mesotelioma: approccio chirurgico alla diagnosi … · journal of thoracic oncoloy, 2012...

MESOTELIOMA: APPROCCIO CHIRURGICO ALLA

DIAGNOSI E ALLA TERAPIA

L. SantambrogioCentro Trapianti di Polmone – Fondazione IRCCS Ca’ Granda,

Ospedale Maggiore Policlinico di MilanoUniversità degli Studi di Milano

1° Congresso Nazionale IART

Cremona, 7-8 Maggio 2015

APPROCCIO DIAGNOSTICO

Versamento pleurico recidivante e/o ispessimenti pleurici:

• TC torace con mdc

• Toracentesi per esame citologico

• Biopsia pleurica– Con ago tranciante, TC-guidata

– Toracoscopia/Mappatura

– In mini-toracotomia

Istotipizzazione

(Butchart ‘79 – Brigham ‘93 – Sugarbaker ‘99)

STADIAZIONE

• PET

• RMN

• Mediastinoscopia

• EBUS

• Toracoscopia/Mappaggio pleurico

• Laparoscopia

In ogni caso, per le caratteristiche della malattia, la stadiazione clinica del MPM basata

sull’imaging è inaccurata.

La stadiazione definitiva può esserci solo dopo exeresi chirurgica

Esplorazione e biopsia

TORACOSCOPIA

Gli accessi toracoscopici dovrebbero essere effettuati nella sede della

potenziale successiva toracotomia

OTTICA COASSIALE

Mappaggio

TORACOSCOPIA

TNM

STADIAZIONE

T1: tumore limitato alla pleura parietale ipsilaterale, con o senza interessamento della pleura mediastinica e diaframmatica

– T1a: senza interessamento della pleura viscerale

– T1b: con interessamento della pleura viscerale

T2: tumore che coinvolge pleura parietale e viscerale e almeno uno tra:

– Muscolo diaframma

– Parenchima polmonare

T3: tumore localmente avanzato, ma potenzialmente resecabile, per interessamento di almeno uno tra:

– Fascia endotoracica

– Tessuto adiposo mediastinico

– Tessuti molli parete toracica (focus isolato)

– Pericardio (non trans-murale)

T4: tumore localmente avanzato, tecnicamente non resecabile, per interessamento di almeno uno tra:

– Parete toracica (plurifocale)

– Peritoneo per via trans-diaframmatica

– Pleura controlaterale

– Organi mediastinici

– Colonna vertebrale

– Pericardio (trans-murale)

N1: metastasi linfonodi broncopolmonari o ilari omolaterali

N2: metastasi linfonodi sottocarenali, e mediastinici, mammari interni, peridiaframmatici, omolaterali

N3: metastasi linfonodi mediastinici e mammari interni controlaterali, sovraclaveari

M1: metastasi a distanza

VALUTAZIONE CHIRURGICA

• Stadio clinico I-III

• Istologia epiteliale o mista

• Età, performance status

� Prove di funzionalità respiratoria

� Scintigrafia polmonare perfusoria

� Test da sforzo

Terapia

MESOTELIOMA PLEURICO

Il M.P. è un tumore:

– Chemioresistente

– Radioresistente

– La chirurgia da sola non offre buoni risultati

– Meglio le terapie multimodali

(N.Martini, 1996)

Terapia chirurgica


• Pleuropneumonectomia (Sugarbaker)

– Pneumonectomia extrapleurica con exeresi

pericardio e diaframma

– Linfoadenectomia mediastinica

• Pleurectomia / decorticazione

• Talcaggio pleurico (palliazione)

CHIRURGIA NEL MPM

Natura diffusa del MPM

� R0 impossibile

� ruolo fondamentale della terapia adiuvante e neoadiuvante

Chirurgia – Palliativa

– Citoriduttiva

– Radicale

Peculiarità

Talcaggio pleurico

CHIRURGIA PALLIATIVA

Comunque, primo tempo

indispensabile per EPP/P-D

Pleurectomia

CHIRURGIA PALLIATIVA

PNEUMONECTOMIA

EXTRA-PLEURICA

Legatura intrapericardica dei vasi

EPP

PNEUMONECTOMIA

EXTRA-PLEURICA

Patch pericardico

EPP

Patch su diaframma

EPP

PNEUMONECTOMIA

EXTRA-PLEURICA

Pleurectomia/Decorticazione

Toracoscopia: Mesotelioma pleurico maligno

epitelioide, con aspetti di crescita prevalentemente

papillari, infiltrante

CHT: Cisplatino 75 mg/mq + Pemetrexed 500 mg/mq

per 4 cicli



destra


sinistra

Terapia chirurgica


Pleurectomia/dec. Mortalità 1,5%

Morbidità 9%

Pleurectomia/dec.

+ impianto barre RT

Sopravv. media 12,6 mesi;

15 mesi se malattia non macroscopic.

visibile

Pleurectomia/dec.

+ CT intraop (Cispl.-Mit.)

+ CT sistemica

Nessun vantaggio

EPP

Solo terapia medica

Mortalità 6%; Sopravvivenza =

Sopravvivenza peggiore

Martini, 1998

Terapia chirurgica (Sugarbaker)


Anni ‘80-2000

1) EPP

2) CT postop. + RT (55Gy)

Sopravvivenza a 2 anni: M+ 0%

N0 71%

Epit. 50%

Sarcom. 7,5%

In view of the high morbidity associated with EPP in this trial and in other non randomised studies

a larger study is not feasible. These data, although limited, suggest that radical surgery in the

form of EPP within trimodal therapy offers no benefit and possibly harms patients.

Lung Cancer, 2012

Extrapleural pneumonectomy for early stage

malignant pleural mesothelioma: a harmful

procedure.

Rena O, et al.

• Prospettico, non randomizzato (1998-2009)

• 77 pz con early stage MPM– 40 EPP

– 37 P/D

+ CHT-RT postoperatoria per entrambi i gruppi

“I, the present study suggests that P/D in a multimodal protocol ischaracterised by a lower morbidity and mortality, warranting abetter QoL up to recurrent disease and a longer survival afterrecurrence when compared with EPP. (I) When a diagnosis ofearly stage disease is made, I it should be proposed a lung-sparing procedure like the P/D in a multimodal protocol since theEPP should be confirmed to be superior in the disease control bydemonstrated evidences”

Annals of Thoracic Surgery, 2012

Quality of life after radical pleurectomy

decortication for malignant pleural mesothelioma.

Mollberg NM, et al.

• Prospettico (2010-2011)

• 28 PD radicale +/- CHT-RT

In conclusion, PD does not negatively impact minimally symptomatic

patients from baseline at intermediate follow-up. Patients who have

significant symptoms at baseline can have significant improvement

in their QoL after surgical resection.

Journal of Thoracic Oncoloy, 2012

Prospective study on functional results after

lung-sparing radical pleurectomy in the

management of MPM.

Bölükbas S, et al.

• Prospettico (2010)

• 16 Radical pleurectomy + CHT-RT

Lung-sparing RP leads to significant improvement of pulmonary

function and perfusion after a recovery time of 2 months. Functional

results are better after preservation of the diaphragm. Preservation

of physiological reserve via lung-sparing RP might allow patients

with MPM to be eligible for further therapeutic options in the long

term.

A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was whether extrapleural

pneumonectomy (EPP) is superior to supportive care in the treatment of patients with malignant pleural mesothelioma (MPM). Overall, 110

papers were found using the reported search, of which 14 represented the best evidence to answer the clinical question. The authors, journal,

date and country of publication, patient group studied, study type, relevant outcomes and results are tabulated. We conclude that EPP

confers no advantage to chemotherapy and palliative treatment in terms of survival and symptom

improvement. Ten studies evaluated the role of EPP in the management of MPM. The median survival was 13 months and perioperative

and 30-day mortality rates were 5.7% and 9.1%, respectively. There was a high morbidity rate of 37% including atrial fibrillation, empyema and

supraventricular arrhythmias. Disease recurred in 73% of patients at a median time of 10 months. Median hospital stay was 13 days and

intensive care unit stay was 1.5 days. At three months postsurgery, improvement in symptoms was achieved in 68% of patients. Significant

advantages were observed in patients with epithelial MPM (19 vs. 8 months, P-0.01) compared to non-epithelial MPM and with N2 disease (19

vs. 10 months) compared to N1 or N0 disease, respectively. Two studies reported outcomes after chemotherapy in patients with MPM. The

median survival was 13 months and symptoms improved in 50% of patients. Response rate of 21% was achieved and the median time to

disease progression was 7.2 months. Postoperative haematological toxicity was common and included neutropenia (25%), anaemia (5%) and

thrombocytopenia (7.4%). Two studies analysed palliative treatment in mesothelioma and reported a median survival of seven months and

improvement in symptoms in 25% of patients at one-year post-treatment. The 30-day mortality rate was 7.8% and complications

included prolonged air leak (9.8%) and empyema (4%). Median hospital stay was seven days. Overall, EPP shows no benefit in terms of

survival or symptom improvement which is compounded by its high operative mortality and recurrence rate.

EPP is a highly morbid operation with high perioperative mortality and recurrence rate. Although a number of

retrospective studies have shown a small benefit in survival with EPP, there is consensual agreement that even

in subgroups with the best prognostic indicators (epithelial histology and N0/N1 disease), EPP still results in

high complication rates with minimal symptomatic improvement. Great weight should be given to the initial

findings of the MARS trial, which has clearly demonstrated the detrimental effects of conducting radical EPP

surgery compared to conservative management.

Guidelines, 2015

National Comprehensive Cancer Network

Importanza dei Trials Clinici


• The Pass trial (Pleural mesotheliomA

Strategies Study)

• Studio randomizzato prospettico

sull’efficacia del P/D (100 casi)

• Inizio Gennaio 2013

Importanza della ricerca di base


• Biobanca dei tessuti patologici

• Genomica

• Studio dei markers diagnostici/prognostici

Gary Lee YC, The Lancet 2014

Surgical resection of mesothelioma:

an evidence-free practice

• Extrapleural pneumonectomy (EPP) I has high postoperative mortality and morbidity. Extendedpleurectomy with decortication removes the samestructures but spares the lungI

• The MesoVATS trialI VAT-PP conferred no survival benefit over talc pleurodesis at 12 monthsI

• MARS (Mesothelioma And Radical Surgery) trialI median survival was 5 months shorter in the EPP group than in the no surgery groupI

• The more aggressive the procedure, the more complications it produces and the more detrimental it is to clinical outcomes.

Gary Lee YC, The Lancet 2014

Surgical resection of mesothelioma:

an evidence-free practice

• It often consists of multifocal tumours that can be histologically distinct (eg, epithelioid vs sarcomatoid) and has a predilection to spread along the pleural surfaces and invade deeper tissues, making complete surgical eradication practically impossible.

• I valuable evidence on the absence of benefit of surgical resection... Further forays into surgical resection of malignant pleural mesothelioma should be regarded as experimental, and should only be done within rigorous, high-quality clinical trials.


Il mesotelioma è una neoplasia maligna di cui

conosciamo molto della sua eziopatogenesi ma

abbiamo poche armi terapeutiche efficaci.

L’impressione è che qualunque terapia non cambi la

naturale evoluzione della malattia e che la

sopravvivenza dipenda dal momento della

diagnosi nell’ambito della naturale evoluzione della

malattia.

G. Chiappino

Conclusioni


• Sappiamo molto della eziopatogenesi del

mesotelioma e tra 20 anni si azzererà la

mortalità per scomparsa dell’amianto

nell’ambiente

• Per il tumore del polmone sappiamo molto

sulla eziologia da fumo. Perché non ci

applichiamo?

• Arriviamo sempre in ritardoI

Conclusioni


mesotelioma: approccio chirurgico alla diagnosi … · journal of thoracic oncoloy, 2012...

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