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
x Ho / ho avuto rapporti (finanziari o di altro tipo) con le Aziende del farmaco
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 Oppiace
i
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
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
TOLLERANZA DIVENTA FEEDBACK DINAMICO CHE PERMETTE AD ALCUNI PROCESSI FUNZIONALI DI RITORNARE OPERATIVI
TOLLERANZA È IL RIPRISTINO
DEL PROCESSO ECCITATORIO NEURONALE
SOPRAVVIVENZA (%) A 5 ANNI PER SEDE TUMORALE IN ITALIA
AIOM - AIRTUM, I numeri del cancro in Italia, 2016
FACING AVDVANCED
CANCER IS….
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
The Lancet Oncology, Volume 13, Issue 2, Pages e58 - e68, February 2012
