Joan Schiller, MD Professor of Medicine Chief, Division of Hematology/Oncology University of Texas Southwestern Medical Center Deputy Director Simmons Comprehensive Cancer Center Dallas, Texas New Issues in Staging and Adjuvant Treatment of the Early-Stage NSCLC Patient This program is supported by an educational grant from

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clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC Presentation Overview  New UICC/AJCC lung cancer staging classification  Current best practices in adjuvant treatment

New UICC/AJCC Lung Cancer Staging Classification

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC The UICC/AJCC 7th Edition Staging Classification of Lung Cancer  Worldwide staging classification of lung cancer updated every 7 yrs by UICC/AJCC –Accounts for changes in TNM data due to changes in staging procedures and outcomes  6th edition based on small number of cases primarily from the US –Most did not have CT scan staging  New criteria based on 100,000 cases worldwide –Most with CT scan, clinical, and surgical staging –Validated using US SEER data  ~ 1 in 6 patients will be allocated to a different stage category because of modifications from 6th to 7th edition of NSCLC TNM staging system Goldstraw P, et al. J Thorac Oncol. 2007;2: IASLC staging handbook in thoracic oncology. Orange Park, Fl: Editorial Rx Press; 2009.

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC Major TNM Changes in New Staging Classification TNMChanges Tumors classified by size  T1a: ≤ 2 cm  T1b: > 2 but ≤ 3 cm  T2a: > 3 but ≤ 5 cm  T2b: > 5 but ≤ 7 cm  T3: > 7 cm Reclassification of other pulmonary nodules  Same lobe: T3  Ipsilateral lobe: T4  Contralateral lobe: M1a Malignant pleural or pericardial effusions, or pleural nodules  M1a Goldstraw P, et al. J Thorac Oncol. 2007;2: IASLC staging handbook in thoracic oncology. Orange Park, Fl: Editorial Rx Press; 2009.

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC Major Stage Grouping Changes in New Staging Classification Stage GroupingChanges Large T2 tumors (T2b) N0Upstaged from IB to IIA Small T2 tumors (T2a) N1Downstaged from IIB to IIA Large T3 tumors (> 7 cm) N0Downstaged from IIIB to IIB T3 tumors (N1, or 2)Downstaged from IIIB to IIIA T4 tumors (N0 or N1)Downstaged from IIIB to IIIA Goldstraw P, et al. J Thorac Oncol. 2007;2: IASLC staging handbook in thoracic oncology. Orange Park, Fl: Editorial Rx Press; 2009.

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC Major Changes in New Staging Classification T and M DescriptorsN0N1N2N3 6th Edition TNM7th Edition TNMStage T1 (≤ 3 cm) T1a (≤ 2 cm)IAIIAIIIAIIIB T1b (> 2-3 cm)IAIIAIIIAIIIB T2 (> 3 cm) T2a (> 3-5 cm)IBIIA (IIB)IIIAIIIB T2b (> 5-7 cm)IIA (IB)IIBIIIAIIIB T3 (> 7 cm)IIB (IB)IIIA (IIB)IIIAIIIB T3 invasionT3IIBIIIA IIIB T4 (same lobe nodules)T3IIB (IIIB)IIIA (IIIB) IIIB T4 (extension)T4IIIA (IIIB) IIIB M1 (ipsilateral lung)T4IIIA (IV) IIIB (IV) T4 (pleural effusion)M1aIV (IIIB) M1 (contralateral lung)M1aIV M1 (distant)M1bIV Goldstraw P, et al. J Thorac Oncol. 2007;2: IASLC staging handbook in thoracic oncology. Orange Park, Fl: Editorial Rx Press; 2009.

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC How Does New Staging System Affect Clinical Practice?  Pulmonary nodule in same lobe as primary is now T3 –T3N0 = IIB (used to be IIIB) –T3N1 = IIIA (used to be IIIB) –Should this be treated with surgery (IIB) or chemo/radiation (IIIA)?  Pulmonary nodule in ipsilateral lobe is now T4 –T4N0 or N1 = IIIA (used to be stage IV) –T4N2 = IIIB (used to be stage IV) –Should these be treated with chemo/radiation (IIIA or IIIB instead of just chemo)? Goldstraw P, et al. J Thorac Oncol. 2007;2: IASLC staging handbook in thoracic oncology. Orange Park, Fl: Editorial Rx Press; 2009.

Adjuvant Treatment

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC Does Chemo Work for Stage IV NSCLC? YrMedian Survival, Mos 1-Yr Survival, %2-Yr Survival, % 1980s (adeno, no brain mets)

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC NSCLC Meta-analysis of Cisplatin Containing Regimens Non-Small Cell Lung Cancer Collaborative Group. BMJ. 1995;311:  8 cisplatin-based trials examined (n = 1394) –Patients randomized to surgery alone or surgery + adjuvant chemotherapy  13% reduction in risk of death with surgery + adjuvant chemotherapy vs surgery alone (P =.08)

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC IALT: Cisplatin-Based Adjuvant Therapy for NSCLC After Complete Resection Arriagada R, et al. N Engl J Med. 2004;350: Patients with stage I-III NSCLC aged yrs with no previous malignancy after complete surgical resection* (N = 1867) Cisplatin-based chemotherapy † (n = 932) No chemotherapy (n = 935) *Postoperative radiotherapy performed at discretion of institution. † Chemotherapy regimens: etoposide: 56.5%; vinorelbine: 26.8%; vinblastine: 11.0%; vindesine: 5.8%.

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC IALT: Survival Benefit Observed With Chemotherapy vs No Chemotherapy Arriagada R, et al. N Engl J Med. 2004;350: Le Chevalier T, et al. ASCO Abstract 6. EndpointChemo (n = 932) Control (n = 935) P Value Median survival, mos <.03 Median DFS, mos < yr survival, % <.03 5-yr DFS, % <.003

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC ANITA: Adjuvant Vinorelbine + Cisplatin vs Observation  Open, multicenter study  Delta expected in the 2-yr survival rate: 10%  Expected deaths: 466 events Douillard JY, et al. Lancet Oncol. 2006;7: Patients with stage IB-IIIA NSCLC aged yrs with no previous malignancy after complete surgical resection* (N = 840) Vinorelbine 30 mg/m 2 IV wkly x 16 + Cisplatin 100 mg/m 2 IV on Days 1, 29, 57, 85 (n = 407) Observation (n = 433) *Postoperative radiotherapy performed at discretion of institution. Stratified by center, stage, and histology

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC ANITA: Survival Advantage With Adjuvant Vinorelbine in Pts With Resected NSCLC Obs Vinorelbine + Cisplatin Median, mos P value.017 HR (95% CI)0.80 ( ) Reprinted from The Lancet Oncology, 7, Douillard JY, et al, Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB–IIIA non-small cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial, , 2006, with permission from Elsevier. OS (%) Mos After Randomization Chemotherapy Observation Patients at Risk, n Observation Chemotherapy

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC JBR.10: Adjuvant Vinorelbine + Cisplatin for Resected NSCLC Patients with completely resected T2N0, T1N1, or T2N1 NSCLC; ECOG PS 0/1 (N = 482) Vinorelbine 25 mg/m 2 * wkly for 16 wks + Cisplatin 50 mg/m 2 on Days 1, 8 every 4 wks for 4 cycles (n = 242) Observation (n = 240) *Dose of 30 mg/m 2 for first 18 patients; reduced due to hematologic toxicity. Median follow-up: 5.1 yrs Median follow-up: 5.3 yrs Winton T, et al. N Engl J Med. 2005;352: Stratified by nodal status (N0 vs N1) and ras status (neg/pos/unknown)

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC JBR.10: Survival Advantage of Vinorelbine Plus Cisplatin for Resected NSCLC Winton T, et al. N Engl J Med. 2005;352: Graphic reproduced with permission. Survival Probability (%) P =.03 Yrs Vinorelbine + cisplatin Observation 69% 54%

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC CALGB 9633: Adjuvant Chemotherapy in Stage IB NSCLC Patients with completely resected T2N0M0 stage IB NSCLC (N = 344) Adjuvant Chemotherapy Paclitaxel 200 mg/m 2 IV + Carboplatin AUC 6 4 cycles over 12 wks (n = 173) Observation (n = 171) Strauss GM, et al. J Clin Oncol. 2008;26: Stratified by squamous vs other, poorly differentiated vs other, and mediastinoscopy: yes vs no

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC CALGB 9633: Adjuvant Chemotherapy in Stage IB NSCLC Strauss GM, et al. J Clin Oncol. 2008;26: Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. ChemotherapyObservation Median OS, mos9578 P value.125 HR (90% CI)0.83 ( ) Survival Probability (%) Chemotherapy (n = 173) Control (n = 171) Mos

CALGB 1B Adjuvant Study: Unique in Many Ways

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC “Positive” Adjuvant NSCLC Studies Since 1995 Meta-analysis StudyRxn5-Yr OS, %HR IALT [1] IB-IIIA Surgery Cis + VP16/vinca CALGB [2] IB Surgery Carbo/paclitaxel JBR.10 [3] IB-II Surgery Cis/vinorelbine ANITA [4,5] IB, II, IIIA Surgery Cis/vinorelbine Arriagada R, et al. N Engl J Med. 2004;350: Strauss GM, et al. J Clin Oncol. 2008;26: Winton T, et al. N Engl J Med. 2005;352: Douillard JY, et al. Lancet Oncol. 2006;7: Douillard JY, et al. ASCO Abstract 7013.

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC “Positive” Adjuvant NSCLC Studies Since 1995 Meta-analysis StudyRxn5-Yr OS, %HR IALT [1] IB-IIIA Surgery Cis + VP16/vinca CALGB [2] IB Surgery Carbo/paclitaxel JBR.10 [3] IB-II Surgery Cis/vinorelbine ANITA [4,5] IB, II, IIIA Surgery Cis/vinorelbine Arriagada R, et al. N Engl J Med. 2004;350: Strauss GM, et al. J Clin Oncol. 2008;26: Winton T, et al. N Engl J Med. 2005;352: Douillard JY, et al. Lancet Oncol. 2006;7: Douillard JY, et al. ASCO Abstract 7013.

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC “Positive” Adjuvant NSCLC Studies Since 1995 Meta-analysis StudyRxn5-Yr OS, %HR IALT [1] IB-IIIA Surgery Cis + VP16/vinca CALGB [2] IB Surgery Carbo/paclitaxel JBR.10 [3] IB-II Surgery Cis/vinorelbine ANITA [4,5] IB, II, IIIA Surgery Cis/vinorelbine Arriagada R, et al. N Engl J Med. 2004;350: Strauss GM, et al. J Clin Oncol. 2008;26: Winton T, et al. N Engl J Med. 2005;352: Douillard JY, et al. Lancet Oncol. 2006;7: Douillard JY, et al. ASCO Abstract 7013.

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC “Positive” Adjuvant NSCLC Studies Since 1995 Meta-analysis StudyRxn5-Yr OS, %HR IALT [1] IB-IIIA Surgery Cis + VP16/vinca CALGB [2] IB Surgery Carbo/paclitaxel JBR.10 [3] IB-II Surgery Cis/vinorelbine ANITA [4,5] IB, II, IIIA Surgery Cis/vinorelbine Arriagada R, et al. N Engl J Med. 2004;350: Strauss GM, et al. J Clin Oncol. 2008;26: Winton T, et al. N Engl J Med. 2005;352: Douillard JY, et al. Lancet Oncol. 2006;7: Douillard JY, et al. ASCO Abstract 7013.

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC Adjuvant Chemotherapy Use and Survival for NSCLC Pts With Surgical Resection  Uptake of adjuvant chemotherapy examined in patients in Ontario diagnosed from who underwent surgical resection (N = 6304)  Proportion of patients receiving adjuvant chemotherapy increased from 7% in time period to 31% in time period (P <.001) –Uptakes coincided with data presented at annual ASCO conferences  Rate of hospitalization did not increase with uptake of adjuvant therapy  Significant improvement in 4-yr OS with uptake of adjuvant chemotherapy from 52.5% to 56.1% (P =.001) Booth CM, et al. J Clin Oncol. 2010;28:

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC Adjuvant Chemotherapy: Is It for Everyone?  Stage

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC JBR.10: Survival by Stage Winton T, et al. N Engl J Med. 2005;352: Graphic reproduced with permission. Yrs Survival Probability (%) Observation Vinorelbine + cisplatin 84 Observation Vinorelbine + cisplatin Stage IB NSCLC Stage II NSCLC Vinorelbine + cisplatin Observation Patients at Risk, n P =.79 Yrs Survival Probability (%) Vinorelbine + cisplatin Observation Patients at Risk, n P =.004

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC IALT: Interaction With P Stage Stage I Stage II Stage III Total effect Chemotherapy BetterControl Better1.00 P = HR Arriagada R, et al. N Engl J Med. 2004;350:

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC ANITA: Survival by Stage Stage IIIA Stage II Mos Stage I StageHRP Value Stage INRNS Stage IINR Stage IIIA*0.54<.001 Douillard JY, et al. ASCO Abstract Graphics reproduced with permission. Observation Chemotherapy *Stage IIIA vs IB-II Mos Mos Obs NVB + CDDP Survival Distribution Function Obs NVB + CDDP Obs NVB + CDDP

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC CALGB 9633: Survival by Tumor Size Tumor ≥ 4 cm Tumor < 4 cm Strauss GM, et al. J Clin Oncol. 2008;26: Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Mos Survival Probability Chemotherapy (n = 99) Control (n = 97) 8040 Mos Survival Probability Chemotherapy (n = 63) Control (n = 71) 8040 HR: % CI: P =.043 HR: % CI: P =.32

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC LACE Meta-analysis of Adjuvant Chemo: Chemotherapy Effect and Stage  Chemotherapy may be detrimental for stage IA, but stage IA patients were generally not given the potentially best combination cisplatin + vinorelbine (13% of stage IA patients vs 43% for other stages) Pignon JP, et al. J Clin Oncol. 2008;26: Stage IA104/ ( ) Stage IB515/ ( ) Stage II893/ ( ) Stage III878/ ( ) Category No. Deaths/ No. Patients HR for OS (Chemo vs Control) HR (95% CI) Chemotherapy BetterControl Better Test for trend: P =.04

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC Adjuvant Chemotherapy: Is It for Everyone?  Stage  Chemotherapy

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC “Positive” Adjuvant NSCLC Studies Since 1995 Meta-analysis StudyRxn5-Yr OS, %HR IALT [1] IB-IIIA Surgery Cis + VP16/vinca CALGB [2] IB Surgery Carbo/paclitaxel JBR.10 [3] IB-II Surgery Cis/vinorelbine ANITA [4,5] IB, II, IIIA Surgery Cis/vinorelbine Arriagada R, et al. N Engl J Med. 2004;350: Strauss GM, et al. J Clin Oncol. 2008;26: Winton T, et al. N Engl J Med. 2005;352: Douillard JY, et al. Lancet Oncol. 2006;7: Douillard JY, et al. ASCO Abstract 7013.

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC Phase III NATCH Study: Adjuvant vs Preop Paclitaxel/Carboplatin vs Surgery Alone Untreated patients with resectable stage IA (T > 2 cm), IB, II and T3N1 NSCLC (N = 624) Paclitaxel 200 mg/m 2 + Carboplatin AUC 6 every 3 wks for 3 cycles (n = 201) Stratified by tumor size ( 5 cm) and age (≤ 60 vs > 60 yrs)  Primary endpoint: 5-yr DFS  Secondary endpoints: toxicity, OS, biomarker analysis Surgery (n = 212) Surgery (n = 181) Surgery (n = 211) Paclitaxel 200 mg/m 2 + Carboplatin AUC 6 every 3 wks for 3 cycles (n = 139) Felip E, et al. J Clin Oncol. 2010;28:

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC Adjuvant vs Preop Paclitaxel/Carboplatin vs Surgery Alone: NATCH Phase III Results  Nonsignificant trend toward improved DFS with preoperative chemotherapy –4.2% improvement in 5-yr DFS  No significant OS difference among arms  More patients in preoperative chemotherapy arm received treatment  Similar resectability rates, surgical procedures, postoperative mortality across arms Treatment Arm Outcome 3-Yr DFS, % 5-Yr DFS, % 5-Yr OS, % Median OS, Mos Surgery alone Chemo → surgery Surgery → chemo Felip E, et al. J Clin Oncol. 2010;28: Felip E, et al. ASCO Abstract 7500.

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC NATCH: Clinical Stages of Patients on Enrollment Clinical Stage, %Preop Chemotherapy (n = 199) Surgery Alone (n = 210) Adjuvant Chemotherapy (n = 210) T1N T2N T1N T2N T3N T3N T4N0*0.5-- Felip E, et al. J Clin Oncol. 2010;28: *Patient not eligible.

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC Adjuvant Chemotherapy: Is It for Everyone?  Stage  Chemotherapy  Does the effect last?

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC IALT Long-term Results: Updated Survival at Median Follow-up of 7.5 Yrs Arriagada R, et al. J Clin Oncol. 2010;28: Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. HR: 0.91 (95% CI: ; P =.10) Chemotherapy: 578 deaths deaths before 5 yrs - 83 deaths after 5 yrs Yrs OS (%) Control: 590 deaths deaths before 5 yrs - 56 deaths after 5 yrs Chemo Control Patients at Risk, n

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC IALT Long-term Results: Additional Outcome Parameters  Nonsignificant trend toward increased nonlung cancer mortality in chemotherapy arm vs control arm (HR: 1.34; P =.06) Outcome at 8 Yrs, Events Chemotherapy (n = 932) Control (n = 935) P Value Distant metastases Second malignancies Arriagada R, et al. J Clin Oncol. 2010;28: Le Chevalier T, et al. ASCO Abstract 7507.

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC IALT Updates Summary  Loss of survival benefit for group as a whole at 7.5 yrs (HR: 0.91; 95% CI: ; P =.10) –Improvement in lung cancer death rate persists –Not due to second malignancies –No clear explanation  Increased noncancer deaths, but why?  How does this relate to other adjuvant trials? Arriagada R, et al. J Clin Oncol. 2010;28:35-42.

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC JBR.10: Updated OS and Survival by Stage and T Size  Long-term (> 9 years median follow-up) OS superior with chemotherapy vs observation  Median OS: 7.8 years vs 6 years with chemotherapy vs observation, respectively –HR: 0.78 (95% CI: ; P =.04)  Benefit persists > 12 yrs –May be limited to stage II and bulky (≥ 4 cm) stage IB NSCLC Vincent MD, et al. ASCO Abstract Graphic reproduced with permission. Disease Stage Median OS, Yrs Vin/CisObsP Value Stage II Stage IB  T < 4 cm  T ≥ 4 cmNR  Significantly higher cumulative incidence of disease-related deaths with obs vs chemo (P =.027) but nondisease-related death rates similar between arms (P =.660)

clinicaloptions.com/oncology New Issues in Staging and Adjuvant Treatment of Early-Stage NSCLC Adjuvant Chemotherapy: Lessons Learned  Agents –Platinum agents important –Probably cisplatin –Not enough data available on carboplatin in an appropriately powered study –Vinorelbine effective –Not enough data on other drugs with appropriate dose of cisplatin  Stage –II-IIIA –IB a question

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