidine, Iseganan [RT, HSCT](Level of evidence II)

– Sucralfate CT/RT (Level of evidence I); HNSCC RT+CT (Level of evidence II)

� Recommendation against use (treatment): – Sucralfate CT (Level of evidence I); RT (Level of ev idence II)

– IV glutamine CT with/without TBI HSCT (Level of evi dence II)

MASCC/ISOO Evidence -Based Clinical Practice Guidelines for Oral Mucositis (2014)

� Suggestions against (Prevention):

– Chlorhexidine in RT (Level of evidence III)– GM-CSF mouthrinse in Auto- allo-HSCT (Level of

evidence II)– Misoprostol mouthrinse in RT (Level of evidence III)– Systemic pentoxifylline in HSCT (Level of evidence I II)– Pilocarpine in HNSCC RT (Level of evidence III), HSC T

with/with TBI (Level of evidence II)

Trends in Oncology Therapy impacting Oral Mucositis

� Increasing toxicity in HNC� Increasing use of targeted therapies� Decreasing toxicity in Hematopoietic Stem Cell Tran splant:

– Mini-transplant– Reduced intensity conditioning– Changing medications in conditioning– Kepivance first FDA approved intervention

� Oral care in cancer therapy, developing interventio ns

Mucositis and QOL

� Impact QOL & completion of Cancer TX� Symptom clusters: shared pathobiology 1,2

� True incidence under-estimated– Most clinical trials toxicity is not primary endpoi nt, report based on PRO, NCI

CTCAE 3

– Health professionals assessment of incidence and se verity lower than patient report 4

1 Aprile G, Ramoni M, Keefe D. Curr Opin Supp Palliat Ca re 2009;3:50-42 Nishimura N, , Nakano K, Ueda K. Support Care Can cer 20113. Saed ED. Ind J Med Res 2011;134:413-84. Bateman E, Keefe D. Semin Oncol 2011;38:358-61

Advances in Cancer Therapy: Targeted Therapy/Immunotherapy

Personalized Medicine

� New drug or TX presents new toxicity(s)� Understanding mechanism of action is key to managem ent� Multimodality TX� Symptoms clusters� Toxicity assessment: validated PROs, scales� Antitumor effect must not be compromised by TX of t oxicity� Risk prediction (personalized medicine).

MucositisA fish hook lodges in my throat.

Splittle, kindergarten paste, thickens everything-e ven vision.Mouth packed with sores and blisters, swollen ulcer ated tongue.Topside sandpapered with number 7 coarsest grade.Taste buds, saliva glands seared.Cool water, corrosive acid now.The tongue rests; the teeth become enemies now.Coiled steel razored wire stop dentate prison walls.Only moans escape my lips. I cannot eat or speak.

Inside a howl festers.

Pain lengthens time.

-Anita Hart Balter…