Place de la chirurgie pulmonaire dans les Cancers primitifs et Chirurgie de Métastasectomie Pulmonaire

Place de la chirurgie pulmonaire dans les Cancers primitifs et Chirurgie de Métastasectomie Pulmonaire A.J. PONCELET, Ph. NOIRHOMME. Department of Cardio-Thoracic Surgery, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium. ECU-UCL 24 Mars 2007

Chirurgie pour tumeurs primitives Plan Introduction Multimodalite Guidelines et Interdisciplinarite Staging Operabilite Resequabilite Evolution a court terme Evolution a long terme

INTRODUCTION Cancer Bronchique non à petites cellules NSCLC (75%) Cancer Bronchique à petites cellules SCLC (25%) Mesothéliome malin

TNM staging system and Surgery for NSCLC (Moutain 1997) T1 T2 T3 T4 N0 Ia Ib IIb IIIb N1 IIa IIb IIIa IIIb N2 IIIa IIIa IIIa IIIb N3 IIIb IIIb IIIb IIIb MULTIMODAL M+ IV IV IV IV

Multimodality Stades (Ib), IIa and IIb Chimiothérapie Adjuvante (à base de Cisplatine) Stade IIIa IALCT, N Engl J Med 2004, 350:351-60 JBR, NEJM 2005, 352;25 :2589-97 Chimiothérapie Néo-adjuvante (ou d induction) - à base de Cisplatine Re-stadification complète et sélection des répondeurs (partiel/complet) Maladie stable (single N2 station) J Clin Oncol 2005, 23:3257-3269

Members of the Guideline Development Committee Respiratory Oncology (2005-2006) Belgian Society Pneumology: Bosquee Leon Duplaquet Fabrice Galdermans Danny Germonpre Paul Lecomte Jacques Ninane Vincent van Meerbeeck Jan Vansteenkiste Johan Belgian Society of CardioThoracic Surgery: Bosschaerts Thierry Capello Matteo De Leyn Paul De Roover Dominique Poncelet Alain Proot Luc Van Schil Paul Vermassen Frank Belgian Society Radiation Oncology: Lievens Yolande Van Houtte Paul Chaltin Marie Bral Samuel Rosier JF Belgian Society Medical Oncology: Humblet Yves Vansteenkiste Johan Pathologist Weynand Brigit

«Guidelines» & Stadification des NSCLC Bronchoscopie (sensibilité de détection faible si tumeur periphérique < 2cm) Chest CT scan (IV contrast) Etage thoracique et abdominal supérieur Informations sur T, N et M FDG-PET Pour patients Stade I-III avec attitude curative, indispensable car améliore la sélection des patients Cytoponction echoguidée par voie endoscopique (transoesophagienne, transbronchique) Examen peu invasif, à recommander en première ligne afin de prouver l atteinte ganglionnaire médiastinale. (! learning curve) Mediastinoscopie (cervicale) Biopsies d au moins 4 des 6 stations ganglionnaires accessibles. (2 ipsilatérales, 1 contralaterale et station 7). Epanchement Pleural Evaluation cytologique indispensable (si (+), T4 irrésequable ) CT cérébral (IV contrast) ou IRM

«Guidelines» & Opérabilité = Evaluation Fonctionnelle Cardio-respiratoire essentiellement Criteria 1 ECOG score 0,1 ou 2 2 Absence de co-morbidité majeure rendant le risque de morbidité-mortalité opératoire prohibitif (cardiac cause) 3 Fonction pulmonaire autorisant la resection parenchymateuse proposée (Valeur de VEMS prédite post-op > 30% des valeurs prédites (ou > 0.8L) pred pofev1 = pre FEV1 (n segm. resséqués/ n total segm.)

Poumon Dt n segm Poumon G n segm. LSD 3 LMD 2 LID 5 LSG 4 LIG 5 1 segm = 1 / 19 or 0.0526 (VEMS préop)

«Guidelines» per-opératoire = Evaluation de la Réséquabilité Résection Complète = Seule attitude acceptable pour chirurgie de résection parenchymateuse 3 Critères doivent être respectés pour un label de Resection Complete : a) Marges de résection saines microscopiquement b) Curage ganglionnaire systématique Le curage devrait inclure au moins six ganglions dont 3 #10 et/ou #11 3 # N2 et au moins 1 ggl #7 c) Pas de rupture capsulaire dans les ganglions prélevés séparément.

Résultats à court terme : Morbidity-Mortality Direct Relationship to Preoperative PFT s Lobectomy # Pneumonectomy Surgical Volume & Outcomes

1/ Preoperative pulmonary function as a prognostic factor for NSCLC Cancer Unrelated Death N = 402 patients All Stage I NSCLC Iizasa T & al. Ann Thorac Surg 2004;77:1896-1902

Preoperative pulmonary function as a prognostic factor for NSCLC Cause of Death FEV1% < 70% (n = 100) FEV 1 % 70% (n = 302) Respiratory disease 13 4 Cardiac disease 4 3 Brain vascular disease 1 5 Second malignancy 10 7 Other 7 4 Total 35 23 b FEV 1 % = percent forced expiratory volume in 1 second. a Values are number of patients. b p value < 0.0001 with 2 test. Iizasa T & al. Ann Thorac Surg 2004;77:1896-1902

2/ Operative risk for Lobectomy Pneumonectomy Lung resection for non small-cell lung cancer in patients older than 70 y.o. Type of resection No. of Patients (n = 125) % Lobectomy 77 62 Bilobectomy 17 14 76 % Pneumonectomy 23 18 Wedge resection 8 6 Birim O. & al. Ann Thorac Surg 2003;76:1796-1801

n = (%) Minor complications 71 57 Supraventricular arrhythmia 38 30 Air leak > 5 d 26 21 Transfusion 19 15 Atelectasis 9 7 Infection 6 5 Paresis of recurrent nerve 3 2 Major complications 16 13 Empyema 6 5 Pneumonia 5 4 Myocardial infarction 2 2 Bronchopleural fistula 2 2 ARDS 2 2 Ventricular arrhythmia 1 1 Ventilatory support > 72 h 1 1 Pulmonary edema 1 1 Cardiac failure 1 1 Overall 30-d Mortality = 3.2% Renal failure 1 1 Birim O. & al. Ann Thorac Surg 2003;76:1796-1801

Mortality and Complications Following Pneumonectomy Variables Rate, % 30-d mortality rate HUG 10.3 CVP 6.3 Cardiovascular complications Major complic. = 27% Arrhythmias 24.9 Heart failure 0.5 Myocardial infarction 0.5 Stroke 1 Pulmonary emboli 2.6 Pulmonary complications Bronchopneumonia 7.8 Atelectasis 2.6 Minor complic. = 31% Bronchopleural fistula 4.7 Re-intubation 2.1 Prolonged chest drainage ( > 7 days) 2.6 Reperfusion edema 2.1 Renal dysfunction Elevation of plasma creatinine ( > 20%) 2.6 Licker M and al. Chest. 2002;121:1890-1897

Low Surgical Volume # High Surgical Volume Mortality Bach. PB. and al. N Engl J Med 2001 345:181-188

Morbidity Bach. PB. and al. N Engl J Med 2001 345:181-188

Similar trends for every major surgical procedures Birkmeyer JD,and al. N Engl J Med 2002; 346:1128-1137

Résultats à long terme : Survie et Récidive(s) 1/ Early Stage Ia 60-65% Ib 50% IIa 45% IIb 35% 1970-1992 van Rens, M. Th. M. et al. Chest 2000;117:374-379

National Cancer Institute of Canada Clinical Trials Group - JBR10 Ib 1997-2001 Ia 85% Ib 70% II IIa 55-60% IIb 45% IALT, NEJM 2004, 350;4 : 351-360 JBR, NEJM 2005, 352;25 :2589-97

2/ Very Early Stage (CT scan screening) 1993-2005 n= 484/31,567 pa Incidence : 1.5% Mean = 13mm Stage I = 85% pa The International Early Lung Cancer Action Program Investigators (IELCAPI). N Engl J Med 2006;355:1763-1771

3/ Advanced Stage 1989-1997 1997-2000 Rosell R, Lung Cancer. 1999 Oct;26(1):7-14 Betticher DC, J Clin Oncol. 2003 May 1;21(9):1752-9.

Small Cell Lung Cancer (SCLC) Most aggressive lung cancer Responsive to chemotherapy and radiation but recurrence rate is high even in early stage WHO revised classification Small cell carcinoma Oat Cell Intermediate Mixed small cell/large cell carcinoma Combined small cell carcinomas

SCLC: Staging and place for surgery Very Limited Stage Defined as solitary tumor, less than 3cm diameter, without mediastinal nodal or extranodal metastatic site. Limited Stage Defined as tumor involvement of one lung, the mediastinum and ipsilateral and/or contralateral supraclavicular lymph nodes. Extensive Stage Defined as tumor that has spread beyond one lung, mediastinum, and supraclavicular lymph nodes. Common distant sites of metastases are the adrenals, bone, liver, bone marrow, and brain.

Multimodality Stages Ia through IIb Chimiothérapie Adjuvante/Neo-adjuvante Prophylactic Cranial Irradiation N 134 patients Retrospective, case control Surg + adj. chemo vs chemo/xrt 67 pa / arm N0 and N1 subgroups Badzio A and al. Eur J Cardiothorac Surg. 2004;26(1):183-8

Malignant Mesothelioma 80% intrathoracic 20% primary site = peritoneum Age : 50-70 M/F 3.6 to 1

Epidemiology and perspectives Period of latency Cugell, D. W. et al. Chest 2004;125:1103-1117

Diagnostic CXR : 80-95% Pleural effusion CT-scan : Sensitivity >>> CXR PET-FDG scan for Nodal and M stating Histologic diagnosis is mandatory Pleural cytology 25-33% Closed-chest needle biopsy 21-77% Thoracoscope biospy 90% VATS >90% and staging XRT post-biopsy for local control

Three histologic types of mesothelioma; epithelioid, 50%; sarcomatous or mesenchymal, 16%; mixed, 34%. The epithelioid subtype has the best prognosis

Surgery as a part of multi-modal treatment : Selection of patients T1a T1b T2 T3 T4 N0 Ia Ib II III IV N1 III III III III IV N2 III III III III IV N3 IV IV IV IV IV M+ IV IV IV IV IV

Pleuro-pneumonectomy Stage Ia, Ib and Stage II Pleurectomy Decortication Stage Ia, Ib and Stage II unfit for EPPn + XRT and chemo-sensitizing molecules Paclitaxel Carboplatin

Treatment Algorythm for Mesothelioma Stage I Epithelial Stage I NON Epithelial Stage II/III All Types Evaluate for EPP NeoAduvant Chemotherapy platin-based pemetrexed or gemcitabin EPP Aduvant Chemotherapy platin-based pemetrexed or gemcitabin Adjuvant XRT Re-Staging Downstaging to N0/1 Evaluate for EPP EPP Ajuvant XRT

EPP Exclusions Criteria ECOG > 1 (KI < 70%) ppofev 1 < 1L/s Room air pco 2 > 45 mmhg Room air po 2 < 65 mm Hg EF < 45% Borderline FEV 1 < 2L/s radionuclide ventilation-perfusion pulmonary scanning D. Sugarbaker, J Thor Cardiovasc Surg, 1999: 117: 54-65

Authors Year Nu Pa Stage Epithelial Operative 2-year surv 5-yr Surv IMIG Mortality Worn 1974 62 N/a N/a N/a 37 10 Butchart 1976 29 N/a 11 31 10 3 DeLaria 1978 11 N/a 9 0 27 N/a Da Valle 1986 33 N/a 20 9 24 6 Ruffie 1989 23 I-III 12 13 17 N/a Allen 1994 40 N/a 26 7.5 22.5 10 Rusch 1996 50(131) N/a (76%) 6 ~ 40 [Med 9.9mo] Sugarbaker 1999 183 I-III 103 3.8 37 14 Weder 2004 19 I-III 14 0 37 [Med 23mo] Stahel (SAKK17/00) 2005 45(61) I-III N/a 2 67 (1-yr) [Med 26.3mo] (18.4 mo) Flores 2005 9 III/IV N/a 0 N/a N/a Edwards 2006 92 I-IV 71 7.6 34 15 Summary 612 NeoAdj Chemo XRT Adj Chemo XRT Adj Chemo or adj. XRT

Place de la chirurgie pulmonaire dans les Cancers primitifs et dans la Chirurgie de Métastasectomie Pulmonaire

Métastasectomies pulmonaires 1/ Introduction 2/ Revue Générale (Registre international) 3/ UCL Experience

Historical aspect of surgery in Pulmonary Metasastic Disease : Survival 1884 (Kronlein, Berl Klin Wschschr) 7 yrs* 1930 (Torek, Arch Surg) n/a* 1939 (Barney and Churchill, J Urol) 23 yrs* 1947 (Alexander and Haight, Surg Gynecol Obstet) n= 24 patients (8 sarcoma, 16 carcinoma) 12/24 tumor recurrence-free, (f-up 1-12yrs) 50% 1965 (Thomford, J Thorac Cardiovasc Surg) n= 205 patients (20% sarcoma, 80% carcinoma) 77% 1-yr survival and at 5-yr f-up 30 %

Métastasectomies pulmonaires Physio-pathologie Poumon = premier lit capillaire de drainage de la plupart des tumeurs primitives Le plus souvent, fixation en périphérie 10 à 20 % des patients avec métastases pulmonaires ont une maladie confinée au poumon

Diagnostic Asymptomatique Découverte lors d un contrôle systématique Ct Scan : sensible (peu de faux [-]) non-spécifique (bcp faux [+]) sous-estime le nombre de lésions Ponction trans-thoracique Nodule solitaire fréquent pour sarcome et mélanome

Indication de résection chirurgicales Si Contrôle local de la tumeur primitive Si Résection complète possible Si Réserve fonctionnelle suffisante Si Absence d autres localisations métastatiques?

Technique opératoire «Wedge» resection (épargne parenchymateuse) Exploration manuelle Thoracoscopie (single) Si bilat : Sternotomie Thoracotomie bilat. séquentielle.

Métastasectomies pulmonaires Analyse de Survie (Toutes origines primitives confondues) Survie à 5ans 36% Survie à 10 ans 26% Survie à 15 ans 22% (médiane de survie : 35 mois)

Patients' features II/ Overview: Métastasectomies pulmonaires (International Registry : 5206 pts) Resection Complete Incomplete Total Age:Mean (range) 44 (2-93) 43 (2-79) 44 (2-93) Sex Male 2587 345 2932 Female 1984 289 2273 Type Epithelial 1984 276 2260 Sarcoma 1917 256 2173 Germ cell 318 45 363 Melanoma 282 46 328 Other 70 11 81 Pastorino et al. J Thorac Cardiovasc Surg 113 (1997) :37-49

Patients' features Resection Complete Incomplete Total Approach Monolateral thoracotomy 2770 341 3111 Bilateral thoracotomy 534 42 576 Sternotomy 1179 236 1415 Thoracoscopy 84 9 93 Resection Wedge 3012 461 3473 Segment. 409 40 449 Lobectomy 1014 95 1109 Pneumonectomy 112 21 133 Other resections 344 102 446 Pastorino et al. J Thorac Cardiovasc Surg 113 (1997) :37-49

Overall Survival : Prognostic Factors Complete Resection Pastorino et al. J Thorac Cardiovasc Surg 113 (1997) :37-49

Overall Survival Intervalle libre Pastorino et al. J Thorac Cardiovasc Surg 113 (1997) :37-49

Overall Survival : Prognostic Factors Nombre de métastases Pastorino et al. J Thorac Cardiovasc Surg 113 (1997) :37-49

Overall Survival : Prognostic Factors Histologie Pastorino et al. J Thorac Cardiovasc Surg 113 (1997) :37-49

Overall Survival : Prognostic Factors combined (CR, FI, Nu mets and Histo) Pastorino et al. J Thorac Cardiovasc Surg 113 (1997) :37-49

Métastasectomies pulmonaires 1/ Introduction 2/ Revue Générale (Registre international) 3/ UCL Experience

Prognostic factors for long-term survival in patients with thoracic metastatic disease: a 10- year experience Study period : 1990-2002 93 patients / 134 procedures Retrospective analysis of consecutive patients All thoracic explorations included Patients data collection Hospital charts, PCP and/or oncologist Follow-up completed from 02/06 and 06/06 Mean follow-up time : 43 months (range 1-169 mo) AJ Poncelet et al., Eur J Cardiothor Surg 31 (2007) :171-180

Patients characteristics Sex ratio (m:f ) 1.2 :1 Mean age 52.2 y.o. (range 3-84) Number of metastasis : 233 (2.5/pa) Number of procedure One : 80 patients (including 9 sequential bilateral) More than one : 18 patients Adjuvant chemotherapy (pre or post): 76/93 patients AJ Poncelet et al., Eur J Cardiothor Surg 31 (2007) :171-180

Operative Strategies Mediastinal LN dissection 49/93 patients nln/pa 4.5/pa (1-33) Wedge 48 Segmentectomy 4 Lobectomy 17 Pneumonectomy 7 Other resections 17 R0 R1/R2 R status 70 pa 23 pa (14/9 pa) 70/93 pr0 (75.2%) AJ Poncelet et al., Eur J Cardiothor Surg 31 (2007) :171-180

RESULTS Pathology (n=93) Epithelial 47 (Colo-rectal, renal and breast) Sarcoma 21 (all histological subtypes) Teratoma 6 Melanoma 4 Other tumors 15 Major Morbidity (5%) 7/139 procedures, requiring reoperations 3/139 pulm infarc 1 empyema 1 diaphr. hernia 1 90-day Mortality (2.2%) 3/139 procedures (sequential lobectomies/bilob) LOS mean 8.4 days (3-57d) AJ Poncelet et al., Eur J Cardiothor Surg 31 (2007) :171-180

Survival at 1-yr 3-yr 5-yr 82% 55% 44% AJ Poncelet et al., Eur J Cardiothor Surg 31 (2007) :171-180

AJ Poncelet et al., Eur J Cardiothor Surg 31 (2007) :171-180

3-yr and 5-yr Survival Pathology (n=) 3-yr 5-yr Epithelial (47) 59% 42 % Sarcoma (21) 47 % 47 % Teratoma (6) 50% 50% Melanoma (4) 50% 50% Others (15) 78% 78% AJ Poncelet et al., Eur J Cardiothor Surg 31 (2007) :171-180

Epithelial Tumors Pathology (n=) 3-yr 5-yr Colo-rectal (26) 69 % 37 % Renal (11) 28 % 19 % Breast (9) 31% 16 % AJ Poncelet et al., Eur J Cardiothor Surg 31 (2007) :171-180

Statistics (1) β p H.R. 95% CI Age 0.27.38 1.3 0.7-2.4 Sex 0.55.08 1.7 0.9-3.2 Primary pn 1.02.09 2.7 0.8-9.2 DFI 0.02.95 1 0.5-1.9 Nu mets 1.38.0000 3.97 2.1-7.4 Other mets 0.1.74 1.1 0.6-2.1 AJ Poncelet et al., Eur J Cardiothor Surg 31 (2007) :171-180

Statistics (2) β p H.R. 95% CI Type 0.33.34 1.4 0.7-2.8 Resection Uni vs 0.4.23 1.5 0.8-2.9 Bilateral Size Mets 0.52.11 1.7 0.9-3.2 pr Status 1.16.0006 3.2 1.6-6.2 pn Status 0.19.69 1.2 0.5-3.2 Redo-Mets -0.58.14 0.6 0.3-1.2 AJ Poncelet et al., Eur J Cardiothor Surg 31 (2007) :171-180

Analysis of Colo-rectal and Sarcoma subgroups Colo-Rectal Metastatic group (n= 26) β p H.R. 95% CI Uni vs Bilat 1.3.04 3.7 1-12.7 Nu mets 3.2.003 23.7 2.8-198 pr status - - - - pn status* 1.4.24 4.2 0.4-47 Prior Hep. Mets* 0.3.7 1.3 0.4-4.6

Analysis of Colo-rectal and Sarcoma subgroups Sarcoma Metastatic group (n= 21) β p H.R. 95% CI Uni vs Bilat 0.7.24 2.1 0.6-7.4 Nu mets 1.8.01 6.1 1.5-24.6 pr status 2.003 7.6 2-29.4 pn status* - - - - Nu redo-mets -1.9.08 0.15 0.2-1.2

Conclusions (1) In those selected patients, understanding that a complete resection can be anticipated, surgery for metastatic disease results in 3-yr and 5-yr overall survival of 60% and 43%, respectively. Both in univariate and multivariate analysis, the number of metastasis and complete pathological resection are significant variables that influences outcome. In this series of patients, variables such as DFI, other site than pulmonary, N status of the primary tumor, type of resection did not had influence on survival.

Conclusions (2) Patients in whom repeated metastasectomies are performed do at least as well as the others. In the colo-rectal subgroup, in addition to number of metastasis and the completeness of surgery, bilateral disease appears to convey a negative outcome. When complete resection can be anticipated, no suitable patient should be denied from surgery.