Approaching early stage disease Surgery vs SBRT vs RFA Ramesh Rengan MD PhD Chief, Thoracic Service Assistant Director of Clinical Operations Department of Radiation Oncology November 16, 2012

DISCLOSURES Speaker Honoraria Philips Healthcare

Introduction: The Scope of the Problem 213,380 patients are diagnosed yearly with lung cancer in the US with approximately 160,390 deaths

What is “Early Stage” Disease? IA T1N0M0 IB T2aN0M0 IIA T2bN0M0 T1N1M0 T2aN1M0 IIB T2bN1M0 T3N0M0 Technically resectable disease without evidence of mediastinal involvement

Prognosis 5yr OS Stage IA 75% Stage IB 55% Stage IIA 50% Stage IIB 40% Small Cell Ca: Limited Stage 15-25% 5yr OS, Extended stage 3% 5yr OS 5yr OS Stage IA 75% Stage IB 55% Stage IIA 50% Stage IIB 40% Stage IIIA 10-35% Stage IIIB 5-8% Stage IV <5%

Medical Operability 2007 ACCP Guidelines Colice GL. Physiologic Evaluation of the Patient With Lung Cancer Being Considered for Resectional Surgery*: ACCP Evidenced-Based Clinical Practice Guidelines (2nd Edition). The preoperative physiologic assessment should begin with a cardiovascular evaluation and spirometry to measure the FEV1. If diffuse parenchymal lung disease is evident on radiographic studies or if there is dyspnea on exertion that is clinically out of proportion to the FEV1, the diffusing capacity of the lung for carbon monoxide (Dlco) should also be measured. In patients with either an FEV1 or Dlco < 80% predicted, the likely postoperative pulmonary reserve should be estimated by either the perfusion scan method for pneumonectomy or the anatomic method, based on counting the number of segments to be removed, for lobectomy. An estimated postoperative FEV1 or Dlco < 40% predicted indicates an increased risk for perioperative complications, including death, from a standard lung cancer resection (lobectomy or greater removal of lung tissue). Cardiopulmonary exercise testing (CPET) to measure maximal oxygen consumption (V̇o2max) should be performed to further define the perioperative risk of surgery; a V̇o2max of < 15 mL/kg/min indicates an increased risk of perioperative complications. Alternative types of exercise testing, such as stair climbing, the shuttle walk, and the 6-min walk, should be considered if CPET is not available. Although often not performed in a standardized manner, patients who cannot climb one flight of stairs are expected to have a V̇o2max of < 10 mL/kg/min. Data on the shuttle walk and 6-min walk are limited, but patients who cannot complete 25 shuttles on two occasions will likely have a V̇o2max of < 10 mL/kg/min. Desaturation during an exercise test has not clearly been associated with an increased risk for perioperative complications. Lung volume reduction surgery (LVRS) improves survival in selected patients with severe emphysema. Accumulating experience suggests that patients with extremely poor lung function who are deemed inoperable by conventional criteria might tolerate combined LVRS and curative-intent resection of lung cancer with an acceptable mortality rate and good postoperative outcomes. Combining LVRS and lung cancer resection should be considered in patients with a cancer in an area of upper lobe emphysema, an FEV1 of > 20% predicted, and a Dlco of > 20% predicted. 2007 ACCP Guidelines Age alone is not a reason to deny resection. Operative mortality for a lobectomy: ~2% for age < 60, ~8% for age > 70 General targets: FEV1 > 1.5L FEV1 > 80% pred DLCO > 60-80% pred Danger signs: FEV1 or DLCO < 40% predicted FEV1/FVC < 50% PCO2 > 50mmHg Cor pulmonale VO2 < 15cc/kg/min Or, ability to walk 1 flight of stairs

Treatment for Early Stage Operable Disease NSLCL, if resectable, should be treated surgically. Contradindications to surger: Spread of tumor beyond the hemithorax incl SCV node involvement, malig pleural effusion, recurrent laryn nerve paralysis, medical inoperability, patient refusal, presence of med LN mets However, some patients with limited mediastinal LN mets remain surgical candidates Lobectomy + Mediastinal LND or LNS Remains current standard of care ACOSOG Z0030 With appropriate pt selection, periop mortality rates are low Pneumonectomy 5% Lobectomy 1-3% Smaller Resections < 1%

Treatment for Early Stage Operable Disease: ACOSOG Z0030 1111 patients enrolled; 1023 randomized Extensive MLNS followed by observation vs MLND No difference in overall survival Darling et al J Thoracic and CV Surgery, 2011

Treatment for Early Stage Operable Disease: Is there a lumpectomy for the lung?

Treatment for Early Stage Operable Disease: Is there a lumpectomy for the lung? LCSG showed trend towards increased likelihood of death with limited resection LCSG showed three-fold increase in local failure with wedge resection vs. lobectomy

Medically Inoperable Early Stage: Role of RT Cor pulmonale Severe coronary artery disease Renal failure Poor pulmonary function DLCO <50% FEV1/FVC ratio < 50 – 75% of predicted Impaired nutritional status

Medically Inoperable Early Stage: Role of RT Study Author n Dose (Gy) 5-yr survival 5-yr CSS 5-yr local Dosoretz 152 60-69 10% Krol 108 60-65 15% 31% 25% Kaskowitz 53 63 6% 13% 0% Sibley 141 55-70 Rosenzweig 32 70.2 33% 39% 43%

Medically Inoperable Early Stage: SBRT Nyman et al Lung Cancer 2006

Fractionation Options Conventionally fractionated radiotherapy - small daily doses - go to very high cumulative doses Ablative radiotherapy - very high daily doses (8-20 Gy) - overwhelm tumor repair - causes “late” effects that may be intolerable

Dose Fractionation: Implications for Tumor Control 100 2 4 6 8 Survival Dose (Gy) 10-1 10-2 single fraction multiple 2 Gy fractions

Early Stage Disease: Stereotactic Body Radiation Therapy Pretreatment 6-weeks Post-treatment

Medically Inoperable Early Stage: SBRT Author # of Patients Local Control Overall Survival Onishi et al. 245 85% 56% (3-yr) Timmerman 70 98% 55% (2-yr) Nyman 45 80% 71% (2-yr) Baumann 57 92% 60% (3-yr) Nagata 31 79% (2-yr) Uematsu 50 94% 66% (3-yr) Koto 78% 72% (3-yr) Fakiris 88% 43% (3-yr)

Dose Fractionation: Implications for Tumor Control 100 multiple 2 Gy fractions Survival 10-1 single fraction 10-2 2 4 6 8 Dose (Gy)

Medically Inoperable Early Stage: Toxicity of SBRT Corradetti et al NEJM 2012 JCO 2006 RTOG 0813 is currently accruing Would not treat centrally located tumors with SBRT off-protocol Standard of care for peripheral medically inoperable NSCLC p = 0.003

SBRT: Emerging toxicity data

Treatment of Early Stage Inoperable Disease: RFA

Treatment of Early Stage Inoperable Disease: RFA Multicenter prospective trial of 106 patients with 183 lung tumors 33 patients with NSCLC 48% 2-year survival 73% 2-year CSS 10% pneumothorax rate Median hospital stay 3 days Lancioni Lancet Oncol 2008

RFA: Emerging toxicity data

Early Stage NSCLC: Conclusions Lobectomy + MLNS or MLND With adjuvant chemotherapy +/- RT in high risk cases NCCN Guidelines, 2012