Tratamiento Multidisciplinar de Estadios Localmente Avanzados en Cáncer de Pulmón Santiago Ponce Aix Servicio Oncología Médica Hospital Universitario 12 de Octubre Madrid
Stage III: heterogenous disease * Stage IIIA - IIIB * Performance Status * Number nodes stations * Resectable/UnResectable
Stage III: heterogenous disease T and M Descriptors N0 N1 N2 N3 6th Edition TNM 7th Edition TNM Stage Stage Stage Stage T1 (! 3 cm) T1a (! 2 cm) IA IIA IIIA IIIB T1b (> 2-3 cm) IA IIA IIIA IIIB T2a (> 3-5 cm) IB IIA (IIB) IIIA IIIB T2 (> 3 cm) T2b (> 5-7 cm) IIA (IB) IIB IIIA IIIB T3 (> 7 cm) IIB (IB) IIIA (IIB) IIIA IIIB T3 invasion T3 IIB IIIA IIIA IIIB T4 (same lobe nodules) T3 IIB (IIIB) IIIA (IIIB) IIIA (IIIB) IIIB T4 (extension) T4 IIIA (IIIB) IIIA (IIIB) IIIB IIIB M1 (ipsilateral lung) T4 IIIA (IV) IIIA (IV) IIIB (IV) IIIB (IV) T4 (pleural effusion) M1a IV (IIIB) IV (IIIB) IV (IIIB) IV (IIIB) M1 (contralateral lung) M1a IV IV IV IV M1 (distant) M1b IV IV IV IV Goldstraw JTO 2007. IASLC staging book 2009
Stage III: heterogenous disease * Stage IIIA - IIIB * Performance Status: weight loss / physiologic age / cardiopulmonary fitness * Number nodes stations: volume of disease / volume to XRT * Resectable/UnResectable
Stage III: heterogenous disease * Stage IIIA - IIIB * Performance Status * Number nodes stations * Resectable/UnResectable
N2: Resectable / UnResectable Definition Resectable / UnResectable / Bulky Disease Thoracic Surgeon Criteria UnResectable / Bulky Disease Different Definitions: - Nodes > 2 cm, extra nodal affections, several nodes stations - SWOG: Node > 3 cm - EORTC: any N2 with non squamous; affections 4R or 5L/6L
N2: Resectable / UnResectable
N2: Resectable / UnResectable Definition Resectable / UnResectable / Bulky Disease Thoracic Surgeon Criteria UnResectable / Bulky Disease Different Definitions: - Nodes > 2 cm, extra nodal affections, several nodes stations - SWOG: Node > 3 cm - EORTC: any N2 with non squamous; affections 4R or 5L/6L
EIIIA N2 Resectable
EIIIA N2 Resectable Intergroup 0139 Albain Lancet 2009
EIIIA N2 Resectable Intergroup 0139 Albain Lancet 2009
EIIIA N2 Resectable Intergroup 0139 OS Lobectomy vs CT/RT Albain Lancet 2009
EIIIA N2 UnResectable EORTC 08941 von Meerbeeck JNCI 2007
EIIIA N2 UnResectable EORTC 08941 von Meerbeeck JNCI 2007
EIIIA N2 Surgery for NSCLC T1-3N2M0 having pathologically verified N2: A prospective multinational phase III trial by the Nordic Thoracic Oncology Group Sorensen JCO 2013
EIIIA N2 Surgery for NSCLC T1-3N2M0 having pathologically verified N2: A prospective multinational phase III trial by the Nordic Thoracic Oncology Group Sorensen JCO 2013
EIIIA N2 Neo-adjuvant chemotherapy with or without preoperative irradiation in stage IIIA/N2 nonsmall cell lung cancer (NSCLC): A randomized phase III trial by the Swiss Group for Clinical Cancer Research (SAKK trial 16/00)
This is the first completed phase III trial to investigate the value of the addition of neoadjuvant radiotherapy to CT and surgery. RT did not improve EFS or survival, nor did it reduce the local failure rate. Nevertheless, the overall survival rates of our neoadjuvant chemotherapy strategy confirm our previous report, and are among the best results reported to date in a multicenter setting.
E IIIA UnResectable / E IIIB
NSCLC Collaborative Group Meta Analysis Sequential vs Concomitant - OS &!! HR=0.84 [0.74;0.95], p=0.004 Survival (%) %! $! #! "!! '!)' '()$ &%)& "')% &!)$! & " ' #! ( Time from Randomization (Years) Absolute benefit in OS with concomitant CT: At 2 years: 5.3% At 3 years: 5.7% At 5 years: 4.5% &()& RT + conc CT RT + seq CT Auperin JCO 2010
V20 definition Percentage volume of the whole lung irradiated by more than 20 Gy Strong relationship between Grade II pneumonitis and V20 (p=0.005) V20 > 35% was associated with > Grade III esophagitis (p=0.032)
Other Approaches To Improve ChemoRadiotherapy Chemo Combinations
Other Approaches To Improve ChemoRadiotherapy Chemo Combinations Comparison of concurrent use of carboplatin-paclitaxel versus cisplatin etoposide with thoracic radiation for stage III NSCLC patients: A systematic review. C.E. Steuer ASCO 2015
Other Approaches To Improve ChemoRadiotherapy Chemo Combinations PROCLAIM! Stage III unresectable LA NSCLC! 1:1 rand. Stratify by:! PS 0 vs 1! gender! IIIA vs IIIB! PET scan use N=600 R 3 cycles of pemetrexed + cisplatin + radiation therapy (66 Gy in 33) sequenced to 4 cycles of pemetrexed Primary objective : survival Superiority design 80% Powered to detect Hazard Ratio=0.74 2 cycles of etoposide + cisplatin + radiation therapy (66 Gy in 33) sequenced to 2 cycles of platinum doublet consolidation Suresh Senan ASCO 2015
PROCLAIM Suresh Senan ASCO 2015
Other Approaches To Improve ChemoRadiotherapy Chemo Combinations A randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) conformal chemoradiotherapy with or without cetuximab for stage III non-small cell lung cancer: Results on radiation dose in RTOG 0617.
Other Approaches To Improve ChemoRadiotherapy Chemo Induction Ph III CALGB 39801 Objetive: increased 40% median survival from 13 m to 18.2 m Vokes JCO 2007
Induction Chemo: Ph III CALGB 39801 MST (mos) 2-y OS (%) 3-y OS (%) CT/RT 12 29 19 IND 14 31 23 Vokes JCO 2007
Other Approaches To Improve ChemoRadiotherapy Chemo Consolidation The Hoosier Oncology Group and US Oncology ChemoRT Cisplatin 50 mg/m 2 IV d 1,8,29,36 Etoposide 50 mg/m 2 IV d 1-5 & 29-33 Concurrent RT 59.4 Gy (1.8 Gy/fr) Stratification Variables: PS 0-1 vs 2 IIIA vs IIIB CR vs. non-cr Randomize Primary objective: Overall survival Secondary objectives: PFS, toxicity Aim: to detect improvement in overall survival of 25 mos vs. 19 mos Docetaxel 75 mg/m 2 q 3 wk! 3 Observation Hanna JCO 2008
The Hoosier Oncology Group and US Oncology Percent of Patients Surviving 100% 75% 50% 25% 0% All Patients: Median: 21.7 months 3 year survival rate 30.2% Observation: Median: 23.2 months 3 year survival rate: 26.1%. Docetaxel: Median: 21.2 months 3 year survival rate: 27.1% P-value: 0.9 0 10 20 30 40 50 60 Months since Registration Randomized Patients (n=147) All Patients (n=203) All Patients Observation (Randomized pts) Docetaxel consolidation (Randomized pts) Hanna JCO 2008
Other Approaches To Improve ChemoRadiotherapy Chemo Consolidation Study MST (months) 2 year 3 year 4 year 5 year S9504 (PE/RT! D) Clin Lung Cancer 2006 26 (18-35)* 54% (43-65)* 37% (24-55)* 29% (19-29)* 29% (19-29)* S9019 (PE/RT! PE J Clin Oncol 2003 15 (10-22)* 34% (21-47)* 17% (7-27)* 17% (6-28)* 17% (6-28)* *95% CI PE: Cisplatin/Etoposide; RT: Radiotherapy (61 Gy); D: Docetaxel Gandara, et al. J Clin Oncol 2003;21:2004-10. Gandara, et al. Clin Lung Cancer 2006;8:116-121.
Other Approaches To Improve ChemoRadiotherapy Chemo Consolidation and Maintenance Kelly JCO 2008
Other Approaches To Improve ChemoRadiotherapy Chemo and Maintenance Butts Lancet Oncol
Other Approaches To Improve ChemoRadiotherapy Others Clinical Trials
PACIFIC Day 1 Max 42 days after the end of chemoradiation Re-treatment for patients who have experienced disease control at end of 12 months treatment but progressed during follow-up Patients with unresectable NSCLC ( Stage III) who have not progressed following definitive, platinum-based, concurrent chemoradiation N = 702 2: 1 Arm 1 MEDI4376 10mg/kg Q2W for up to 12 months (MAX 26 doses) Arm 2 Placebo (matching placebo for infusion Q2W iv for up to 12 months (MAX 26 doses) OS PFS using PI assessments according to RECIST 1.1* Follow-up Period MEDI4736 will commence treatment on Day 1 and continue on a Q2W schedule for a maximum of 12 months (26 doses) or until PD IV administration
Other Approaches To Improve ChemoRadiotherapy XRT Dose A randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) conformal chemoradiotherapy with or without cetuximab for stage III non-small cell lung cancer: Results on radiation dose in RTOG 0617.
Other Approaches To Improve ChemoRadiotherapy XRT Dose
Recommendations ASCO Unresectable stage III NSCLC. A. In unresectable stage III disease, chemotherapy plus radiotherapy prolongs survival compared with radiation alone and is most appropriate for individuals with good performance status ESMO The preferred treatment of unresectable LA-NSCLC is definitive concurrent chemotherapy and radiotherapy with a dose no less than the biological equivalent of 60 Gy in 2.0 Gy fractions [I, A]. Vansteenkiste Ann Onco 20133; Pfister JCO 2004
Conclusions Over the past 50 years combined modality regimens for inoperable stage III NSCLC have almost tripled the median survival of this disease
Conclusions Multi modality treatment play a key role in stage III Treatments should be evaluated by a multidisciplinary team Concurrent chemoradiotherapy is the standard of care for fit patients with unresectable stage III NSCLC Any third generation chemotherapy can be given at full dose when combined with thoracic radiation
GRACIAS sponceaix@gmail.com