Stage III Non-Small Cell Lung Cancer, Is There Any Progress? HARMESH R NAIK, MD. KARMANOS CANCER INSTITUTE 2/24/99

Stage III Non-Small Cell Lung Cancer, Is There Any Progress? HARMESH R NAIK, MD. KARMANOS CANCER INSTITUTE 2/24/99

Introduction 1/3 of the total lung cancer cases few patients are cured with single modality Majority requires multi-modality therapy systemic and local control

Progress in last few years Cisplatin based chemotherapy (with RT) improves long term outcome Concurrent chemo-rt may cure 30-40% Newer chemotherapy regimens in stage IV Advances in staging (PET Scan)

Questions remaining Is surgery necessary for all? Optimal Induction: C or C-RT Concurrent or sequential C-RT What chemotherapy drugs and what schedule Radiation dose and fractionization

Interpretation of data: current problems Variable staging methods CT + mediastinoscopy: IIIA or IIIB Uniform staging comparison Heterogeneity of the disease T3N0 is now IIB T4N1 and T2N3 PS and weight loss criteria

Interpretation of data (cont.) Endpoints: Survival: most useful, 2 or 5 years Response rate: commonly reported Down staging data CR

Evaluation Crucial in planning treatment Performance status: single most imp Weight loss Co-morbid conditions Age: not a deterrent

Staging History and Physical exam, PS CBC, chemistry Chest x-ray, CT chest with liver & adrenals 10-30% false neg. for mediastinum 25-35% false positives CT or MRI brain:? cost-effectiveness Bone scan:? cost-effectiveness

Staging (ct.) Bronchoscopy Mediastinoscopy: Uniform staging,? N2 or N3 low morbidity (1-2%) and mortality (<0.1%)?PET scan Thoracoscopy PFTs & Quantitative V/Q scan

Multi-modality options Surgical resection?c +?RT (Adjuvant) Induction Surgery (Neo-adjuvant) Preop-Chemo Preop-chemo-RT Definitive chemo-rt Concurrent: C-RT Sequential: C RT

Surgery (IIIA only) Mayo (Sawyer et al.) 75% had one nodal station involved 22% 5 year survival Martini et al. Microscopic N2: 29% at 5 years Clinical N2: 8 % at 5 years

Surgery (IIIA only): (ct.) Few are candidates Neg mediastinoscopy: 90% resectable Without mediastinoscopy: 50% resectable Highly selected series: 20% cure Microscopic N2 does better than clinical N2 Reasonable for CT + m.scopy neg. pts

Radiation alone for stage III Cures <10% Many with poor PS 5-10% 5 yr survival historically 3-6% 5 yr. in phase III RT arms BID same CHART may be better

Induction chemotherapy Radiation Definitive sequential Improved survival when added to RT Better than RT alone in selected patients Meta-analysis confirmed the advantage Most +ve studies used platinum agent May include IIIB patients

Definitive sequential Au. Arm Med. 2yr 5yr Dillman CT+RT 13.7m 26% 17% RT 9.5m 13% 13% Le Che CT+RT 12m 21% 6% RT 10m 14% 3%

Definitive sequential(cont.) An RTOG study confirmed above. Mattson et al. And Gregor et al.: Negative Considered standard by many PS and Weight loss are important in selection of patients

Concurrent chemo-rt Phase II trials: Full dose RT (up to 70 Gy) Median survival 13-19 months 2 year survival 24-26% Concurrent vs Sequential (Furuse et al.) longer survival in concurrent group

Concurrent chemo-rt Taxol-Carboplatin with RT two small phase II studies 39% 3 year survival (Belani et al.) esophagitis is a concern need confirmation

Neoadjuvant chemo Surgery Randomized trials better med. Surv., 2 yr and 5 yr survival small trials,? Stagin methods Meta-analysis: 5% improvement All used Cisplatin based Chemotherapy Benefit because of distant control Similar resection rates

Neoadjuvant chemo Surgery Rosell et al: MIP chemotherapy Med surv 26 vs 8 m resection 90 vs 77% 5 yr survival 8 vs 0% Local reccurence 54% Distant failure 55% Included 27% T3N0-1 staged pts.

Neoadjuvant chemo Surgery Roth et al.: CEP chemotherapy Med surv 64 vs 11m 2 and 3 yr survival 60 vs 25% & 56 vs 15% Complete resection 39 vs 31% 5 yr survial 40 vs 18% 27% T3N0-1 patients

Neoadjuvant chemo Surgery NCI and CALGB trials: No benefit phase II trials 65-75% Response Rates 15-19m median survival 17-19% 5 yr survival may cure 20% of the patients newer drugs may be better

Induction chemo-rt Surgery Attempts maximum synergy Phase II trials (several) & 1 phase III: median survival 13-25 months 5 yr survival 22-37% (pt selection) Preop RT dose: 45 Gy Cisplatin based chemotherapy BID RT is under investigation

Is Surgery needed for all stage III patients after induction therapy? Non surgical trials: 6-23% 5 yr survival Surgery included: 17-37% 5 yr survival 5-15% have pathological CR at surgery CR is needed for cure current ongoing intergoup study chemo-rt vs same surgery

Summary results RT alone 5-10% 5 yr survival Surgery alone Mediastinoscopy +N2: 9% Incidental N2: 24% Induction therapy: 17-37% pre-op chemo: 17-19% pre-op chemo-rt: 22-37%

What is the optimal induction strategy? Unclear answers at present Chemo alone or chemo-rt surgery Timing of RT Once a day or BID RT Which chemotherapy? How many cycles?

Chemotherapy followed by chemo-rt CALGB trial Induction chemotherapy with 4 different chemotherapy regimens x 2 cycles RT follows with concurrent chemotherpy Vinorelbine, Paclitaxel and Gemcitabine in combination with platinum agents currently ongoing

Future therapies Antiangiogenesis agents Tumor vaccines Gene replacement therapy Antisense oligonucleotides?? 50% 5 year survival

What should we do until then? Aggressive staging IIIA: Induction therapy surgery Induction chemo or chemo-rt IIIB or poor risk IIIA Chemo-RT (definitive) Negative mediastinoscopy: Surgery alone +? adjuvant therapy