Heterogeneity of N2 disease

Transcription

1 Locally Advanced NSCLC Surgery? No. Ramaswamy Govindan M.D Co-Director, Section of Medical Oncology Alvin J Siteman Cancer Center at Washington University School of Medicine St. Louis, Missouri Heterogeneity of N2 disease Good Prognosis Single station ti Single node Microscopic involvement Station 5 or 6 Small volume disease Performance status Weight loss Pulmonary function Co-morbidities Biology Bad Prognosis Multi-station t disease Multi-nodal Extracapsular extension Station 4L or 9 Bulky disease Fixed (invasion of mediastinal structures) Skip metastasis Kassis Thorac Surg Clin 18 (2008)

2 Locally Advanced NSCLC Improving Median Overall Survival (months) Chemotherapy Sequential Chemotherapy concurrent Radiation therapy planning and delivery Supportive Care Issues Heterogeneous group Morbidities and mortalities with surgery Distant micro-metastasis- major problem 4 2

3 The Classical Dogma of N2 Disease Only 25% of clinical N2 patients can be completely resected mandating a surgical role for staging in these patients The 5 year survival of completely resected pn2 patients is approximately 25% Hence, surgery as a primary treatment for N2 disease will have only a 6% - 5 year survival Fortuitous Resection of N2 Disease Study N Radiographic Stage Mountain 307 cno-2 Maggi 236 cno-2 Mediastinoscopy performed Selected patients Selected patients Mediastinoscopy results 5 year survival Negative 31 Negative 19 Miller 147 cno-2 Selected patients Negative 24 Goldstraw 127 cno-2 Selected patients Negative 20 Nakanishi 45 cno-2 Selected patients Negative 21 Vansteenkiste 58 cno-2 All Patients Negative 32 Pearson 25 cno-2 All Patients Negative 41 Andre 332 Minimal N2 Selected Patients Negative 29 3

4 Prognostic Factors: Resected IIIA N2 5-Year Survival (%) Present Absent Factor Mean Mean Trend P<0.05 n+/n- Incomplete Resection /11 9/9 577/1782 Multiple stations /12 7/11 802/1119 Extracapsular extension /4 2/3 207/317 Subcarinal node involvement /12 4/11 602/778 AP window node /6 0/5 179/368 High Paratracheal node /3 0/2 97/203 N1 positive /2 0/2 173/92 Non squamous histology /10 1/8 912/613 T Status T1 38 T2 25 T /12 6/8 T1: 344; T2:1344; T3:509 Andre Study JCO patients with documented N2 disease treated by resection from Mediastinoscopy for nodes > 1 cm (70% of time) Defined postoperatively as Minimal N2 disease at one level (mn2l1) Minimal N2 disease at many levels (mn2l2+) Clinical i l N2 (>1 cm, med [+] or med not done and [+] confirmed at thoracotomy)at one level (cn2l1) Clinical N2 at multiple levels (cn2l2+) 4

5 The Impact of Nodal Clearance with Induction Chemotherapy In 86 patients receiving 3 cycles docetaxel-cisplatinum cisplatinum with mediastinoscopy proven N2 disease (only 18% with microscopic disease), mediastinal clearance resulted in a 61% 3 year survival vs 11% without clearance Betticher DC, et al. J Clin Oncol 2003;21:

6 Lung Intergroup Trial 0139 Treatment-Related Mortality During induction none, either arm CT/RT during or 3 (1.6%) after consolidation CT/RT/S total 14 (7%) postoperative cx 10 (5%) misc. other 4 (2%) INT 0139 Treatment-Related Deaths on CT/RT/S (n=14) Type of Surgery N Cause of Death (L) Lobectomy 1 PE (R) Bilobectomy 1 ARDS Pneumonectomy 12 ARDS/respiratory, 8; miscellaneous, 4 (R) simple 5 (R) complex 3 (L) complex 4 6

7 RTOG 0139 ASCO 2005 RTOG 0139 Surgical Subset Analysis 7

8 42% 24% 8% Lung INT 0139: Patterns of Failure No Significant Difference Between Arms Overall Site CT/RT/S CT/RT p Local relapse only 17% 26%.08 primary 5% 16% nodes 9% 4% both 3% 5% Brain only 16% 21%.28 8

9 Chemoradiation Sequence in NSCLC Study Furuse et al (N = 314) Curran et al (N = 400) Zemanova et al* (N = 102) Fournel et al (N = 205) Choy et al* (N = 178) Chemotherapy mitomycin vindesine cisplatin cisplatin vinblastine cisplatin vinorelbine cisplatin vinorelbine carboplatin paclitaxel** RT (Gy) Schedule Sequential Concurrent Sequential Concurrent Sequential Concurrent Sequential Concurrent Sequential Concurrent Median Survival (mos) Actuarial Survival (%) 9 (5-year) 19 (5-year) 18 (3-year) 26 (3-year) 26 (2-year) 39 (2-year) 31 (2-year) 35 (2-year) P cycles of chemo given *Randomized, phase II trials **Low-dose concurrent Furuse K et al. J Clin Oncol. 1999;17: Curran WJ Jr et al. Proc Am Soc Clin Oncol. 2003;22:621. Abstract Zemanova M et al. Proc Am Soc Clin Oncol Abstract Fournel P et al. J Clin Oncol. 2005; 23: Belani CP et al. J Clin Oncol 2005; 23: HOG LUN 01-24/USO ChemoRT Cisplatin 50 mg/m 2 IV d 1,8,29,36 Etoposide 50 mg/m 2 IV d 1-5 & Concurrent RT 59.4 Gy (1.8 Gy/fr) Stratification Variables: PS 0-1 vs 2 IIIA vs IIIB CR vs. non-cr Randomize Docetaxel 75 mg/m 2 q 3 wk 3 Observation Hanna et al JCO 26:

10 HOG LUN 01-24/USO ChemoRT Cisplatin 50 mg/m 2 IV d 1,8,29,36 Etoposide 50 mg/m 2 IV d 1-5 & Concurrent RT 59.4 Gy (1.8 Gy/fr) 203 Stratification Variables: PS 0-1 vs 2 IIIA vs IIIB CR vs. non-cr Randomize Docetaxel 75 mg/m 2 q 3 wk 3 Observation Hanna et al JCO 26: W Overall Survival (ITT) Docetaxel Median: 21.5 months ( ) 3 year survival rate: 27.2% Observation: Median: 24.1 months ( ) 3 year survival rate: 27.6% P-value: Hanna et al JCO 26:

11 W Progression Free Survival Observation: Median: 12.9 months ( ) Docetaxel: Median: 12.3 months ( ) Hanna et al JCO 26: Grade 3/4 Non-Hematological Toxicities Toxicity PE/XRT Docetaxel OBS *p-value Esophagitis 17.2% Infections 8.9% 11.0% 0.0% Pneumonitis %** 1.4% <0.001 Rx-related death 1.5% 5.5% 0.0% *p-value corresponds to comparison of Docetaxel vs. Observation groups **Includes 1 patient death 22 Hanna et al JCO 26:

12 W Overall Survival All Patients (n=203) Median: 21.1 months ( ) 3 year survival rate 27.8% Median follow-up time: 25.6 mos 23 Hanna et al JCO 26: CALGB Schema A Randomized Phase II Trial R A N D O M I Z E Arm A Arm B Carboplatin AUC 5 q3week x 4 cycles Pemetrexed 500/mg² q3week x 4 cycles XRT 70 Gy over 7 weeks Carboplatin AUC 5 q3week x 4 cycles Pemetrexed 500/mg² q3week x 4 cycles XRT - 70 Gy over 7 weeks + Cetuximab 400mg/m² loading and 250mg/m² weekly Pemetrexed 500 mg/m 2 q3 weekly x 4 12

13 CALGB Overall Survival Probability CALGB 30407: Overall Survival Arm A (N=48) Arm B (N=51) p-value=0.779 Median Overall Survival Arm A 21.2 months (95% CI: 7.4- NA) Arm B 22.4 months (95% CI: 13- NA) 18 Month Overall Survival Arm A 56% (95% CI 43-74) Arm B 51% (95% CI 38-68) Survival Time (Months) Median follow up: 23 months (as of ) H0: p 0.35 versus H1: p 0.55 p = survival probability at 18 months registration Phase III Trials : Standard RT Dose Trial RT DOSE Median Survival RTOG Gy 17.1 months CALGB Gy 14 months HOG LUN Gy 21.1 months 14.9 months ECOG Gy SWOG Gy 19 months 13

14 POST CHEMORADIATION RESPONSE ASSESSMENT WITH FDG PET SCAN ACRIN 6668/ RTOG 0235 R E G I S T E R F D G - P E T S U V Concurrent chemo-xrt (+/- adjuvant chemo as per MD) M.D.) Sample size = 250 pts. FDG - PET SUV to be done 12 to 16 weeks following XRT and at least 4 wks after adjuvant chemo (if given). Courtesy: J Bradley Issues Heterogeneous group Morbidities and mortalities with surgery Distant micro-metastasis- major problem 28 14

15 Lung Trial Enrollments by Year Cooperative Groups 2500 ( ) 2000 Total (projected) 29 Year Courtesy: Walter Curran MD 15