Surgery for stage IIIA NSCLC? Sometimes! Anne S. Tsao, M.D. Associate Professor Director, Mesothelioma Program Director, Thoracic Chemo-Radiation Program May 7, 2011 The University of Texas MD ANDERSON CANCER CENTER Department of Thoracic/Head & Neck Medical Oncology Outline Background Epidemiology Stage IIIA Standards of Care Induction chemo Trials summary Prognostic factors for surgery Induction chemoxrt Intergroup 0139 Future Strategies Predictive models Targeted agents to molecular status 1
Lung Cancer Epidemiology 87% NSCLC 13% SCLC 2010 USA estimates 222,520 new cases with 157,300 deaths per year 45% stage III, most are unresectable Stage 1 Stage II Stage IIIA Stage IIIB Stage IV 5-year survival rates Stage IA 67% Stage IB 57% Stage IIA 55% Stage IIB 38-39% Stage IIIA 23-25% Stage IIIB 3-7% Stage IV 1% Jemal et al. CA Cancer 60 : 277-300, 2010 AJCC Staging 6 th edition Stage III NSCLC IIIA IIIB Wet IIIB T 3 N 1 M 0 T 1-3 N 2 M 0 T 1-4 N 3 M 0 T 4 N 0-2 M 0 T 4 N any M 0 Malignant pleural or pericardial effusion T 4 = Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, esophagus, vertebral body, carina, or separate tumor nodules in the same lobe, or tumor with a malignant pleural effusion 2
New Staging Stage III Detterbeck F C et al. Chest 2009;136:260-271 Classic Stage IIIA Patient Presentations Early clinical stage Surgery find microscopic disease in N 2 Lymph nodes so pathologic stage IIIA Radiation then adjuvant chemotherapy Multi-station N 2 lymph nodes Induction chemo then chemoxrt Induction chemo then surgery then XRT Induction chemoxrt then surgery ChemoXRT Single station N 2 lymph nodes Induction chemo then chemoxrt Induction chemo then surgery then XRT Induction chemoxrt then surgery ChemoXRT T3-4 chest wall invasion (superior sulcus tumors) Induction chemo then chemoxrt ChemoXRT Induction chemoxrt then surgery 3
Stage III NSCLC Treatment The optimal regimen has not been defined yet although stage III patients require multi-modality therapy to achieve long-term survival. Concurrent chemo-radiation is better than XRT alone and sequential chemo-radiation in unresectable stage III NSCLC 24 22 20 17 (n=709) WJLCG GLOT 18 16 14 12 14 (n=716) CZECH LAMP RTOG 9410 BROCAT 10 Sequential Concurrent Choy, ASCO 2003 P < 0.05 (Kruskal-Wallis Test) Stage III NSCLC Treatment ASCO Guidelines Patients with a good performance status (FEV 1 > 800 cm 3 ) should receive 2-4 cycles of platinum-based chemotherapy and should receive no less than the biologic equivalent of 60 Gy XRT in 1.8 2.0 fractions Pfister et al. JCO 22 (2): 330-353, 2004 4
Stage III NSCLC Unanswered questions: Optimal chemotherapy, dosing, timing Induction regimen Consolidation Sequencing Tri-modality Therapy Biologic therapies Outline Background Epidemiology Stage IIIA Standards of Care Induction chemo Trials summary Prognostic factors for surgery Induction chemoxrt Intergroup 0139 Future Strategies Predictive models Targeted agents to molecular status 5
Phase III Induction Chemo-Surgery Trials for IIIA Trial Therapy n Median survival (months) Survival (%) P-value NCI PE +Surg 13 28.7 42 (3-yr) Surg+XRT 14 15.6 12 (3-yr) 0.095 Rossell MIC+Surg Surg (XRT) 30 30 26 8 30 (3-yr) 0 (3-yr) <0.005 Roth CEP+Surg Surg 28 32 21 14 36 (5-yr) 15 (5-yr) 0.048 Depierre MIC+Surg+MIC 187 37 52 (3-yr) Surg 186 26 41 (3-yr) 0.15 Van Meerbeeck Chemo + Surg Chemo + ChemoXRT 167 165 16.4 17.5 15.7% (5-yr) 14% (5-yr) NS PE = cisplatin, etoposide MIC = mitomycin, ifosfamide, cisplatin CEP = cisplatin, etoposide, cyclophosphamide Depierre et al. found that the benefit of chemo was in N 0-1 disease (RR 0.68) and not in N 2 disease (RR 1.04) Pass et al Ann Thor Surg 1992, Rosell et al NEJM 1994, Roth JNCI 1994, Depierre JCO 2002 Induction Chemotherapy Trials Bimodality Lung Oncology (BLOT) (carboplatin, paclitaxel) French Thoracic Cooperative Group (gemcitabine, cisplatin vs. carboplatin, paclitaxel) Medical research Council LU-22 (MIC vs. mitomycin, vinblastine, and cisplatin) NATCH (carboplatin, paclitaxel) CLINCH (carboplatin, paclitaxel) CHEST(gemcitabine, cisplatin) The role of surgery in IIIA patients after neoadjuvant chemotherapy remains controversial. 6
Prognostic factors for improved survival to surgery after neoadjuvant chemo Response to chemotherapy Down-stage N2 disease Single-station N2 is better than multistation N2 disease R0 resection Pathologic CR Outline Background Epidemiology Stage IIIA Standards of Care Induction chemo Trials summary Prognostic factors for surgery Induction chemoxrt Intergroup 0139 Future Strategies Predictive models Targeted agents to molecular status 7
Phase II Induction ChemoXRT-Surgery Trials Trial Pt. Chemo Intergroup 9416 Intergroup 8805 Superior sulcus T 3-4 N 0-1 IIIA (N 2 ) IIIB (N 3 or T 4 ) Cisplatin etoposide x2 + XRT 45 Gy Cisplatin etoposide x2 + XRT 45 Gy % Surgery 87% 85% 2-yr OS 55% all pts 70% with complete resection 37% IIIA 39% IIIB Trimodality therapy is feasible with significant benefit for superior sulcus tumors. Rusch et al, JTCVSurg 121:472-483, 2001; Albain et al. JCO 13: 1880-1892, 1995 INT 0139 Phase III Trial of CT/RT vs. CT/RT/S Stage IIIA T 1-3 pn 2 Surgery Feasible Predicted postsurgery FEV 1 > 800cc Medically fit * R A N D O M I Z E Induction PE x 2 + XRT Chemotherapy (PE) Cisplatin 50 mg/m 2 d1, 8, 29, 36 Etoposide 50 mg/m 2 d1-5, d29-33 Radiation Thoracic Radiation 45 Gy starting on Day 1 (1.8 Gy/day) Surgery XRT to 61 Gy + PE x 2 * Stratified by KPS, T-stage Primary endpoint: overall survival in ITT 8
INT 0139 Compliance PE x 2 + XRT 45Gy There was no difference in amount of chemotherapy delivered. N=202 N=194 (n=177) 88% Eligible for Surgery Thoracotomy 164 (81%) Complete resection 144 (71%) Incomplete resection 11 (5.5%) No resection 9 (4.5%) (n=179) 92% Eligible for CT/RT Consolidation Consolidation 155 (80%) 155 resections: 3 wedge, 98 lobectomies, 54 pneumonectomies Grade 3-5 Toxicity CT/RT/S N=202 CT/RT N=194 Grade Toxicity Gr 3 Gr 4 Gr 5 Gr 3 Gr 4 Gr 5 Leucopenia 41% 7% 0% 39% 16% 0% Neutropenia 27% 11% 0% 24% 17% 0% Anemia 12% <1% 0% 22% 3% 0% Thrombocytopenia 5% 2% 0% 6% 6% 0% Nausea or vomiting 13% 1% 0% 11% 2% 0% Neuropathy 5% 0% 0% 2% 2% 0% Esophagitis 8% 1% 0% 19% 4% 0% Pulmonary 8% <1% 6% 12% 2% 2% Cardiac 2% 1% 1% 4% 1% 0% Hemorrhage 0% 0% <1% 0% <1% 0% Fatigue 5% 0% 0% 5% 0% 0% Only esophagitis rate was significantly higher in chemoradiation alone arm (p=0.0006) 9
INT 0139 PFS favors tri-modality arm % Alive without Progress sion 100 75 50 25 0 CT/RT/S CT/RT 5-yr Median PFS (mo) 12.8 10.5 5-yr PFS Rate 22.4% 11.1% / HR 0.77, p=0.017 CT/RT/S N=202 / /// / // / / // / // / / / / / / / / / / CT/RT N=194 0 12 24 36 48 60 Months from Randomization Patterns of first site of relapse ChemoXRT-Surgery (n=202) ChemoXRT (n=194) Local-only relapse 10% 22% Primary tumor site 2% 14% Hilar, mediastinal, supraclavicular nodes only 7% 3% Both primary and LN 1% 5% Brain 11% 15% Distant 37% 42% There were fewer local-only relapses in the chemo-radiation-surgery arm but otherwise, no other differences in first site of relapse. 10
INT 0139 Overall Survival 100 CT/RT/S CT/RT 5-yr Median OS (mo) 23.6 22.2 75 5-yr OS Rate 27.2% 20.3% % Alive 50 HR 0.87 p=0.24 CT/RT/S N=202 25 0 CT/RT N=194 0 12 24 36 48 60 Months from Randomization INT 0139 Deaths Chemo-XRT (n=179) ChemoXRT-Surgery (n=177) Induction ChemoXRT 0 0 30 days Postoperative period - 10 (5%) Consolidation ChemoRT 4 (2%) - Other 0 6 (3%) Total 4 (2%) 16 (8%) Deaths on surgery arm mostly occurred in pneumonectomy patients (14 of the 16 pts). 26% (n=14/54) of all pneumonectomy cases died; mostly from ARDs and respiratory failure. 11
% Alive INT 0139 OS by Pneumonectomy vs CT/RT 100 75 50 25 / CT/RT/S N=38 CT/RT N= 42 / CT/RT/S CT/RT Median OS (mo) 18.9 29.4 3yrOS 36% 45% 5 yr OS 22% 24% / / / / / p = NS / / / 0 0 12 24 36 48 60 Months from Randomization % Alive INT 0139 OS by Lobectomy vs CT/RT 100 75 25 CT/RT/S N=57 CT/RT/S CT/RT Median OS (mo) 33.6 21.7 5 yr OS 36% 18% CT/RT N=74 p = 0.002 50 /// / / // / / / / // / / / / / / / / / 0 0 12 24 36 48 60 Months from Randomization 12
INT 0139 OS by Pathologic Nodal Status at Time of Surgery 100 % Alive 75 50 Pathologic N0 (n=76) Pathologic N1-3, unknown (n=88) No surgery (n=38) p < 0.0001 25 0 0 20 40 60 80 100 120 Months from Randomization Pathologic findings after neoadjuvant chemoradiation (n=202) 164 thoracotomies were done 29 T 0 N 0 31 T 1 N 0 16 T 2-4 N 0 85 N 1-3 3 unknown Path Stage Median OS 5 yr OS rate T 0 N 0 39.8* 42% T any N 0 34.4 41% T any N 1-3 or unknown 26.4 24% No surgery after neoadjuvant chemoxrt 79 7.9 8% p < 0.0001 *Pneumonectomy had been done for 13 of 29 (45%) T 0 N 0 specimens 13
Cox OS model Clinical characteristics that are independent predictors of better outcome: Absence of major weight loss (p=0.003) Female (p=0.009) One N2 positive nodal station versus more stations involved (p=0.024) Summary: INT 0139 Neoadjuvant chemo-radiation before surgery improves PFS but not OS over definitive chemoradiation in stage IIIA (T 1-3 pn 2 ) NSCLC patients. There was a trend towards increased 5-year OS rates with the tri-modality arm. N 0 status at surgery predicts for greater 5-yr survival; i.e. down-staging is associated with improved survival. 14
Summary: INT 0139 No significant differences in toxicity beyond increased esophagitis in the chemo-radiation alone arm. In patients that require a pneumonectomy, neoadjuvant chemo-radiation is associated with a high risk of post-operative death (26%). At this time, can safely consider neoadjuvant chemo-radiation in very good PS patients who can receive a lobectomy. Future Issues How to determine which patient should receive aggressive tri-modality? Develop prognostic molecular models to help guide treatment decisions How to optimize down-staging? Improve systemic therapies Improve systemic therapies Personalize medicine to molecular genotype 15
Outline Background Epidemiology Stage IIIA Standards of Care Induction chemo Trials summary Prognostic factors for surgery Induction chemoxrt Intergroup 0139 Future Strategies Predictive models Targeted agents to molecular status Potential of Genomics in NSCLC Analyze gene expression profiles in lung cancer development and change our classification system Predict risk in early stage patients recommend adjuvant therapy or more aggressive treatment Predict for response and treatment outcome to chemotherapy and targeted agents in early and late stage patients 16
Genomic Strategy to Refine Prognosis in Early Stage NSCLC: Lung Metagene Model Surgically resected stage I patients have a 30-35% chance of recurrence. Gene-expression profiles may predict risk of recurrence. Potti et al. N Engl J Med. 2006;355:570-580. Stage IA NSCLC and Lung Metagene Model Predictor also identified subgroup of IA patients at high risk who may benefit from adjuvant chemotherapy Potti et al. N Engl J Med. 2006;355:570-580. 17
Systemic therapy Clear survival benefit seen in stage III with down-staging Distant relapse remains a significant cause of death in stage III patients Improving systemic therapies would potentially improve survival outcomes Stage IV NSCLC PATIENT Non-SCC SCC Neuroendocrine Adenocarcinoma Avoid pemetrexed or bevacizumab Platinumetoposide EGFR TKI 1 st or 2 nd line Maintenance (IPASS, BR.21, SATURN) EGFR mutation EML 4 ALK crizotinib EGFR wild-type Consider 2 nd line EGFR TKI or maintenance erlotinib (BR.21, SATURN) Platinum-doublet-bevacizumab Platinum-pemetrexed + bevacizumab Non-platinum or platinum based doublet Switch Maintenance: pemetrexed, erlotinib (E4599, AVAiL, Pointbreak, SATURN, JMEN) 18
Surgery for stage IIIA NSCLC? Sometimes! Trials have shown that surgery combined with chemo or chemoradiation can sometimes yield impressive survival results. I-0139 showed that patients had improved PFS with surgery after neoadjuvant chemoxrt. Improved survival outcomes were especially seen in lobectomy patients. Patients with pathologic CR or N2 down-staging from either neoadjuvant chemo or neoadjuvant chemoxrt have significant survival benefit with surgery. The future of tri-modality therapy is promising as we continue to identify predictive biomarkers and personalize systemic therapy to individual patients, we will likely improve rates of down-staging and therefore survival outcomes for IIIA NSCLC. 19