CARDIONCOLOGIA

Mauro GIORGIS.C.D.U. CARDIOLOGIA - OSP. MOLINETTE

CITTA’ della SALUTE e della SCIENZA di TORINO

Cardiologi ed Oncologi/Ematologi: per lungo tempo 2 mondi separati

TOSSICITÀ TARDIVA

Dati su bambini lungo-sopravviventi

hanno dimostrato che la cardiotossicità

non ha un limite “temporale” nella sua

manifestazione tanto da rendersi

evidente anche molti anni dopo*.

*Lipshultz SE, et al; N Engl J Med 324:808-815, 1991

Due concetti chiave !

TOSSICITÀ ANCHE A BASSI DOSAGGI

• 240-300 mg/m2: • EF > 55%... …ma Scinti Ac Antimiosina ⊕ nel 94% dei Pts

Carioni, J Nucl Med 1995

TOSSICITÀ ANCHE TARDIVA

• Follow Up a 11 aa (analisi retrospettiva):

significativa riduzione EF (< 40%) nel 32 %

J Clin Oncologic 2004

Epidemiologia

Approximately 60% of anthracycline-t r e a t e d c h i l d r e n w i l l d e v e l o p echocardiographic evidence of cardiac dysfunction, and 10% of those treated with high-dose anthracyclines will develop congestive heart failure within the 20 years after therapy.

Cardiac Outcomes in Survivors of Pediatric and Adult Cancers. Can J Cardiol. 2016 Jul;32(7):871-80.

La malattia CANCRO sta diventando una malattia CRONICO-DEGENERATIVA e pone problematiche NUOVE

AnthracyclinesTaxanesAnti-HER25-FUBevacizumabTKI- Sunitinib- Sorafenib- Nilotinib- ………..

Radiotherapy

BoneMarrowtransplant

CANCER

DramaticImprovementInSurvival

Oncologist

Screening

EarlyDiagnosis

AnthracyclinesTaxanesAnti-HER25-FUBevacizumabTKI- Sunitinib- Sorafenib- Nilotinib- ………..

Radiotherapy

BoneMarrowtransplant

CANCER

Oncologist

Cardiologist—>CardiOncologistComorbidities

Elderly

MAGGIORE SOPRAVVIVENZA

NUOVE PROBLEMATICHE

CARDIO-ONCO-EMATOLOGIA

Una nuova branca della Cardiologia che studia:

la cardiotossicità provocata da terapie antitumorali (CHTh e RXTh) ed ematologiche

la possibilità di diagnosticarla precocemente e a livello subclinico

strategie di cardioprotezione

Cosa dobbiamo aspettarci?

• La CTX è un fenomeno destinato ad espandersi :

-aumento del n° di nuove diagnosi tumore annuali

-ma anche aumento del n° PTs stabilizzati

-aumento aspettativa di vita

-per molti di essi nuovi cicli di CHT nel corso degli anni

-ricorso a terapie antitumorali multiple, combinate e ripetute, sempre più aggressive e potenzialmente cardiotossiche

SCENARI ODIERNI• Pts con cardiopatia in atto che si ammalano di cancro

• Pts onco-ematologici che manifestano malattie cardiocircolatorie

• Terapie onco-ematologiche che causano cardiopatie

• Cardiopatie in lungosopravviventi e guariti (“cancer survivors”)

• Compatibilità tra terapie onco-ematologiche e cardiologiche

Conseguenze di una gestione non corretta

L’inadeguatezza nel predire le conseguenze a lungo termine del trattamento anti-tumorale associate alla cardiotossicità può comportare: a) sottostima ➠ incapacità di prevenire eventi avversib) sovrastima ➠ inappropriata interruzione di un t rat tamento potenzia lmente “lifesaving”

Cardiovascular toxicity induced by chemotherapy,targeted agents and radiotherapy: ESMO ClinicalPractice Guidelines†

G. Curigliano1, D. Cardinale2, T. Suter3, G. Plataniotis4, E. de Azambuja5, M. T. Sandri6,C. Criscitiello1, A. Goldhirsch1, C. Cipolla2 & F. Roila7, on behalf of the ESMO Guidelines WorkingGroup*1Department of Medicine, Division of Medical Oncology; 2Division of Cardiology, Cardiology Unit, European Institute of Oncology, Milan, Italy; 3Swiss CardiovascularCenter, Inselspital, Bern University Hospital, Bern, Switzerland; 4Department of Oncology, Aberdeen Royal Infirmary Foresterhill, Aberdeen, UK; 5Institut Jules Bordet andUniversité Libre de Bruxelles, Brussels, Belgium; 6Division of Laboratory Medicine, European Institute of Oncology, Milan, Italy; 7Department of Medical Oncology,S. Maria Hospital, Terni, Italy

Cardiovascular (CV) toxicity is a potential short- or long-term complication of various anticancer therapies. Some drugs,such as anthracyclines or other biological agents, have been implicated in causing potentially irreversible clinicallyimportant cardiac dysfunction. Although targeted therapies are considered less toxic and better tolerated by patientscompared with classic chemotherapy agents, rare but serious complications have been described, and longer follow-up is needed to determine the exact profile and outcomes of related cardiac side-effects. Some of these side-effectsare irreversible, leading to progressive CV disease, and some others induce reversible dysfunction with no long-termcardiac damage to the patient. Assessment of the prevalence, type and severity of cardiac toxicity caused by variouscancer treatments is a breakthrough topic for patient management. Guidelines for preventing, monitoring and treatingcardiac side-effects are a major medical need. Efforts are needed to promote strategies for cardiac risk prevention,detection and management, avoiding unintended consequences that can impede development, regulatory approvaland patient access to novel therapy. These new ESMO Clinical Practice Guidelines are the result of a multidisciplinarycardio-oncology review of current evidence with the ultimate goal of providing strict criteria-based recommendations onCV risk prevention, assessment, monitoring and management during anticancer treatment.

introductionThe rationale for Cardiology–Oncology Clinical PracticeGuidelines has a strong basis which can be outlined in severalissues: (i) the awareness of the toxicity of anthracyclines andnewer targeted agents and the planning of the optimaltreatment regimens that reduce cardiotoxicity withoutcompromising anticancer efficacy; (ii) the detection ofpotential cardiovascular (CV) effects needs to be an integralpart of treatment when potential cardiotoxic agents are used.This begins with careful clinical assessment, paying attentionto subtle signs and symptoms such as minor impairment ofexercise capacity and a resting tachycardia; (iii) the preventionof CV side-effects is a major issue. A careful CV work-upshould be undertaken before the initiation of chemotherapyknown to be associated with significant cardiotoxicity. Strictattention should be paid to patient comorbidities, especially

coronary artery disease and hypertension, in those patientsreceiving multitargeted agents, and these comorbidities shouldbe robustly managed before and during therapy; (iv) theidentification of areas of uncertainties related to (a) theheterogeneity of the treated population in clinical trials; (b) thefragmentation and limitation of prospective on long-termsurvival data, treatment strategies and monitoring and (c) theabsence of information on elderly patients.The purpose of these guidelines is to summarize the current

state of knowledge regarding CV complications, such as leftventricular (LV) dysfunction (LVD), myocardial ischemia,hypertension and QTc prolongation, associated withcommonly used anticancer drugs and radiotherapy (RT).Following this assessment, the multidisciplinary boardprovided recommendations on: (a) CV risk assessment andprevention in cancer patients; (b) optimal screening andmonitoring of cardiac function during cancer treatment(considering costs, feasibility and outcomes); (c) activemanagement of pre-existing cardiac disease to promote themost effective cancer therapy; (d) active management ofchemotherapy, targeted agents or RT-induced cardiac toxicity.These guidelines summarize the deliberations of a cross-disciplinary working group, but do not bring together

†Approved by the ESMO Guidelines Working Group: February 2010, last update July2012. This publication supersedes the previously published version—Ann Oncol 2010;21(Suppl 5):v277–v282.

*Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via L.Taddei 4, CH-6962 Viganello-Lugano, Switzerland; E-mail: clinicalguidelines@esmo.org

clinicalpractice

guidelines

clinical practice guidelines Annals of Oncology 23 (Supplement 7): vii155–vii166, 2012doi:10.1093/annonc/mds293

© The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology.All rights reserved. For permissions, please email: journals.permissions@oup.com.

by guest on May 3, 2015

http://annonc.oxfordjournals.org/D

ownloaded from

La cardiotossicità è caratterizzata da almeno uno tra: -sintomi di scompenso cardiaco -segni clinici di scompenso cardiaco (es. T3 o tachicardia) -Riduzione di EF di almeno 5% sotto i 55% con sintomi o segni di scompenso -Riduzione del 10% sotto i 55% senza segni o sintomi associati

Classification of AC-induced cardiotoxicity

Modified from Grantis et al. Crit Rev Oncol Hematol 1998, and Grenier and Lipshultz Semin Oncol1998

Characteristics Acute cardiotoxicity Early-onset, chronic cardiotoxicity

Late-onset, chronic cardiotoxicity

Onset During or within 2 weeks after AC treatment

Within 1 year after the completion of AC treatment

>1 year after the completion of AC treatment

Dose dependent Unknown Yes Yes

Clinical featuresDepression of myocardial contractility

Dilated/Hypokinetic cardiomyopathy

Dilated/Hypokinetic cardiomyopathy

Course Usually reversible Usually irreversible. Refractory to traditional HF therapy Poor prognosis

Usually irreversible. Refractory to traditional HF therapy Poor prognosis

ACUTE EARLY-CHRONIC LATE

performed 2 to 3 weeks after the baseline diagnostic study showingthe initial decrease in LVEF. LVEF decreasemay be further categorizedas symptomatic or asymptomatic, or with regard to reversibility:

! Reversible: to within 5 percentage points of baseline! Partially reversible: improved by $10 percentage points from the nadir butremaining >5 percentage points below baseline

! Irreversible: improved by <10 percentage points from the nadir and remain-ing >5 percentage points below baseline

! Indeterminate: patient not available for re-evaluation

In this expert consensus document, a classification of CTRCD onthe basis of the mechanisms of toxicity of the agents is used (Table 1).

2. Classification by Mechanism of Toxicity. a. Type I CTRCD.Doxorubicin is believed to cause dose-dependent cardiac dysfunctionthrough the generation of reactive oxygen species. Recently, investi-gators using an animal model proposed that doxorubicin-inducedCTRCD ismediated by topoisomerase-IIb in cardiomyocytes throughthe formation of ternary complexes (topoisomerase-IIb–anthracy-cline–deoxyribonucleic acid). These complexes induce deoxyribonu-cleic acid double-strand breaks and transcriptome changesresponsible for defective mitochondrial biogenesis, and reactive oxy-gen species formation.8 The damage caused by the anthracyclines oc-curs in a cumulative dose–dependent fashion. The expression ofdamage is related to preexisting disease, the state of cardiac reserveat the time of administration, coexisting damage, and individual vari-ability (including genetic variability). Electron microscopy of myocar-dial biopsies shows varying degrees of myocyte damage: vacuolarswelling progressing tomyofibrillar disarray and ultimately cell death.9

Once myocytes undergo cell death, they have minimal potential forreplacement via regeneration. In this regard, cardiac damage at thecellular level may be deemed irreversible, although cardiac functionmay be preserved and compensation optimized through antiremod-eling pharmacologic therapy, and/or less frequently, mechanicalintervention. Agents that are associated with type I CTRCD includeall of the anthracyclines (doxorubicin, epirubicin, and idarubicin) aswell as mitoxantrone. These agents are now considered to haveincreased potential for long-term cardiac dysfunction, increasedmorbidity, and mortality.10,11

b. Type II CTRCD. A number of agents do not directly cause celldamage in a cumulative dose–dependent fashion. There is consider-able evidence for this: first, the typical anthracycline-induced celldamage by electron microscopy is not seen with these agents, and

second, in many instances, these agents have been continued for de-cades, without the progressive cardiac dysfunction that would be ex-pected with type I agents. Finally, functional recovery of myocardialfunction is frequently (albeit not invariably) seen after their interrup-tion, assuming a type I agent was not given before or at the time oftherapy.10 This document uses trastuzumab as the classical exampleof type II CTRCD and presents evidence and consensusrecommendations for cardiac evaluation of patients receiving this tar-geted therapy, primarily indicated for HER2-positive breast cancer(summarized in Section V of this document). The role of cardiacassessment and imaging in patients receiving this regimen is furthercomplicated by the fact that type I (doxorubicin) and type II agents (tras-tuzumab), are often given sequentially or concurrently. Such sequentialor concurrent use may increase cell death indirectly by compromisingthe environment of marginally compensated cells, contributing to theconcern that type II agents can still result in cell death at the time ofadministration.We recognize that in the setting of a variety of predispos-ing factors, varying cumulative dosages of recognized cardiotoxicagents, and use of other agents that are known to increase oxidativestress and compromise myocyte stability, the algorithm proposed inthis document cannot be based on strong clinical data.

Since the approval of trastuzumab, numerous agents have enteredthe therapeutic armamentarium, including the small-molecule tyro-sine kinase inhibitors. It is difficult to make broad generalizationsabout these agents, because they often have different kinase targets.However, it appears that the most problematic are the agents thattarget vascular endothelial growth factor (VEGF) and VEGF recep-tors. These agents typically are associated with severe systemic arterialhypertension and ischemic events. The development of CTRCD inthese patients may be related to transient impairment of the contrac-tile elements within the cell or to the increased afterload on a compro-mised ventricle. The most concerning of this group are thenonselective agents, including sunitinib and sorafenib, because thesedrugs can target up to 50 different kinases, in addition to the intendedtarget.12 Because those ‘‘off-target’’ kinases play important roles in theheart and vasculature, the risk for toxicity is increased. As a result ofthe unspecific nature and predictability of myocardial damage, it isdifficult to provide general recommendations regarding how tomonitor patients receiving these agents. A number of attempts havebeen made to unify approaches to manage these patients, all stoppingshort of proposing guidelines; one attempt focused on arterial hyper-tension13 and the other on CTRCD.14 Careful management ofcomorbidities was urged in these documents.

Table 1 Characteristics of type I and II CTRCD

Type I Type II

Characteristic agent Doxorubicin TrastuzumabClinical course and typical response toantiremodeling therapy (b-blockers, ACEinhibitors)

May stabilize, but underlying damageappears to be permanent and irreversible;recurrence in months or years may berelated to sequential cardiac stress

High likelihood of recovery (to or nearbaseline cardiac status) in 2–4 monthsafter interruption (reversible)

Dose effects Cumulative, dose related Not dose relatedEffect of rechallenge High probability of recurrent dysfunction that

is progressive; may result in intractableheart failure or death

Increasing evidence for the relative safety ofrechallenge (additional data needed)

Ultrastructure Vacuoles; myofibrillar disarray and dropout;necrosis (changes resolve over time)

No apparent ultra structural abnormalities(though not thoroughly studied)

ACE, Angiotensin-converting enzyme.

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patients in whom extracardiac masses represent a concern.225

Measurements from CMR, echocardiography and nuclear tech-niques cannot be regarded as identical or be directly comparedfrom one modality to another. Ideally, a single technique shouldbe chosen for baseline assessment and follow-up studies duringand after cancer treatment.

Disadvantages of CMR include its lesser flexibility and availabilityand higher operational cost compared with echocardiography.221 Inaddition, issues with claustrophobia and hazards associated withferromagnetic devices need to be considered. Contraindications forCMR imaging that may be particularly relevant in some patientswith cancer include the presence of ferromagnetic componentswithin some breast tissue expanders (i.e., Contour Profile TissueExpander [Mentor, Santa Barbara, CA], which contains a magnetic in-jection dome) used for breast reconstruction after mastectomy.

3. Beyond the LVEF: AdvancedCMRAssessments. Contrast-enhanced CMR offers a unique capability to assess myocardial tissuecharacteristics compared with other imaging techniques. This tech-nique has demonstrated excellent ability to outline myocardialfibrosis and is commonly used in detection of myocardial scar andworkup of cardiomyopathies.226 All CMR contrast agents are gado-linium based, and at the present time, contrast-enhanced CMR ofthe heart represents an off-label use for all US Food and DrugAdministration–approved agents. Their main limitation is a potentialto cause nephrogenic systemic fibrosis, an exceedingly rare butserious condition.227 The risk for nephrogenic systemic fibrosis in-creases in patients with renal insufficiency, and contrast CMR useshould be limited to patients without significant kidney dysfunction.Gadolinium accumulates in the normal myocardium a few secondsafter contrast injection. LGE can be observed 10 to 20 min aftercontrast injection and represents myocardial fibrosis. Lack of LGE isthe most common finding in patients who develop anthracycline-induced CTRCD (Figure 11).121,214 LGE has been the mostfrequently used technique to exclude other causes ofcardiomyopathy, such as myocardial infarction, cardiac sarcoidosis,or amyloid heart disease. The recent findings from a single center ofthe presence of lateral wall LGE in patients who received HER2therapies156 have not been reproduced. CMR may also have addedvalue in the evaluation of cardiac metastasis or invasion tumor tothe heart.

More recently, gadolinium-based contrast has also been used in T1mapping, a novel, quantitative CMR technique that identifies subtlemyocardial abnormalities such as diffuse fibrosis, not visible on LGEimaging.228,229 One recent study in a small cohort of 13 patientsafter anthracycline therapy and with normal LV functiondemonstrated no correlation between anthracycline dose andmyocardial fibrosis, though there was a relationship with increasedLV volume.230 Using this technique, Neilan et al.231 recently reportedincreased extracellular volume as a surrogate of myocardial fibrosis in42 patients treated with anthracyclines, compared with age- andgender-matched controls. A positive association was found betweenthe extracellular volume and the left atrial volume, and a negativeassociation was found between the extracellular volume and LVdiastolic function. Although this technique suggests promise for futurediagnosis and possibly prediction of risk for cardiomyopathies, itscurrent use is limited to research studies.

C. Specific Challenges

Patients with breast cancer (the majority of patients to whom thisdocument applies) present specific challenges in their cardiac imaging.The feasibility of 2DE, 3DE, and strain imaging may be limited by theinability to obtain images of diagnostic quality because of mastec-tomy, radiation, or the presence of breast implants. It is importantto adequately document these limitations in the report and to refrainfrom reporting findings if uncomfortable with the technical quality ofthe study. In these specific situations, the use of echocardiographiccontrast (please see Section II.G) may be useful for an accurate calcu-lation of ejection fraction. If with the administration of contrast thecalculation of LVEF is still not feasible using the biplane method ofdisks, CMR is recommended. It is important to inquire about the pres-ence of ferromagnetic components, if the patient has breast tissueexpanders.

Key Points

! The calculation of LVEF by MUGA is highly reproducible. The main limita-tions are radiation exposure and the lack of ability to report on pericardialand valvular heart disease and RV function.

Figure 11 CMR image using LGE in four-chamber projection ina patient with a history of anthracycline-induced cardiomyopa-thy. The left ventricle is dilated with wall thinning. There is no ev-idence of LGE.

Figure 12 Cancer therapeutics regimens associated with type Iand type II CTRCD.

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CLASSIFICAZIONE della CTX

Meccanismi di danno

Antracicline

à sui miociti attraverso processi di apoptosi mitocondriale, produzione di radicali liberi e successivo danno alle strutture cellulari (proteine, lipidi, DNA)

à apoptosi cellulare

Radioterapia

à su endotelio, di tipo infiammatorio fino alla sostituzione fibrosa

Inci

denz

a C

HF

0%

8%

15%

23%

30%

Dosi antracicline

< 200 mg/m2 200-600 mg/m2 > 600 mg/m2

Correlazione dose ‒ effetto

>30Gy

250 mg/m2

RAPPORTO DOSE / RISCHIO

Lancet Oncology Vol 16 March 2015

Radioterapia

✓ Danno acuto à pericardite acuta

✓ Danni a distanza à ✓ Danni valvolari ✓ Coronaropatia ✓ Cardiomiopatia ✓ Disturbi del sistema elettrico ✓ Patologia del pericardio

Mulrooney at al, Cancer; 2014CAD prevalence: 39% (normal population: 8.5-11%)

TARGET THERAPHY

• Obiettivo: inibire la crescita tumorale attraverso il blocco delle molecole attivate in modo aberrante nelle cells tumorali

• Farmaci “biologici” o “intelligenti” o “a bersaglio molecolare”: agiscono selettivamente su recettori cell specifici, risparmiando le cells normali

• Miglioramento del profilo di tollerabilità

• Azione sinergica con Chemioterapia e Radioterapia

Classificazione

• ANTICORPI MONOCLONALI (-ab):

-contro geni mutati specifici: Trastuzumab, Rituximab

-contro fattori di crescita: Cetuximab (EGF), Bevacizumab (VEGF)

• INIBITORI DI ENZIMI (TIROSIN KINASI) (-ib): Imatinib, Nilotinib, Dasatinib, Ponatinib, Erlotinib, Ibrutinib

• INIBITORI DI FATTORI DI CRESCITA (VEGF): Sunitinib, Sorafenib

• INIBITORI DEL PROTEOSOMA: Bortezomib, Carfilzomib

EGF: Epidermal Growth FactorVEGF: Vessel Endothelial Growth Factor

CTX TRASTUZUMABREVERSIBILE

NONDOSEDIPENDENTE

INIBITORI TIROSIN KINASI (TKI) E ANTIANGIOGENETICI

Bevacizumab(Avastin®)Cetuximab(Erbitux®)Sorafenib(Nexavar®)Sunitinib(Sutent®)Thalidomide(Thalomid®)

Sorafenib(Nexavar®)Imatinib(Gleevec®)Gefitinib(Iressa®)

Lapatinib(Tykerb®)Dasatinib(Sprycel®)Nilotinib(Tasigna®)

Temsirolimus(Toricel®)Erlotinib(Tarceva®)

VascularEndothelialGrowthFactor

• ABL:protectionfromoxidativestress• KIT:remodellingaftermiocardialinfarction• FAK1:physiologiccardiachypertrophy• RAF1:protectionfromoxidativestressandarterial

hypertension• JAK/STAT:anti-apoptoticeffect,regulationofmiocardial

capillaritydensity• RSK:anti-apoptoticeffect• mTOR:upregulationofHIF(hypoxiainduciblefactors),

includingVEGFR

Heart - Tyrosine-Kinase Proteins

EFFETTI dei FARMACI ANTITUMORALI• ANTRACICLINE (Doxo, Epi, Ida) à CHF

• ANTIMETABOLITI (5 fluorouracile, capecitabina) à spasmo coronarico (S.C.A. = angina, infarto)

• AGENTI ALCHILANTI (ciclofosfamide, cisplatino) à CAD

• TAXANI (Taxolo, Paclitaxel, Docetaxel-Taxotere) à aritmie (spt bradicardia, BAV I-III), CHF

• AC MONOCLONALI* (trastuzumab, rituximab) à CHF

• INIBITORI TIROSINCHINASI* (lapatinib, sunitinib, sorafenib): HP, CHF, aterosclerosi (arteriopatia periferica, CAD)

• INTERFERONE , INTELEUKINAà aritmie, CHF

• ANTIESTROGENI (tamoxifene, in. aromatasi) àCHF

• ALCALOIDI VINCA (vinblastina, vinorelbina) àCHF

Qualepazientedobbiamocurare?

Differenza di popolazione tra

linfoma giovanile, K mammella e

CML

ChetipodiPtdobbiamocurare?

- Differenza di età tra K mammella e CML- L’incidenza aumenta con l’età con mediana a

45-55 anni - fino al 30% dei Pts hanno >60 aa - conta l’aspettativa di vita - Vièmaggioreprobabilitàdi:

– Ipertensione – Patologie cardiovascolari – Patologie metaboliche – Patologie respiratorie

Coronary arterydisease

44,6%

Cerebral arterydisease

16,6%

8.4%

1.6%

1.2%4,7%

PAD

4,7%

COEXISTENCE OF CARDIOVASCULAR DISEASES

Data from REACH study, Batth et al. JAMA 2006

MANAGEMENT

Qual è il primo step per prevenire la

cardiotossicità tardiva?

La definizione del profilo cardiovascolare, del rischio

individuale e la messa in atto di un monitoraggio clinico

continuo sono essenziali nella gestione dei pazienti con

pregresso trattamento antitumorale

CLINICAL WORK UP

Anamnesi personale e famigliare Individuazione e correzione dei FRC Visita / esame obbiettivo Profilo biochimico completo (funzionalità renale ed epatica, assetto lipidico, HbA1C) ECG (+ ECG Holter e stress test se CAD nota) ECHO EcoDoppler arterioso (se FRC) e venoso - ABI BNP / Troponina (?)

The first step to identify patients

at increased risk for

cardiotoxicity consists of a

careful baseline assessment of cardiovascular risk factors It is critical to detect subclinical cardiac abnormalities, which may

influence clinical decisions

regarding the choice of

chemotherapy, indication for

cardioprotection or increased

surveillance frequency (e.g.

asymptomatic LV dysfunction

2.1.2 DIAGNOSTIC AND THERAPEUTIC MANAGEMENT

PROCESSO ATEROGENETICO

DISLIPIDEMIA OBESITÀ

FUMO

STRESS

DIABETE

SEDENTARIETÀ IPERTENSIONE

Il rischio globale

I fattori di rischio interagiscono comportando

un AUMENTO ESPONENZIALE del rischio cardiovascolare

Per ridurre il RISCHIO CARDIOVASCOLARE GLOBALE è necessario identificare e trattare

i principali fattori di rischio COESISTENTI nello stesso paziente

Paesi a Basso Rischio

Stratificazione Pts in 4 gruppi di rischio: - basso - moderato - alto - molto alto

Il numero riportato nelle celle rappresenta il rischio di eventi CV fatali a 10 anni espresso in valore assoluto %

Educazione del paziente

• Diario dei valori pressori e FC • Controllo del peso corporeo • Dieta con adeguato apporto nutrizionale, ma

iposodica (dieta mediterranea)

• Astensione dal fumo • Esercizio fisico aerobico regolare • Riconoscimento dei sintomi di disfunzione cardiaca,

ischemia e aritmie

TARGET

• HbA1c < 7.0% (< 6.5% se lunga durata)

• PAO < 140/90 mmHg (meglio <130/80)

• CHOL:- LDL < 115 mg/dl (Chol Tot < 190 mg/dl)-Alto rischio: LDL < 100 mg/dl-Rischio molto alto: LDL < 70 mg/dl- Basse HDL ed ipertrigl sono F.R. indipendenti

Problema: il target

• M a n c at o ra gg i u n g i m e n t o d e l t a rge t terapeutico in un’elevata quota di pazienti a rischio cardiovascolare elevato/moderato

• Scarsa consapevolezza della correlazione tra riduzione del rischio cardiovascolare e obiettivi terapeutici suggeriti dalle Linee Guida

• Mancato monitoraggio dell’efficacia del trattamento ipocolesterolemizzante

• Inadeguatezza dei farmaci (“dose tritation”)

Quali esami devono essere effettuati periodicamente?

Diagnostica delle CTXLa cardiotox può interessare tutte le strutture cardiache

(miocardio, pericardio, coronarie, tessuto di conduzione, valvole)

• ECG basale • ECG HOLTER - LOOP RECORDER • TEST ERGOMETRICO • SCINTIGRAFIA MIOCARDICA SFORZO • CORO-TC e/o CORONAROGRAFIA • RMN • ECOCARDIOGRAFIA • MARKERS BIOCHIMICI (TnI – BNP): in fase acuta

Con che cadenza devono essere

effettuati i controlli?

TEMPISTICA del FOLLOW UP

TEMPISTICA del FOLLOW UP

Children’s Oncology Group, 2014

TEMPISTICA del FOLLOW UP

ANTRACICLINE

Tempistica di sorveglianza

•Assenza di vere guidelines

•Basata su opinioni di consenso

• Primi controlli: 1° e 2° anno da fine terapia

•Quindi, ogni 5 anni, tenendo conto del rischio del Paziente (età, tipo e dosi di terapia: se > 300 g/m2 o RT > 30 Gy ogni 2 anni)

•Utile, inoltre, test di ischemia ogni 10 anni

Quali indicazioni si possono ricavare

dall’Ecocardiografia?

RUOLO dell’ECOCARDIOGRAFIA

• Al giorno d’oggi è quasi inimmaginabile fare una diagnosi di una cardiopatia senza ricorrere all'echo

• Capacità di misurare parametri strutturali e funzionali del cuore

• L’Echo è l’esame cardine nella valutazione dei Pts pre, durante e dopo terapie antitumorali

• Ampia disponibi l i tà , versat i l i tà , faci le ripetibilità, trasportabilità, sicurezza (assenza di radiazioni, IRC)

VALVULOPATIE

VERSAMENTO PERICARDICO

PRESSIONI POLMONARI

La cardiotossicità è caratterizzata da almeno uno tra: -sintomi di scompenso cardiaco

-segni clinici di scompenso cardiaco (es. T3 o tachicardia)

-Riduzione di EF di almeno 5% sotto i 55% con sintomi o segni di scompenso

-Riduzione di EF del 10% sotto i 55% senza segni o sintomi associati

2D SIMPSON BIPLANO

3D

Confronto tra 2D-biplano, 2D-biplano/contrasto, Triplano, Triplano/contrasto, 3D, 3D/contrasto

Accurate calculation of LVEF should be done with the best method available in the echo laboratory (ideally 3DE)

Quali sono i limiti nella valutazione dell’EF?

EF e PITFALLS• Ogni Pt è caratterizzato da condizioni funzionali ed

emodinamiche diverse

• L’EF non riflette accuratamente lo stato contrattile del miocardio, essendo influenzata dalle condizioni di carico ( annotare FC e PAO durante gli esami)

• L’EF non sempre riflette la portata cardiaca, che può:

– essere conservata in Pts con bassa EF, ma VS di volumetria aumentata

– essere ridotta in Pts con EF normale, ma piccola volumetria ventricolare / ipertrofia o insufficienza mitralica severa o compromissione della funzione diastolica

•↓ EF = perdita di cardiomiociti (danno irreversibile)

• EF normale anche con alterazioni cinesi segmentaria

EF = indice tardivo, poco sensibile e poco specifico, con bassa accuratezza diagnostica e scarso potere predittivo

VALUTAZIONE dell’EF: LIMITI

OBIETTIVO DEL CARDIONCOLOGO:identificazione precoce dei Pts a rischio di sviluppare una disfunzione VS ➙ personalizzazione del programma terapeutico cht e cardioprotezione

(= identificazione del danno in fase pre-clinica)

Esistono altre tecnologie per evidenziare una CTX,

prima della riduzione dell’EF?

MAPSE

V.N. > 12 mm

MAPSE = “Mitral Annular Plane Systolic Excursion"

DOPPLER TISSUTALE

S2 ≧ 8 cm/s

s

S1: evidente in ipertensione, ipertrofia, anziani, CMP

ipocinetica, CAD

FUNZIONE DIASTOLICA

Quinones ASE Review 2007

PW: E/A

TDI: E/E’

PW: E/A

PW: vv polmonari

PW: E/A

Color m-mode: VP

Index of Myocardial Performance (IMP)

Valutazione sisto-diastolica: durata del periodo di contrazione isovolumetrica (IVCT) e di rilasciamento isovolumetrico (IVRT) su eiezione ao (ET) = TEI Index

V.N. < 0.4 (PW)

< 0.55 (TDI)

Nelle ultime Linee Guida si dà molta rilevanza allo

STRAIN: di cosa si tratta?

Il cuore: i fasci muscolari

Le FIBRE MIOCARDICHE

‣Subendocardio: longitudinali

‣Midwall: circonferenziali

‣Subepicardio: longitudinali (radiali)

L’EF valuta solo l’accorciamento radiale,

ma l’accorciamento longitudinale contribuisce al 60% della contrazione !

SPECKLE TRACKING

• The random distribution of the speckles ensures that each region of the myocardium has an unique pattern, a fingerprint.

•The speckles follow the motion of the myocardium so when the myocardium moves from one frame to the next, the position of this fingerprint will shift slightly, remaining fairly constant.

•Thus, if a region (kernel) is defined in one frame, a search algorithm will be able to recognise the lie sized and shaped area with the most similar speckle pattern in the next frame, within a defined search area and hence, to find the new position of the kernel

KERNEL

Lo speckle è una nuova metodica in grado di valutare lo

strain tramite un’acquisizione

standard 2D

2D STRAIN: AFI

2D STRAIN: AFI - BULL’S EYE

GLPSGlobalLongitudinalPeakSystolic

V.N. < -18%

Miglior predittore CTX =Global Longitudinal Strain S.T.: ⬇10-15%

STRAIN

Quali strategie terapeutiche si possono adottare per

prevenire la cardiotossicità?

CARDIOTOSSICITÀ: CONSEGUENZE

• Condizionamento dell’oncologo nella scelta della terapia

• Riduzione della dose per evitare danni permanenti (riduzione dose = limitazione efficacia)

• Limitazione della potenziale efficacia della cura

TERAPIE ONCO EFFICACI, MA MENO DANNOSE

DIAGNOSI PRECOCE di CARDIOTOX

CARDIOPROTEZIONE

OBBIETTIVO

NON DISMETTERE LA TERAPIA

ONCO- EMATOLOGICA

™

Infusione continua per evitare picchi di concentrazione (danno acuto)

Analoghi della antracicline à epirubicina, idarubicina, mitoxantrone, antracicline liposomiali

Farmaci cardioprotettivi à coenzima Q10, Vit E, carnitina, Cardioxane

PREVENZIONE DEL DANNO DA ANTRACICLINE

Limitare la dose (cut off 240 mg/m2, max 550)

Prevenzione del danno da RT

Riduzione della dose di radiazione

Da 35-45 Gy à 15-25 Gy

Frazionare la dose di irradiazione

Max 2 Gy/die

Limitare il campo di irradiazione

Involved – field, involved – node

3D RT

Stereotassi

In caso di evidenza di cardiotossicità quali

farmaci si possono usare?

STADIO A

Alto rischio per scompenso ma senza malattia

cardiaca strutturale o

sintomi di scompenso

Es.pazienti con•ipertensione •diabete mellito

•USO DI FARMACI CARDIOTOSSICI

•storia familiare di cardiomiopatie

STADIO B

Pazienti con malattia cardiaca

strutturale ma senza sintomi di scompenso

Es.pazienti con• pregresso IMA• disfunzione

sistolica ventricolo sinistro

• valvulopatie asintomatiche

STADIO C

Pazienti con malattia cardiaca

strutturale e sintomi presenti

o passati di scompenso

Es.pazienti con• malattia cardiaca

strutturale nota• dispnea,

fatigabilità, ridotta tolleranza allo sforzo

STADIO D

Scompenso refrattario che

necessiti di interventi

specializzati

Es.pazienti con sintomi

severi nonostante terapia massimale (pazienti con frequenti ospedalizzazioni che richiedono supporto terapeutico speciale)

Sviluppo di patologia cardiaca

strutturale

Comparsa di sintomi

scompenso cardiaco

Sintomi di scompenso cardiaco

refrattari, a riposo

CLASSIFICAZIONEAHA/ACC

Quale beta-bloccante?

CARVEDILOLO e BISOPROLOLO:• Riducono la formazione di ROS nei miocardiociti isolati esposti alla

doxorubicinaSpallarossaP,Mol.Cell.Cardiol.37(2004)837–846.

• Previenelaperossidazionelipidicaedaumentaleconcentrazionidivit.E

NEBIVOLOLO:• Induce l’espressione di NO-sintasi endoteliale, con effetto

vasodilalatore• Previenelaformazionediradicaliliberi MoenMB,Drugs66(2006)1389–1409;R.P.Mason,Circulation112(2005)3795–3801.

Statine

Uno studio osservazionale di coorte che ha arruolato pazienti con tumore mammario trattato con antracicline ha mostrato che le statine possono ridurre il rischio di scompenso cardiaco

S. Seicean, J. Am. Coll. Cardiol. 60 (2012) 2384–2390.

La simvastatina in studi sull’animale è in grado di proteggere i cardiomiociti attraverso l’attivazione della NO-sintasi ed i canali ATP-sensibili del potassio (riduzione del danno del DNA e della fibrosi)

S.P. Jones, Circ. Res. 93 (2003) 697–699.

Esercizio aerobico

Hadimostratodiridurrelamortalitàpertuttelecauseinpazientitrattaticonantracicline.

Ipotesi:riduzioneformazioneROS.

JonesLW,LancetOncol2009;10:598-605.

ScottJM,Circulation2011;124:642-650

Esistono altri farmaci?

Nuove strategie di cardioprotezione

•IVABRADINA •RANOLAZINA •Al momento “off label”

Ivabradina: indicazioni

ANGINA PECTORIS cronica stabile negli adulti con coronaropatia e normale ritmo sinusale e frequenza cardiaca ≥ 70 bpm. • negli adulti che non sono in grado di tollerare o che hanno una

controindicazione all’uso dei beta- bloccanti• o in associazione ai beta-bloccanti nei pazienti non adeguatamente

controllati con una dose ottimale di beta-bloccante

INSUFFICIENZA CARDIACA CRONICA in classe NYHA da II a IV con disfunzione sistolica, in pazienti con ritmo sinusale e la cui frequenza cardiaca sia ≥ 75 bpm, in associazione con la terapia convenzionale che include il trattamento con un beta-bloccante o nel caso in cui la terapia con un beta-bloccante sia controindicata o non tollerata.

TACHICARDIA SINUSALE INAPPROPRIATA SINTOMATICA

Na+

K+

Ca++

K+

Na/K+-ATPasi

I l n o r m a l e c i c l o d i contrazione/ri lasciamento d i p e n d e i n g r a n p a r t e dall’attività dei canali Na+ s i t u a t o a l l ’ i n t e r n o d e i cardiomiociti, attivati nel momento in cui la membrana cell si depolarizza

La corrente del Na+ è responsabi le del la fase ascendente del potenziale d’azione e contribuisce alla fase di plateau, consentendo la normale attività elettrica c a r d i a c a . D o p o p i c c o , corrente breve tardiva (chiusura ritardata)

RANOLAZINA

Ranolazine: mechanism of action

Ischaemia

Late INa

Na+ overload

Ca++ overload

Ranolazine

NCX

Hasenfuss G, Maier LS. Clin Res Cardiol 2008;97:222-26.

Maier LS. Cardiol Clin 2008;26:603-14.

Mechanical dysfunction Diastolic tension Contractility

Electrical dysfunction Arrhythmias

O2 supply & demand ATP consumption ATP formation

NCX: sodium-calcium exchanger

Possibile uso “off label”:Ranolazina come

cardioprotezione nella cardiotossicità di terapie

antitumorali

CORONARY ARTERY DISEASE

ponatinib

… typically manifests 10 – 15 years after the initial treatment, and younger patients are more susceptible

• Assessment of CAD should be based on the history, age and gender of the patient, considering the use of chemotherapy drugs as a risk factor for CAD.

• Clinical evaluation and, when necessary, testing for detection of myocardial ischemia is key to identify pts with latent pre-existing CAD. This may have implications in the selection of cancer treatment.

• Patients treated with pyrimidine analogues should be closely monitored for myocardial ischaemia using regular ECGs, and chemotherapy should be withheld if myocardial ischaemia occurs.

• Drug rechallenge after coronary vasospasm should be reserved for when no other alternatives exist, and only under prophylaxis and close monitoring of the patient. Pretreatment with nitrates and/or calcium channel blockers may be considered in this setting.

• Long-term clinical follow-up and, when required, testing for the presence of CAD may be useful to identify patients with cardiac disease who develop long-term complications of chemotherapy and radiotherapy.

ARRHYTHMIAS

Arrhythmias can be present at baseline in 16–36% of treated patients with cancer.

QTc normale: < 450 ms ♂, < 460 ms ♀

Gradi di tossicità (National Cancer Institute):

I : QTc > 450-470 msec

II : QTc 470-500 msec o > 60 ms rispetto al basale

III : QTc > 500 msec

IV : QTc > di 500 con segni e sintomi (TV, torsioni di punta, ipotensione, scompenso)

A 12-lead ECG should be recorded and the QT interval, corrected for heart rate with Bazett’s or Fridericia’s formula, should be obtained in all patients at baseline.

Patients with a history of QT prolongation, relevant cardiac disease, treated with QT-prolonging drugs, bradycardia, thyroid dysfunction or electrolyte abnormalities should be monitored by repeated 12-lead ECG.

Consider treatment discontinuation or alternative regimens if the QTc is >500 ms, QTc prolongation is >60 ms or dysrhythmias are encountered.

Conditions known to provoke torsades de pointes, especially hypokalaemia and extreme bradycardia, should be avoided in patients with drug-induced QT prolongation.

Exposure to other QT-prolonging drugs should be minimized in patients treated with potentially QT-prolonging chemotherapy.

The initial approach to the management of atrial fibrillation and atrial flutter requires the usual decisions regarding rhythm management, thromboembolic prophylaxis and effective stroke prevention with oral anticoagulation

The balance between thromboembolic and bleeding risks of atrial fibrillationis particularly challenging in patients with cancer. While cancer may cause a prothrombotic state, it may also predispose to bleeding. On the other hand, the CHA2DS2-VASc and HAS-BLED risk scores have not been validated in patients with cancer

In patients with a CHA2DS2-VASc score ≥ 2, anticoagulation can generally be considered if the platelet count is >50 000/mm3

CHOICE OF ANTICOAGULANT

RoleofNOACinCancerPatients

Overallsimilarefficay,bettersafetyforNOAC.However:• AllmajorNOACtrialsincludedfewcancerpatients(1.1%to6%)• Many chemotherapy drugs induce or inhibits CYP3A4 (rivaroxaban,

apixaban)andp-gp(dabigatran,edoxaban)• Cancerpatientspredispositiontobleeding(thrombocytopenia,mucositis/

enteritis,anti-angiogenictherapy)• Renaldysfunction(sptdabigatran)• Difficulty in swallowing, nausea, vomiting, diarrheamay limit intake and

absorption• GIbleedingsmaybeincreased(dabigatran)• Availabilityofantidotes(rivaroxaban,apixaban,edoxaban)

Carrier M et al., Journal of Thrombosis and Haemostasis, 2013 11: 1760–1765

HYPERTENSION

Hypertension should be adequately treated according to the current standing clinical practice guidelines, and blood pressure should be monitored before initiating cancer treatment and periodically during treatment, depending on the patient’s characteristics and adequate blood pressure control (<140/90 mmHg or lower in case of proteinuria).

Hypertension in Pts with cancer is manageable with conventional antihypertensive treatment, but early and aggressive treatment is encouraged to prevent the development of cardiovascular complications.

ACEi or ARBs, beta-blockers and dihydropyridine calcium channel blockers are the preferred antihypertensive drugs.

Non-dihydropyridine (Verapamil, Diltiazem) calcium channel blockers should preferably be avoided due to drug interactions (CYP3A4)

Dose reduction and reinforcement of antihypertensive treatment or discontinuation of VEGF inhibitors can be considered if blood pressure is not controlled. Once blood pressure control is achieved, VEGF inhibitors can be restarted to achieve maximum cancer efficacy.

FARMACI ANTIIPERTENSIVI

LINEE GUIDA ESC-ESHNORMALE NORMALE

ALTA Grado I Grado II Grado III

120-129

80-84

130-139

85-89

140-159

90-99

160-179

100-109

> 180

> 110

NO FRC

Nessun trattam.

Nessun trattam.

Stile vita … +

farmaci

Stile vita … +

farmaci

Stile vita + farmaci

1-2 FRC

Stile vita Stile vitaStile vita

… + farmaci

Stile vita … +

farmaci

Stile vita + farmaci

3 o > FRC

Stile vita Stile vitaStile vita + farmaci

Stile vita + farmaci

Stile vita + farmaci

CCA Stile vita + farmaci

Stile vita + farmaci

Stile vita + farmaci

Stile vita + farmaci

Stile vita + farmaci

IpertensioneeTKIs

E. Abruzzese, M. Breccia, R. Latagliata, BioDrugs 2013

IpertensioneeTKIs

E. Abruzzese, M. Breccia, R. Latagliata, BioDrugs 2013

THROMBOEMBOLIC DISEASE

Tumour cells can trigger coagulation through different pathways, including procoagulant, antifibrinolytic and pro-aggregating activities, release of pro-inflammatory and pro-angiogenic cytokines and interaction with vascular and blood cells through adhesion molecules

Venous thrombosis and VTE occur frequently in patients with cancer, may affect up to 20% of hospitalized patients

Antithrombotic prophylaxis should be given for a minimum of 4 weeks after surgery

The detection of thrombotic events in patients undergoing chemotherapy is based mainly on clinical symptoms. No systematic screening strategy has shown any benefit

The decision to administer anticoagulation for VTE prevention in patients with cancer should always take into consideration the patient’s bleeding risk and life expectancy

Treatment of a confirmed episode of acute VTE in haemodynamically stable patients consists of LMWH given over a period of 3–6 months. This strategy is superior to VKA therapy in patients with cancer in terms of reduced VTE events, with no difference regarding mortality or bleeding in clinical trials.

PERIPHERAL VASCULAR DISEASE and STROKE

Can occur (in up to 30%) in patients treated with nilotinib, ponatinib or BCR-ABL TKIs used for chronic myeloid leukaemia, even in the absence of CVD risk factors

PAD can occur as early as in the first months of therapy or as a late effect several years after treatment. Other cancer therapy–related peripheral arterial toxicity includes Raynaud’s phenomenon and ischaemic stroke (i.e. with L-asparaginase, cisplatin, methotrexate, 5-FU and paclitaxel)

The risk of stroke is increased—at least doubled—after mediastinal, cervical or cranial radiotherapy.

The assessment of PAD risk at baseline (risk factor assessment, clinical examination, ankle–brachial index measurement) is recommended.

Antiplatelet drugs should be considered mostly in symptomatic PAD.

EdinburghClaudicationQuestionnaire

Leng G et al., J Clin Epidemiol 1992; 45: 1101-1109.

Ankle-BrachialIndex

PrimaryProphylaxis• Given thatarterial thrombotic risk fromponatinib ishigh,and that

ponatinib per se introduces thrombotic risk, primary prophylaxiswith aspirin (75-100mg/day) or clopidogrel (75mg/day)might beconsideredevenforlowriskpatients.

• There isnolevelofevidence tosupportsuchtherapeuticdecision,which therefore restswith haematologists and cardiologists jointlyassessing patients risk scores and the added risk introduced byponatinib.

• In cases when antiplatelet drugs were prescribed, platelet countshould be checked periodically and prophylaxis should bediscontinuedwhenplateletcountsdecreasestobelow50.000/µL,asafetycut-offreportedinthesummaryofproductcharacteristics.

Breccia M et al, Ann Hematol 2016, DOI 10.1007/s00277-016-2820-x

PULMONARY HYPERTENSION

Pulmonary hypertension is a rare but serious complication of some cancer agents and stem cell bone marrow transplantation (TKIs family: imatinib, dasatinib)

Dasatinib, used as second-line treatment for chronic myelogenous leukaemia, can induce severe precapillary pulmonary hypertension.

This condition appears 8–40 months after exposure to dasatinib, with clinical and haemodynamic presentation suggestive of PAH. Unlike other forms of PAH, this is often reversible after drug discontinuation or replacement with another TKI, such as nilotinib.

Recently, cyclophosphamide and other alkylating agents were suggested as contributing to the development of pulmonary veno-occlusive disease

STRATEGIES FOR PREVENTION AND ATTENUATION OF

CARDIOVASCULAR COMPLICATIONS OF CANCER

THERAPY

Quali difficoltà si possono incontrare nel

follow-up?

PROBLEMATICHE del F.U.

•Controlli troppo assidui in Pts “guariti” (ansia)•Rischio di “drop out” dei Pts (giovani)•Sottovalutazione del problema CTX•Sovraccarico degli Ambulatori ed Echo-Lab•Importanza della precisione delle valutazioni•Dove fare i controlli?•Chi è il “gate-keeper”? (Oncologo, MdF, Cardiologo?)

Non tutti i centri cardiologici dispongono

di questa expertise: come ci si deve

comportare?

SPOKE

HUBOncologia Ematologia

Cardiologia osp/amb

- Molinette- Mauriziano- GiovanniBosco- Candiolo- Orbassano

VALUTAZIONE BASALE anamnesi, EO, TnT, ECG, ECHO

RIVALUTAZIONE PERIODICA

Troponina prima di ogni ciclo CHT

ECHO dopo 3 - 6- 12 mesi,

2 anni, quindi a 5 anni

Alterazioni Troponina

CENTRO RIFERIMENTO Molinette, Mauriziano, Candiolo,

S.Giovanni Bosco

ECHO AVANZATO

ALTERATO

NORMALE

RIVALUTAZIONE + CARDIOPROTEZIONE

RMN ? F.U. programmato

SE VARIAZIONI

AOU/AO 2017

ASL 2017

TERRITORIO 2017

Quali messaggi conclusivi?

FOLLOW UP: CAVEAT

1) Per TUTTI (cardiologi, oncoematologi, internisti, mdf): attenzione alle variazioni dello stato clinico–correzione stile di vita–anamnesi: comparsa di sintomi–esame obiettivo–ECG: aritmie, BBS

2) ECOCARDIOGRAFISTI: “minimum data set”, in particolare alterazioni diastole, EF, strain

Cardiologo ospedaliero e territoriale, Oncologo, Ematologo, Radioterapista, Internista, Angiologo, Pneumologo, Diabetologo

—>MMG

PATTO di COLLABORAZIONE MEDICO-PAZIENTE

L’informazione dettagliata al Pt e la ricerca della suacollaborazione, oltre che doverose, sono funzionali almigliorrapportorischio/beneficiodiunaterapiasalvavita.

IlCardiologodevesaperspiegarel’importanzadellacorrezionedei FRC, dell’aderenza alla terapia e deiperiodici controlli acuiilpazienteoncologicodevesottoporsi.

IlPazientedeve,peraltro,essereresponsabile.