Lectureship Overview:The purpose of this lectureship series is to bring in outside thought leaders in the field of esophageal and lung surgery who are innovators in the field. The visit is designed for the exchange of ideas and to enrich and energize practitioners, faculty, trainees and staff.

Objective: • Review the current medical and surgical approaches to the treatment of GERD • Discuss recent innovations made in the diagnosis and treatment of GERD and laryngopharyngeal reflux (LPR) • Describe outcomes and complications of surgical and endoscopic therapies for GERD September 18, 2015Chevalier Jackson General Thoracic LectureshipHonored Guest Speaker: Nasser K. Altorki, MDNew York-Presbyterian/Weill Cornell Medical College, New York, NY

December 4, 2015George Liebler Thoracic Oncology LectureshipHonored Guest Speaker: Wayne Hofstetter, MDMD Anderson Cancer Center, Houston, TX

In this issue of Allegheny Health Network Esophageal and Lung Institute’s Clinical Update, Dr. Lana Schumacher provides a background in the clinical utility of resection of lesions from remote primary malignancies that have metastasized to the lungs. The first pulmonary metastasectomy combined with chest wall resection was performed by the European thoracic surgical pioneer Weinlecher in 1882. Giants of thoracic surgery/oncology, Tudor Edward – metastatic sarcoma (1927), Churchill and Bailey – renal cell cancer (1933), and Blaylock - colon cancer (1944) led the way in suggesting a potential role for pulmonary metastasectomy in the first half of the twentieth century. Nevertheless, controversy regarding the role of resection of metastases to the lungs has continued over the years.

Metastasis to the lungs is a relatively common event noted among patients with untreated or recurrent cancers originating from other organs. The organ of origin of the primary malignancy and the extent of pulmonary involvement by the metastatic process are key determinants of success with pulmonary metastasectomy. Certainly, other factors such as the absolute number of metastatic lesions present and the interval of time from the initial management of the primary malignancy and the appearance/recognition of the lung metastases are important in deciding for or against pulmonary metastasectomy. Importantly, tumor biology is the paramount determinant affecting the clinical course for these patients. These points are emphasized by Dr. Schumacher in this overview.

Dr. Schumacher, a graduate of the general surgical program at Stanford University, obtained her cardiothoracic surgical training at UPMC. She is a leading proponent of minimally invasive thoracic surgery, and, particularly, robotic-assisted thoracic surgery for a number of thoracic surgical problems. We hope that this overview of the role of pulmonary metastasectomy and the other editions of the ELI Clinical Update series assist you in the management of your patients with esophageal and lung problems.

Esophageal and Lung Institute Clinical UpdateA Message from the Director

Rodney J. Landreneau, MD, Co-Director, Esophageal and Lung Institute, Chief of the Division of Thoracic Surgery, and System Director of Thoracic Oncology

Blair A. Jobe, MD, FACS, Director, Esophageal & Lung Institute

Blair Jobe, MD Director ELI

Rodney J. Landreneau, MD Co-Director ELI ELI SurgeonsToshitaka Hoppo, MDMathew VanDeusen, MDLana Schumacher, MD ELI Pulmonary MedicineMarvin Balaan, MDDenise Swidwa, MDSteven Sotos, MD Giath Shari, MDTerry Obringer, DO ELI GastroenterologyShyam Thakker, MDAbhijit Kulkarni, MDManish Dhawan, MDMarcia Mitre, MDKatie Farah, MDRicardo Mitre, MDSuzanne Morrissey, MD

Medical OncologyEugene Finley, MDMoses Raj, MDScott Long, MDCasey Moffa, DOJane Raymond, MD Antonios Christou, MD Dulabh Monga, MD Larisa Greenberg, MDShifeng Mao, MDJason Thomas, MDDavid Mayernik, MDHelen Analo, MD

Radiation OncologyDavid Parda, MDAthanasios Colonias, MDPatrizia Guerrieri, MDSteven Anolik, MD

RheumatologyMary Chester Wasko, MDMichael Lucke, MD

ELI ResearchAli Zaidi, MDEmily Lloyd, CCRCKelli S. Davis, RN, MSN-CNL, OCN

Lead Physician ExtenderKim Swendsen, CRNP

Swallowing CenterJoan Schrenker, RN, CGRN

Speech PathologyPaula Tirpak, MS,CCC/SLP

DietitianRachel Harkin, MS, RD, LDN

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ELI Clinical Update Mission: To provide healthcare professionals with focused and timely coverage of important clinical topics which affect the esophagus and lung.

Upcoming TopicsJune Lung Cancer Edition July Esophageal Motility DisordersAugust Lung Cancer Staging TodaySeptember Swallowing Center Edition

October Laryngopharyngeal RefluxNovember Alternatives to PneumonectomyDecember ELI Outcomes by Disease

Esophageal and Lung Institute

Rodney J. Landreneau, MD

Esophageal and Lung Institute

Clinical UpdatesPulmonary metastasectomy

May 2015

s p o n s o r e d b y

The Esophageal and Lung Institute Allegheny Health NetworkPittsburgh, Pennsylvania

Esophageal & Lung Institute Visiting Lectureship Series

Bernard Dallemagne Lectureship in Surgical InnovationInaugural presentation by Bernard Dallemagne, MD

Saturday, April 11, 2015Magovern Conference CenterAllegheny General HospitalPittsburgh, Pennsylvania

Rainfall Trial – (Eli Lilly)This randomized, placebo-controlled clinical trial compares Capecitabine / Cisplatin with or without Ramucirumab for patients with metastatic gastric or gastroesophageal adenocarcinoma. Primary objective is comparison of progression free survival (PFS) outcomes. Ramucirumab (Cyramza) is a fully humanized monoclonal antibody targeting VEGFR2. Approximately 800 patients nationwide will be recruited.

CALGB 140503 – The “Altorki” TrialRandomized phase 3 NIH supported trial comparing sublobar resection to lobectomy for Stage 1A Non-small cell lung cancer (NSCLC). Patients are preregistered based upon tumor diameter ≤ 2 cm on preoperative CT imaging. Intraoperatively, patients are randomized to receive sublobar resection versus lobectomy after confirmation of pathologic negative mediastinal and hilar nodes. Primary aim is to assess survival and recurrence differences between less than lobectomy to lobectomy for this early stage NSCLC population.

GO29436 and GO29437 (Genentech/Roche)GO29436 is a randomized, Phase III, multicenter, open-label study designed to evaluate the safety and efficacy of MPDL3280A (PDL-1 inhibitor) in combination with carboplatin + paclitaxel with or without bevacizumab compared with treatment with carboplatin + paclitaxel + bevacizumab in chemotherapy-naïve patients with Stage IV non-squamous NSCLC.

GO29437 is a randomized, Phase III, multicenter, open-label study designed to evaluate the safety and efficacy of MPDL3280A (PDL-1 inhibitor) in combination with carboplatin + paclitaxel or with carboplatin + nab-paclitaxel compared with treatment with carboplatin + nab-paclitaxel in chemotherapy-naïve patients with Stage IV squamous NSCLC.

Both of these industry-supported trials require tumor tissue to test PDL- status prospectively, which will be used for treatment response stratification. The objective of both trials is to test the efficacy of MPDL3280A in the intent-to-treat (ITT) population as measured by investigator-assessed progression-free survival (PFS). MPDL3280A targets human programmed death−ligand 1 (PD-L1) and inhibits its interaction with its receptors, constitutively improving immune response to tumor antigens.

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ELI Trials

Esophageal and Lung Institute Visiting Lectureship Series

Chevalier Jackson General Thoracic LectureshipHonored Guest Speaker: Nasser K. Altorki, MD

Pulmonary Metastasectomy

Pulmonary metastasis are usually asymptomatic and only 10-15% have symptoms including cough, hemoptysis, chest pain or spontaneous pneumothorax. Computed tomography is the modality of choice for detection. The sensitivity of conventional CT was 100% for nodules measuring 10 mm. High resolution CT with thin slices of 3 mm, has a sensitivity of 88.8% for all nodules and specifically the sensitivity for 1-4 mm nodules was 74.7%.4 Two thirds of the metastasis are found in the periphery of the lung and are typically a well circumscribed nodule. Surgical ResectionComplete resection of all the disease with clear margins and preserving lung function is the goal of pulmonary metastasectomy. Traditionally the approach has been with an open thoracotomy, median sternotomy or bilateral anterior thoracotomies depending on the bilaterality or central location. Now most surgeons are offering a minimally invasive surgery with a VATS (video-assisted thoracoscopic surgery) approach. This minimally invasive approach provides excellent exposure of the lung surface, reduces surgical trauma, minimizes postoperative pain, provides earlier patient mobilization and decreases hospital length of stay. Pulmonary metastases are often small nodules located in the periphery allowing wedge resections with a VATS approach to be very suitable. Initially there was concern that the VATS approach would miss metastases due to the inability to manually palpate the entire lung, however with improved imaging, studies have shown comparable survival rates compared to thoracotomy.5 VATS also offers the advantage of repeat operations with fewer adhesions without the morbitidy of a repeat thoracotomy. Recurrence of disease and repeat surgeryRecurrence of disease after pulmonary metastasectomy is not uncommon. In the International Registry of Lung Metastases, the rate of recurrence of disease was 54% for all patients who underwent complete resection. The rate of recurrence varied among tumor types. Sarcoma and melanoma recurred more frequently than epithelial tumors (64% vs 46%). The site of recurrence differed with

sarcomas recurring most frequently intrathoracic (66%) compared to melanoma for which the relapse was extrathoracic (73%). The 5 year survival for all patients with repeat surgery was 44%.6

ConclusionPatients with untreated metastatic disease have a 5 year survival rate of less than 5-10% and for a patient with isolated metastatic disease to the lungs, pulmonary metastasectomy is often the best hope for prolonged survival. It is a safe and effective treatment. Complete resection is the most important factor for improved survival. Low morbidity and mortality rates, and lack of any other effective systemic treatments, justify this aggressive approach for surgery. Minimally invasive thoracoscopic resection is a valid option for patients with few, peripherally located metastases. Recurrence of pulmonary disease also warrants repeat metastasectomy. Patients should be treated in a multidisciplinary fashion with close collaboration of the thoracic surgeon, medical oncologist and radiologist.

Lana Schumacher, MD, Director of eastern regionEsophageal and Lung InstituteAssistant Professor, Temple UniversityDepartment of Cardiothoracic SurgeryMcGinnis Thoracic and Cardiovascular Surgery

Pulmonary metastasectomy is the surgical resection of metastases in the lung. The first series of pulmonary metastasectomies was published in 1947 by Alexander and Haight. The lungs are one of the most common organs to which cancer metastasizes, and approximately 30% of all cancer patients will develop lung

metastasis at some point.1 Pulmonary metastasectomy from a primary tumor elsewhere is widely believed to improve survival in selected patients. Most resections are performed in patients with a long disease-free interval with few metastases limited to one or both lungs from a variety cancer types. In patients with a solitary or few metastases with intervals longer than 2–3 years from resection of the primary tumor to metastasectomy, 5-year survival rates of 30–50% are recorded. 1 These survival rates in these patients are superior to any other treatment. Appropriate patient selection for metastasectomy is important for successful outcomes. Some adverse prognostic factors include rapid tumor doubling time, shorter disease free interval and number of metastases, however no clear cut off beyond which resection is useless has been defined.2 Most strongly support the selection criteria listed below:3

Selection Criteria:

The primary tumor is controlled or is controllable

No extrapulmonary tumor exists

No better method of proven treatment value is available

Adequate medical status for planned resection

Complete resection is possible based on computed tomographic evaluation

Long Term Survival After Pulmonary Metastasectomy by Primary Tumor, International Registry of Lung Metastasis 6

Tumor Type No. Patients 5 Year Survival % 10 Year Survival % Median Survival (Mo)

Epitheilial

Overall 1894 37 21 40

Colorectal 653 37 22 41

Breast 411 37 21 37

Kidney 402 41 24 41

Sarcoma

Overall 1917 31 26 29

Osteosarcoma 734 33 27 40

Soft Tissue 938 30 22 27

Melanoma 282 21 14 19

Germ Cell 318 68 63 -

References1. Davidson RS et al. The surgical management of pulmonary metastasis: current concepts. Surg Oncol 2001; 10:35-422. Hornbech K et al. Current status of pulmonary metastasectomy. Euro Assoc for cardiothoracic Surg. 20103. Landreneau RJ et al. Therapeutic VATS surgical resection of colorectal pulmonary metastasis. Eur J Cardiothorac Surg 2000;18:671-6764. Pastorino U et al. Pearson’s Thoracic and Esophgeal Surgery, 3rd Edition 20085. Pfannschmidt J et al. Thorac Cardiovasc Surg 2008; 56:471-4756. Long term results of metastasectomy; prognostic analysis based on 5206 cases. The International Registry of Lung Metastases. J Thorac Cardiovasc Surg 1997;113-37-49.

CT of the chest revealing Metastatic Sarcoma

CT of the chest: Metastatic Germ Cell

Intercostal incisions used to accomplish pulmonary metastasectomy.

Dr. Lana Schumacher performing minimally invasive thoracoscopic resection.