Tristate Lung Meeting 2014 Pro-Con Debate: Surgery has no role in the management of certain subsets of N2 disease Jennifer E. Tseng, MD UFHealth Cancer Center-Orlando Health Sep 12, 2014
Background Approximately 10 to 20% patients have stage IIIA (N2) disease, with overall 5 year survival of 16% Marked variability in prognosis of patients with N2 disease Current staging does not differentiate between the degree and the bulk of N2 disease burden Mountain CF. Chest 1997; 111: 1710-1717 Detterbeck FC et al. Chest 2013; 143(5) suppl):e191s-e210s Rusch VW et al. J Thorac Oncol 2007; 2(7): 603-612
Subgroups of N2 disease Ruckdescehl JC. Semin Oncol 1997; 111: 1710-1717 Robinson et al. Chest 2007; 132: 243S-265S
Subgroups of N2 disease: 3 subgroups of stage III disease from Chest 2013 guidelines summary: 1. Infiltrative stage III (N2 and N3 disease where discrete nodes can no longer be clearly distinguished and measured), (radiographic group A, Silvestri et al) 2. Discrete N2/N3 involvement: patients in whom individual nodes can be distinguished (radiographic groups B and C, patients with central tumors or suspected N2 disease with chance of N2/N3 involvement of 20-25%) 3. Occult N2 disease despite preoperative staging: found intraoperatively or postoperatively to have N2 nodes Silvestri et al. Chest 2013; 143(5) (Suppl): e211s-e250s
Prognosis of N2 IIIA disease A. Survival of N2 disease varies widely depending on bulk and extent of N2 disease B. Many studies conducted in IIIA N2 NSCLC have been limited by a number of challenges: 1. Heterogeneous patient populations 2. Variable and at times imprecise staging (variable use of PET scans, variable pathologic confirmation of N2 disease) 3. Slow patient accrual C. Survival of clinical N2 disease patients varies widely by geographic region and database type Detterbeck FC et al. Chest 2013; 143(5) suppl):e191s-e210s Martins RG et al. JNCCN 2012; 10: 599-613
Detterbeck FC et al. Chest 2013; 143(5) suppl):e191s-e210s
National Cancer Database survival data for clinical stage IIIA-N2 disease Koshy MK et al. J Thor Oncology 2013; 8: 915-922
Treatment options for IIIA N2 disease 1. Induction chemotherapy followed by resection 2. Induction CRT followed by resection 3. Definitive CRT without surgery 4. Surgery followed by adjuvant chemotherapy/+/- RT
Does surgery have a role in the management of IIIA (N2) disease?
Point #1 Outcomes with primary surgery alone for patients with preoperatively identified N2 disease are poor
Pearson FGet al. J Thorac Cardiovasc Surg 83: 1-11, 1982
Ramnath N et al. Chest 2013; 143(5) (Suppl): e314s-e340s
Andre F, Le Chevalier et al. JCO 18: 1981-1989, 2000
Point #2 For patients with preoperatively identified N2 disease, preoperative chemotherapy followed by surgery is superior to surgery alone
Roth JA et al. J Natl Cancer Inst 86: 673-680, 1994
Rosell R et al. NEJM 1994; 330: 153-8
Andre F, Le Chevalier et al. JCO 18: 1981-1989, 2000
Ramnath N et al. Chest 2013; 143(5) (Suppl): e314se340s
Point #3 The available randomized phase III studies do not demonstrate survival benefit of surgery after neoadjuvant chemoradiotherapy treatment
INT 0139 Trial Design Albain K et al. Lancet 2009; 374: 379-386 Diagram from Martins RG et al. JNCCN 2012; 10: 599-613
INT0139 survival results PFS of ITT population PFS 12.8 mo in group 1 vs 10.5 mo in group 2 OS of ITT population 5 year survival 27% in group 1 vs 20% in group 2 Albain K et al. Lancet 2009; 374: 379-386
INT0139: Overall survival in group 1 by pathological nodal substage Median survival for patients with N0 disease at surgery was 34.4 mo vs N+ disease of 26.4 mo Median survival was 7.9 months if no surgery Albain K et al. Lancet 2009; 374: 379-386
INT0139: lobectomy vs pneumonectomy Overall survival in ITT population: lobectomy subset of group 1 MST 33.6 mo group 1 vs 21.7 mo in group 2 Overall survival in ITT population: pneumonectomy subset of group 1 MST of 18.9 mo group 1 vs 29.4 mo group 2 Albain K et al. Lancet 2009; 374: 379-386
INT0139 Study did not meet primary endpoint of improved overall survival with trimodality therapy compared to bimodality therapy Patients with best results after surgery are those with pathological CR at thoracotomy and who undergo lobectomy Surgery associated with greater early mortality but with more late survivors By year 3, trend was seen towards better survival with surgery 38% vs 33% respectively Operative mortality was 17.6% for pts undergoing pneumonectomy and 1.1% for pts with lobectomy High surgical mortality in pts who underwent pneumonectomy may have offset benefit from surgery in group 1
EORTC 8941 Trial Design Van Meerbeeck et al. J Natl Cancer Inst 2007; 99: 442-450 Diagram from Martins RG et al. JNCCN 2012; 10: 599-613
EORTC 8941 Overall Survival Van Meerbeeck et al. J Natl Cancer Inst 2007; 99: 442-450
EORTC 8941 Progression Free Survival Van Meerbeeck et al. J Natl Cancer Inst 2007; 99: 442-450
EORTC 8941 Exploratory Analyses Van Meerbeeck et al. J Natl Cancer Inst 2007; 99: 442-450
Thomas M et al.lancet Oncol 2008; 9; 636-648 GLCCG study schema
GLCCG study Progression Free Survival Overall survival Thomas M et al.lancet Oncol 2008; 9; 636-648
GLCCG study clinical outcomes Thomas M et al.lancet Oncol 2008; 9; 636-648 Table from Martins RG et al. JNCCN 2012; 10: 599-613
Ramnath N et al. Chest 2013; 143(5) (Suppl): e314s-e340s
Thomas M et al.lancet Oncol 2008; 9; 636-648
Conclusions 1. Lobectomy after neoadjuvant treatment may offer survival benefit for selected patients after neoadjuvant chemoradiotherapy, especially for those patients with nodal downstaging Pneumonectomy after induction should only be performed in a high volume center with demonstrated low mortality rate for pneumonectomy
Point #4 Neoadjuvant chemoradiotherapy does not offer clear survival advantage over neoadjuvant chemotherapy alone
Pre-operative chemotherapy in stage III NSCLC: Total of 755 pts treated in 11 trials using neoadjuvant chemotherapy Median survival of 19 months Martins RG et al. JNCCN 2012; 10: 599-613
Pre-operative chemoradiotherapy in stage III NSCLC: 627 patients treated in 11 phase 2 trials assessing concurrent CRT Median survival of 16 months Martins RG et al. JNCCN 2012; 10: 599-613
Neoadjuvant CRT vs chemo alone Is induction CRT superior to induction chemo? Shah et al: Review of 7 studies that met criteria for analysis, including 1 RCT, 1 phase II study, 3 retrospective reviews, 2 published abstracts of RCT s None of the studies demonstrated survival benefit to adding induction RT to induction chemo Meta-analysis performed on retrospective studies also did not demonstrate survival benefit Shah AA Ann Thorac Surg 2012; 93(6): 1807-12
Preoperative chemotherapy vs chemoradiotherapy for stage III NSCLC Shah AA Ann Thorac Surg 2012; 93(6): 1807-12
Forest plots of overall survival of patients in (A)RCT and in (B) retrospective studies comparing induction chemotherapy vs CRT A. Randomized controlled studies B. Retrospective studies Shah AA Ann Thorac Surg 2012; 93(6): 1807-12
Advantages of induction chemo over CRT 1. Ability to deliver higher doses of pre-operative systemic chemotherapy 2. In vivo assessment of biology of the tumor 3. Interruption of potentially curative doses of chemoradiation for surgical exploration may be detrimental for those patients show tumors are then shown to be unresectable 4. Some studies (but not all) show lower complication rates when pre-operative chemo alone is used compared to preoperative CRT 5. Pre-op RT may be associated with pneumonitis and fibrosis as well as cardiac dysfunction, all of which may contribute to post-operative complications
Conclusions: point 4 Neoadjuvant chemoradiotherapy does not offer clear superiority over neoadjuvant chemotherapy alone, based on pooled results of multiple phase II studies There is a trend toward higher perioperative morbidity and mortality when neoadjuvant radiation is added
Point #5 Response to neoadjuvant treatment predicts favorable prognosis after surgery Although the rate of mediastinal clearance is only moderate with neoadjuvant chemotherapy alone, those patients have superior to survival compared to patients without nodal response to neoadjuvant treatment
Data from randomized phase II study Betticher et al: Multicenter phase II study enrolled 90 pts with pathologically confirmed IIIA N2 disease All pts received 3 cycles neoadjuvant docetaxel and cisplatin Overall response rate 66% Pathologic CR occurred in 15% pts Pathologic downstaging to N0 status was observed in 31% patients and to N1 status in 29% Betticher DC et al. J Clin Oncol 2003; 21: 1752-1759
Patients with downstaging to N0-1 status at surgery had 3 year survival of 61% and median survival of 33 mo Patients with persistent N2 disease had 11% survival at 3 years, median survival 16.2 months Betticher DC et al. J Clin Oncol 2003; 21: 1752-1759
Betticher DC et al. J Clin Oncol 2003; 21: 1752-1759
Retrospective data: Predictive value of nodal status at surgery Brigham and Women s Hospital series of all patient who underwent surgery for stage IIIA N2 NSCLC 103 patients received neoadjuvant therapy Preop treatment consisted of platinum based chemotherapy (76), radiotherapy (18) or chemoradiation (9) Operations included pneumonectomy in 38, bilobectomy in 6, and lobectomy in 59 R Bueno et al. Ann Thorac Surg 2000; 70: 1826-31
Brigham and Women s Hospital series 29 patients patients who were downstaged to N0 with 5 year survival of 35.8% 74 patients with persistent N1 or N2 disease had 5 year survival of 9% R Bueno et al. Ann Thorac Surg 2000; 70: 1826-31
Brigham and Women s Hospital series Cancer free survival based on nodal status at surgery Cancer free survival based on histology R Bueno et al. Ann Thorac Surg 2000; 70: 1826-31
Point #6 Poor response to neoadjuvant treatment predicts for poor prognosis A. Patients with persistent pathological N2 disease after neoadjuvant treatment have 5 year survival rates of 9 to 29%, with average of 16% among 8 series B. Patients with lack of response after induction chemotherapy have average 5 year survival of 14% and median survival of 17 months among 17 series
Ramnath N et al. Chest 2013; 143(5) (Suppl): e314se340s
Ramnath N et al. Chest 2013; 143(5) (Suppl): e314se340s
Point #7 Patients with occult/unsuspected N2 disease and who undergo surgery have more favorable survival compared to patients with preoperatively detected N2 disease
Occult N2 disease Patients with cn0-n1, single station involvement, and T1/T2 tumors have better prognosis with average 5 year survival of 25-30% Multistation involvement, cn2 by CT scan, multilevel N2, T3 tumors or subcarinal nodal involvement: predict worse survival (5 year survival approximately 15%) Detterbeck F. J Thor Oncol 2008; 3(3): 289-302
Retrospective cohort study: survival of patients with unsuspected N2 disease Cerfolio et al: Retrospective review of prospective database with total of 148 pts; all pts with preoperative clinical stage of N0 or N1 48% underwent RUL lobectomy 93% received adjuvant chemotherapy 13% received adjuvant RT also Overall 5 yr survival of 35% Cerfolio RJ and Bryant AS. Ann Thorac Surg 2008; 86: 362-7
Survival of patients with unsuspected N2 disease 5 yr OS for patients with single station N2 vs multistation N2 involvement: 40% vs 25% Cerfolio RJ and Bryant AS. Ann Thorac Surg 2008; 86: 362-7
Conclusions: Surgery has no role in the treatment of the following subgroups of patients with N2 disease: A. Patients with bulky or fixed multistation N2 disease B. Patients without response after neoadjuvant treatment C. Patients who require pneumonectomy after neoadjuvant treatment (unless performed in a high volume center with demonstrated low mortality rate for pneumonectomy)
Conclusions: Surgery does have a role in the treatment of certain favorable subgroups of patients with IIIA N2 disease: A. Patients who are candidates for lobectomy after neoadjuvant treatment B. Patients with nodal downstaging and/or overall response after neoadjuvant treatment C. Patients with unsuspected/occult N2 disease
Ongoing controversies How is resectable vs unresectable defined Best neoadjuvant treatment (chemotherapy vs chemoradiation): No clear advantage in phase III randomized studies for either approach over the other Directions for future: Improvement in systemic treatments: role of molecularly customized treatment Better radiotherapy techniques