Sublobar Resection and Intraoperative Brachytherapy for Lung Cancer: ACOSOG Update

1. Sublobar Resection and Intraoperative Brachytherapy for Lung Cancer:ACOSOG Update Rodney J. Landreneau, MD Professor of Surgery The Heart Lung and Esophageal Surgery Institute University of Pittsburgh Medical Center Surgical Treatment of Lung CancerRadiofrequency Ablation to VATS LobectomyNovember 13-14, 2008Pittsburgh, Pennsylvania

2. Surgical Resection of the Lung Standard of Care for Peripheral Nodules 1940’s Pneumonectomy 1960’s Lobectomy 1990’s ? Segmentectomy/Wedge (and adjuvant local/systemic Rx)

3. Background • Non-small cell lung carcinoma (NSCLC) identified in patients with impaired cardiopulmonary reserve creates important therapeutic challenges. • Sublobar pulmonary resection is often utilized in these patients, however, local recurrence is high (15-25%).

4. How Can Therapy to Customized for Patients with Poor Cardiopulmonary Reserve? • Primary external beam radiation therapy • ? survival • Chemotherapy • no defined role as primary therapy • Radiofrequency Ablation • ? survival • Sublobar resection • Sublobar resection with adjuvant radiation therapy

7. Background • Postoperative (postop) external radiotherapy following sublobar resection is time consuming and can result in additional loss of pulmonary function. • We review our experience using intra-operative 125I lodine brachytherapy following sublobar resection of stage I NSCLC in patients with impaired cardiopulmonary reserve.

8. Methods • From 1/1989 to 7/1994, 102 patients (mean age 69.5 years) with pathologic stage I NSCLC and poor cardiopulmonary reserve (mean % predicated FEV 1 preop = 65%) underwent sublobar resection as primary therapy. • We have since (1/1997 to 6/2002) introduced adjunctive intraoperative brachytherapy with 125I to sublobar resection among 96 stage I patients with similar cardiopulmonary compromise (mean % predicted FEV1 preop = 53%).

10. Methods • After resection, a vicryl™ implant containing 125I seeds, sewn at 1cm² intervals, was placed over the resection staple line covering a 2cm lateral margin. A local radiation does of 10,000 cGy was delivered. • No post-op patient isolation was required per national radiation safety guidelines • Mortality and morbidity, local recurrence and disease free survival have been compared.

18. Results • The FEV 1 did not change postoperatively in the sublobar resection with brachytherapy group in the interval of follow-up

19. Conclusions • Local recurrence of NSCLC following sublobar resection with intra-operative 125Ibrachytherapy (1%) appears to be less than following sublobar resection alone (18.6%). • This safe, pulmonary function preserving, and practical intra-operative brachytherapy method may be considered when sublobar resection is utilized as compromise therapy of stage I NSCLC.

20. ACOSOG Z4032 Sublobar Resection vs. Sublobar Resection with Intraoperative Brachytherapy for High Risk Stage IA Non Small Cell Lung Cancer Patients

21. SCHEMA REGISTRATION FOLLOW UP HistologicalconfirmationNSCLC andconfirmationN2/N3negative lymphnodes(if necessary)** ARM 1:SublobarResection(SR) Pre-Registration andRandomizationto Z4032 High riskpatients withsuspected orproven NSCLC ARM 2:SublobarResection +Brachytherapy(SRB)

22. Patient Selection

23. Eligibility Criteria Part I: Pre-Operative Criteria (Pre-Registration/Randomization): • Patients must have a suspicious lung nodule for clinical Stage I NSCLC. • Patient must have a mass ≤ 3cm maximum diameter by CT size estimate: Clinical stage Ia or selected Ib (i.e., with visceral pleural involvement. • Patient must have a CT scan of the chest with upper abdomen within 60 days prior to date of pre-registration.

24. Eligibility Criteria Part I: Pre-Operative Criteria (Pre-Registration/Randomization): • Patient must meet at least one major criteria or meet a minimum of two minor criteria as described below: • Major Criteria • - FEV1 ≤50% predicted - DLCO ≤ 50% predicted

25. Eligibility Criteria Part I: Pre-Operative Criteria (Pre-Registration/Randomization): • Minor Criteria • - Age ≥ 75 • - FEV1 51-60% predicated • - DLCO 51-60% predicated • - Pulmonary hypertension (defined as a pulmonary artery systolic pressure greater than 40mmHg) as estimated by echocardiography or right heart catheterization

26. Eligibility Criteria Part I: Pre-Operative Criteria (Pre-Registration/Randomization): • Minor Criteria • - Poor left ventricular function (defined as an ejection fraction of 40% or less) • - Resting or Exercise Arterial pO2 ≤55mm Hg or SpO2≤88% • - pCO2 45mm Hg • - Modified Medical Research Council (MMRC) Dyspnea Scale ≥3

27. Eligibility Criteria Modified Medical Research Council Scale

28. Eligibility Criteria Part I: Pre-Operative Criteria (Pre-Registration/Randomization): • Patient must not have had previous intra-thoracic radiation therapy. • Women of child-bearing potential must have negative serum or urine pregnancy test. • No prior invasive malignancy, unless disease-free for ≥ 5 years prior to pre-registration (Exceptions: non-melanoma skin cancer, in-situ cancers).

29. Eligibility Criteria Part II: Intra-Operative Criteria (Registration): • Patient must have biopsy-proven NSCLC. • Patient must have all suspicious mediastinal lymph (>1 cm short-axis dimension on CT scan or positive on PET scan) assessed by one of the following methods to confirm negative involvement with NSCLC (Mediastinoscopy, endo- esophageal ultrasound guided needle aspiration, CT-guided, video-assisted thoracoscopic or open lymph node biopsy).

30. ACOSOG Z4032 Accrual Summary • 174 Patients Accrued Nationally • Accrual Goal is 226 Patients • Estimated Study Closure - November 2009

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