IL DOLORE DIFFICILE

DA METASTASI OSSEE

Gaetano Lanzetta Oncologia Medica

I.N.I. - Grottaferrata ( RM )

Modulo dichiarazione conflitto di interessi

Relationship Company/Organization

Advisory Board , Speaker’s fee KYOWA KIRIN

Advisory Board JANSSEN

Advisory Board ITALFARMACO

Advisory Board

ASTELLAS

Tutti i rapporti finanziari intercorsi negli ultimi due anni devono essere dichiarati. Non ho rapporti (finanziari o di altro tipo) con le Aziende del farmaco

Ho / ho avuto rapporti (finanziari o di altro tipo) con le Aziende del farmaco x

BONE METASTESES

CTIBL

BONE MARROW MICRO-ENVIRONMENT

BONE HEALTH IN CANCER PATIENTS

THERE ARE THREE AREAS OF CANCER MANAGEMENT THAT MAKE BONE HEALTH IN CANCER PATIENTS OF INCREASING CLINICAL IMPORTANCE

Nuova metastasi

ELEVATO TURNOVER OSSEO (eta’ –livelli vit D – Terapia ormonale adiuvante- metastasi)

Perdita ossea Homing delle cellule tumorali

Crescita della metastasi ossea

CTIBL FRAGILITÀ

PROGRESSIONE OSSEA

CTX NTX P1NP

SDF-1 TGF b PDGF IGF-1 OP

CTX NTX P1NP

SDF-1 TGF b PDGF

OP

CTX NTX P1NP

SDF-1 TGF b PDGF OP

SRE

Scheletro non metastatico Nicchia premetastatica Metastasi ossea

Courtesy by Bertoldo F

Fracture

Hypercalcemia

Surgery to bone

Rx therapy to bone

Disease SRE

Loss of autonomy

Bone pain

Consequences to functional independence and QOL

Bone metastases

SCC or vertebral collapse

Anxiety and depression

1. Gainor, Buchert. Clin Orthopaed Rel Res 1983;178:297–302; 2. Saad F et al. Cancer 2007;110:1860–7; 3. Poor et al. Osteoporos Int 1995;5:419–26; 4. Loblaw et al. Supp Care Cancer 2007;15:451–5; 5. Hellman, Krasnow. J Palliat Med 1998;1:277–83; 6. Maranzano et al. Tumori 2003;89:469–75; 7. Katzer et al. Arch Orthopaed Trauma Surg 2002;122:251–8; 8. Loblaw et al. J Clin Oncol 2005;23:2028–3.

BONE METASTASES HAVE DEBILITATING CONSEQUENCES

•Metastatic cancer induced bone pain ( CIBP) is a severe clinical problem that is often inadequately treated by current analgesic. •CIBP is a complex pain syndrome involving background pain ( typically opiod responsive ), which can be describe as a dull ache that increase in intensity with progression of the disease •CIBP involves spontaneous breakthrough pain and movement-related pain, which are generally difficult to treat with opioids without intolerable side-effects. •While the etiology of CIBP remains to be fully elucidated, increasing evidence suggest that CIBP is uniquely complex and is accompained by neurochemical changes distinct from other chronic pain pathologies ( neuropathic pain, inflammatory pain).

Only about 40% of patients reported adequate relief of pain from bone metastases

75-80% of patients had pain

65%

80%

Osteoclast activity source of

algogenic stimulations

Neoplasia source of algogenic stimulations

Role of the nervous system in mantaninig

the pain in bone metastases

PATHOPHYSIOLOGY OF CANCER INDUCED BONE PAIN

Neoplasia source of algogenic stimulations

PATHOPHYSIOLOGY OF CANCER INDUCED BONE PAIN

“CANCER MICROENVIRONMENT”

Osteoclast activity source of algogenic

stimulations

PATHOPHYSIOLOGY OF CANCER INDUCED BONE PAIN

RANK Ligand is an essential mediator of the vicious cycle of bone destruction

Activated osteoclasts

Osteoblasts

Bone resorption Growth factors (eg, TNF, IL-1, TGF-β)

RANK Ligand

PDGF, BMPs, TGF-β, IGFs, FGFs, Ca2+ Tumour

1. Adapted from: Boyle WJ, et al. Nature 2003;423:337–42; 2. Roodman GD. N Engl J Med 2004;350:1655–64.

Role of the nervous system in mantaninig

the pain in bone metastases

PATHOPHYSIOLOGY OF CANCER INDUCED BONE PAIN

Nerve growth factor

Fenomeno del “perineural involvement ”, invasione e proliferazione del cancro nel nervo, associato a dolore

CELLS EAVESDROP AND

MONITOR THE ACTIVITY OF SYNAPSES

ROLE OF GLIA: MICROGLIA - ASTROCYTES STRENGTHENS THE PERCEPTION OF PAIN

Fractalina, NRP, O, SP GLUTAMMATO, CGRP, ATP, Pg

Citochine pro-infiammatorie IL-1, IL-6, TNFα

COMPLEX PAIN

SYNDROME

CIBP: A COMPLEX PAIN SYNDROME

INFLAMMATORY MECHANISM

MECHANISM NEUROPATHIC

MECHANISM ISCHEMIC

COMPRESSION MECHANISM

rapid growth

intratumoral hemorrhage invasion nerve entrapment osteolysis organ damage

secretion of humoral mediators

activation and excitation of primary afferent neurons

CHEMICAL MECHANISM

low pH intra and extracellular

It affects a large percentage of cancer patients

30-50% moderate to severe 25-40% very intense (Dickerson 2001)

QoL (Weinfurt KP 2002)

FANS

Oppiacei

Paracetamolo Cannabinoidi

Cannabinoidi

Oppiacei

Gabapentinoidi

30

COMPLEX PAIN SYNDROME

Oppiacei

Peggioramento del dolore per esposizioni prolungate a morfina ed attivazione osteoclasti (King 2007)

Incremento della glia (Honore 2000, Scholz 2007)

Downregulation delle popolazioni recettoriali per gli oppioidi (eg mu) Ridotta risposta a morfina (Yamamoto 2008)

Aumento dei dosaggi per analgesia (10 volte) (Luger 2002)

Incrementi di peptidi nocicettivi ( dinorfina) (Vanderah 2001)

Sensibilizzazione dei neuroni WDR (Urch 2003)

OPIOIDS AND BONE METASTASIS

SINAPSI SILENTE

RECETTORI TLR4 : TOLL LIKE RECEPTOR Recettori di Pedaggio

Potenti attivatori della glia

INIBIZIONE AZIONE SVOLTA DAGLI OPPIODI

TOLLERANZA

DIPENDENZA

IPERALGESIA IBUDILAST

…nel 2019… ?!?

Scala antalgica OMS 1982…

vvvvv

GRAZIE PER LA VOSTRA ATTENZIONE

DISCLOSURES

Advisory Boards / Honoraria / Speakers’ fee / Consultant for:

• ITALFARMACO

• KIOWA KIRIN

• PFIZER

• JANSSEN

• ASTELLAS

• NOVARTIS

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CENTRI SUPERIORI

STIMOLO DOLOROSO

Fractalina, NRP, O, SP Glutammato, CGRP, ATP, Pg

Citochine pro-infiammatorie IL-1, IL-6, TNF

ROLE OF GLIA: MICROGLIA - ASTROCYTES STRENGTHENS THE PERCEPTION OF PAIN

79

Comparsa del picco: 3-5 minuti

Spesso intensità da moderata a severa

Durata mediana: 30 minuti (range 1-240)

Numero di episodi: 4 al giorno (mediana)

CARATTERISTICHE DEL BTcP SU CUI BASARE IL TRATTAMENTO

Zeppetella G. et al. Curr Op Supp Pall Care Darwish et al. Poster presented at the

British Pharmacological Society, December 15th 2010.

Variabilità INTRA- e INTER-

INDIVIDUALE

ETEROGENEITÀ degli episodi di BTcP

Dolore di Base controllato

Farmaco ideale per controllare

il BTcP

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TOLLERANZA DIVENTA FEEDBACK DINAMICO CHE PERMETTE

AD ALCUNI PROCESSI FUNZIONALI DI RITORNARE OPERATIVI

TOLLERANZA È IL RIPRISTINO DEL PROCESSO ECCITATORIO NEURONALE

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SOPRAVVIVENZA (%) A 5 ANNI PER SEDE TUMORALE IN ITALIA

AIOM - AIRTUM, I numeri del cancro in Italia, 2016

FACING AVDVANCED CANCER IS….

http://www.google.it/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjWl7OFmLTUAhXE6xQKHV3HCjcQjRwIBw&url=http%3A%2F%2Fit.paperblog.com%2Fmorte-o-inizio-di-un-altra-vita-1413652%2F&psig=AFQjCNHdlFeZiK_EpI2NAlU2QiiN-gtpxQ&ust=1497215370017447

TRAFFICKING DOWN REGULATION

…..IL SISTEMA PIU SEMPLICE UTILIZZATO DALLA CELLULA PER DIMINUIRE IL NUMERO

DEI RECETTORI…

CELLS EAVESDROP AND

MONITOR THE ACTIVITY OF SYNAPSES

ROLE OF GLIA: MICROGLIA - ASTROCYTES STRENGTHENS THE PERCEPTION OF PAIN

Fractaline, NRP, O, SP GLUTAMATE,

CGRP, ATP, Pg

Proinfilammatory Cytokines L-1, IL-6, TNFα

ROLE OF GLIA: MICROGLIA - ASTROCYTES STRENGTHENS THE PERCEPTION OF PAIN

Fenomeno del “perineural involvement”, invasione e proliferazione del cancro nel

nervo, associato a dolore

https://www.google.it/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwj2oZrt3rfXAhVJtxQKHQJnDoMQjRwIBw&url=https%3A%2F%2Fwww.intechopen.com%2Fbooks%2Fpain-relief-from-analgesics-to-alternative-therapies%2Fparacetamol-update-on-its-analgesic-mechanism-of-action&psig=AOvVaw22Oj00qDfHW40O1134pJAj&ust=1510531591034536

The Lancet Oncology, Volume 13, Issue 2, Pages e58 - e68, February 2012