In this month of Clinical Updates, Dr. Landreneau tackles the complexities of Stage IIIa non-small cell lung cancer and provides us with an organized framework for understanding the nuances of therapy in the context of clinically overt (bulky or PET/CT positive) vs. subclinical (microscopic) ipsilateral lymph node positive disease. Dr. Landreneau guides us through the landmark clinical trials that have shaped this particular arena, and identifies the subgroup differences in disease free and overall survival in the setting of induction and adjuvant chemoradiation. For example, the “stage migration” that occurs secondary to limitations in clinical staging methods often impacts the overall sequence of events in the delivery of multimodal therapy which have important implications for clinical outcome. He highlights the need for a personalized chemotherapeutic approach to a given individual’s tumor biology, which is bolstered by the observation of improved survival in complete responders to platinum based therapy. I hope you enjoy this important edition of Clinical Updates and that you can use it to the benefit of your patients.

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 TopicsMarch Research Edition April Minimally Invasive EsophagectomyMay Pulmonary MetastasectomyJune Lung Cancer Edition July Esophageal Motility Disorders

August Lung Cancer Staging TodaySeptember Swallowing Center Edition October Laryngopharyngeal RefluxNovember Alternatives to PneumonectomyDecember ELI Outcomes by Disease

Esophageal and Lung Institute

ALCHEMIST This NIH-funded group of studies, Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST), is a collection of three trials to identify patients with early-stage lung cancer who have tumors that contain uncommon genetic changes and evaluate whether drug treatments aimed at those changes can improve their survival.

ALCHEMIST Screening TrialParticipants enrolled in ALCHEMIST screening trial need to have been diagnosed with non-squamous NSCLC and must be planning to undergo surgery or have tissue available for testing.

ALCHEMIST Treatment Trials Participants with tumors found to contain EGFR mutations or rearrangement in the ALK gene will then be referred to one of the two randomized, placebo-controlled treatment trials evaluating specific drugs targeted against these genetic alterations, erlotinib and crizotinib, respectively.

Randomized Phase II Study of Pre-Operative Chemo-radiotherapy +/- Panitumumab followed by consolidation chemotherapy in potentially operable locally advanced (Stage IIIA, N2+) Non-Small Cell Lung CancerNSCLC patients who are going to have surgery will be randomized pre-operatively to receive chemo-radiation or chemo-radiation + panitumumab, a monoclocal antibody. The trial compares these two groups in relation to mediastinal lymph node response and assesses the impact on survival outcomes.

Blair A. Jobe, MD

Esophageal and Lung Institute

Clinical UpdatesManagement of Ipsilateral

Lymph node positive (Stage IIIa) Non-Small Cell Lung Cancer

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PET/ CT of stage IIIa non-small cell lung cancer

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

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

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. Saturday, April 11, 2015Magovern Conference Center Allegheny General Hospital, Pittsburgh, PA 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 June 6, 2015Edward Kent Lectureship in Thoracic OncologyHonored Guest Speaker: James R. Jett, MDNational Jewish Health, Denver, CO September 19, 2015Chevalier Jackson General Thoracic LectureshipHonored Guest Speaker: Nasser K. Altorki, MDNew York-Presbyterian/Weill Cornell Medical College, New York, NY

December 5, 2015George Liebler Thoracic Oncology LectureshipHonored Guest Speaker: Wayne Hofstetter, MDMD Anderson Cancer Center, Houston, TX

February 2015, Part II

Regionally Advanced NSCLC Trials

Management of Ipsilateral Lymph node positive (Stage IIIa) Non-Small Cell Lung Cancer

but small patient numbered, randomized studies demonstrated remarkable survival benefits with multimodality therapy compared to surgery alone.

Other investigators have examined the role of surgery following combined chemo-radiation therapy. The SWOG 8805 trial looked at the role of surgical resection following induction cisplatin / etoposide with 45 GY of thoracic irradiation.[8] Among responders to chemo-radiation therapy undergoing surgical resection, 85% were able to undergo complete resection and had a three-year survival of nearly 30%. Interestingly, those patients with sterilization of mediastinal metastasis noted at surgical resection had a three-year survival of over 40% compared to those patients with residual disease in the mediastinum (less than 20% survival at 3 years). This finding of the prognostic importance of sterilization of mediastinal disease has also held true for patients undergoing combined therapy in subsequent studies. The varying opinions regarding the most appropriate management of stage IIIa NSCLC are primarily spurred by the “heterogeneity” of disease extent within stage IIIa. Indeed, patients with “microscopic” mediastinal node involvement identified only at pathologic review of resected lung and nodal dissection specimens considered clinically to have stage I or II NSCLC are grouped with “bulky” clinically obvious mediastinal node involvement by radiographic evaluation[3] (Figure 1).

This is unfortunate as it appears from the above-mentioned work – and investigations to be discussed, that there is an important survival advantage associated with multimodality therapy (chemotherapy with possibleradiation therapy) combined with complete surgical resection among NSCLC patients with minimal

mediastinal node involvement (Figures 2a and b) (identified microscopically only or with small volume, single location mediastinal nodal involvement)[9] [TABLE I].

Support of tri-modality (including surgery) followed, due to improved survival among patients undergoing this therapy who had total clearance of their cancer. Confirmation of nodal sterilization was identified at final pathologic review of complete surgical resection.[8] Interestingly, many thoracic oncologists began to challenge the importance of surgery in this clinical setting, if chemo-radiation therapy apparently cleared the disease locally. These concerns led to the celebrated investigation of induction chemo-radiation therapy to 45 Gy followed by randomization to surgery or continuation of radiation therapy to 60 Gy [10]. Tumor progression-free survival favored patients of the surgical arm of the study (Figure 3), however, there was no significant difference in the overall survival between treatment arms (Figure 4). Subset analysis demonstrated that the primary deterrent of survival among the surgically treated patients was the need for pneumonectomy. The patient group undergoing pneumonectomy faired significantly less well than primary non-surgically treated patients (Figure 5). Conversely, surgical patients who could undergo complete resection with lobectomy had an importantly improved survival versus the non-surgical treated group (Figure 6). Additionally, as with earlier mentioned investigations[2,8], the greatest benefit from therapy was noted among the subset of surgical patients who had sterilization of mediastinal nodes with a five-year survival of 42% compared to patients with residual cancer in the mediastinal nodes following induction therapy and surgical resection – 24%.[10]

Modern radiographic evaluation with Computed Tomographic and Positron Emission Tomography (CT /PET) has led to identification of suspicious mediastinal nodal activity which would not have been identified with CT imaging alone (Figure 7). Before this CT/PET technology was made available to most medical centers in the first decade of this millennium, a significant number of patient with apparently clear CT studies were found to have microscopically positive lymph node involvement after surgical resection. This “surprise stage IIIa” pathololgic status may be the case from 15 to 30% of patients undergoing surgical resection for “clinical” stage I NSCLC.[1] This “clinical/pathologic stage shift” associated with the present

Rodney J. Landreneau, MDDivision Chief, General Thoracic SurgeryCo-Director of the Esophageal and Lung InstituteDirector of the Thoracic Oncology Program of the Allegheny Cancer Institute

Surgical resection remains the gold standard of care for physiologically fit patients with clinically “mediastinal node negative,” regionally limited (stage I), non-small cell lung cancer (NSCLC).[1] Lymph node positivity within the pulmonary parenchyma which is to be resected or limited to the ipsilateral pulmonary hilum (stage II) NSCLC is also managed primarily with surgical resection of all affected lung tissues; however, systemic

chemotherapy is recommended following recovery from surgery.[2]

The management of stage III NSCLC, which is defined primarily by the presence of peritracheal and mediastinal lymph node metastases, has long been a controversial topic among medical, radiation, and surgical thoracic oncologist.[3] Stage IIIa represents mediastinal lymph node involvement limited to the ipsilateral side of the trachea to that of the primary tumor. Stage IIIb primarily represents mediastinal spread of disease also to the contralateral mediastinal nodal basin. Stage IIIb disease is recognized to be beyond the scope of surgical resection with radiation therapy chosen to provide local control of the malignant process to the mediastinum. During the 1970s and 1980s, definitive thoracic radiation therapy alone was the standard of care for both stage IIIa and IIIb NSCLC, however, important investigations identified superior survivorship among stage III NSCLC patients undergoing “combined” platinum based chemotherapy and radiation therapy compared to radiation therapy alone. The results of these investigations demonstrating a doubling of long term survival from 9% with monotherapy to 18% with combined chemo-radiation therapy for stage III NSCLC have changed the therapeutic paradigm for this stage of regionally advanced disease. [4] Today, with modern platinum based chemotherapy regimens, objective response rates have been noted to occur in over 70% of stage III NSCLC patients treated. [5]

However, because of a high local and distant failure with such non-surgical management of stage III NSCLC, several investigators explored the utility of the addition of surgical resection following “induction” chemotherapy, particularly for anatomically resectable disease.[6,7] These independent clinical investigations performed in Europe and America demonstrated a significant improvement in survival among patients with resectable stage IIIa NSCLC managed with induction chemotherapy followed by complete surgical resection compared to similar patients undergoing surgery alone. Postoperative radiation therapy was variably applied following resection in investigations. Both of these influential,

Figure 1 Bulky mediastinal disease IIIa– PET/CT

Figure 2a Minimal mediastinal disease IIIa – CT

Figure 2b PET scan image of same patient with small right upper lobe PET positive nodule and ipsilateral “single station” occult peri-tracheal PET positive lymph node.

limitations of preoperative staging modalities (including PET/CT and endoscopic bronchial ultrasound (EBUS) – FNA biopsy evaluations) further supports the role of surgical resection in this age of “adjuvant chemotherapy” for resected IIIa NSCLC.

Based upon the common finding of “surprise” ipsilateral mediastinal node involvement (stage IIIa) following surgical resection of lung cancer, preoperatively presumed to be “clinically” node negative (stage I), several randomized trials have been performed demonstrating the value of adjuvant chemotherapy in this setting.[2,9,11] Note also that a potential local control and survival advantage has been speculated with adjuvant postoperative radiation therapy (PORT) in this setting of “surprise IIIa disease”.[12] This is based upon analysis of the SEER database, however, this has not been supported by any recent controlled clinical trial. The most important of these randomized studies was the IALT and the ANITA trials,[2,11] both conducted outside of the United States, demonstrating a 5 to 13% improvement in five-year survival for stage IIIa NSCLC patients treated with adjuvant chemotherapy compared to surgical resection alone (Figure 8). A subsequent meta-analysis of over 4,500 lung cancer patients undergoing resection followed by adjuvant chemotherapy (LACE) demonstrated an overall 5% survival benefit among patients with stage IIIa disease compared to resected IIIa patients without adjuvant therapy.[13]

Further improvements in survival with multimodality therapy for IIIa NSCLC is anticipated with the advent of individualized therapies based upon molecular biologic characteristics of the tumor suggestive of enhanced response to a specific systemic therapy. Conversely, “individualized” lung cancer patient benefit may be achieved through the avoidance of ineffective local and systemic therapies, through similar molecular biologic assessments of tumor biology.

References1. Landreneau RJ, Normolle DP, Christie NA, et al. Recurrence and survival ouctomes after anatomic segmentectomy versus lobectomy for clinical stage I non-small-cell lung cancer. A propensity-matched analysis. J Clin Oncol 2014;10:32:2449-2455.2. Douillard JY, Rosell R, Delena M. 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 randomized controlled trial. Lancet Oncol 2006;7:719-729.3. Goldstraw P. The International Association for the Study of Lung Cancer International Staging Project on Lung Cancer. J Oncology 2006;1:191-203.4. Dillman RO, Herndon J, Seagren SL Eaton WL JR, Green MR. Improved survival in stage III non-small-cell lung cancer: seven year follow-up of cancer and leukemia group B (CALGB) 8433 trial. J Natl Cancer Inst 1996;88:1210-1215.5. O’Brien ME, Splinter T, Smitt EF, et al. EORTC Lung Cancer Group. Carboplatin and paclitaxel (Tacol) as an induction regimen for patients with biopsy-proven stage IIIA N2 non-small cell lung cancer. An EORTC phase II study ( EORTC 08958). Eur J Cancer 2003;29:1416-1422.6. Rosell R, Maestre J, Font A, et al. A randonmized trial of mitomycin/ifosfamide/cisplatin preoperative chemotherapy plus surgery versus surgery alone in stage IIIA non-small cell lung cancer. Semin Oncol 1994;21 (3 suppl 4):28-33.7. Roth JA, Fossella F, Komaki R, et al. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung Cancer. J Natl Cancer Inst.1994;86:673-680.8. Albain KS, Rusch VW, Crowley JJ et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed b surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group Phase II study 8805. J Clin Oncol 1995;13:1880-1892.9. DeCamp MM, Ashiku S, Thurer R. The role of surgery in N2 non-small cell lung cancer. Clin Cancer Res 2005;11(13 PT 2):5033s-5037s.10. Albains KS, Swann RS Rusch VW, et al. Radiotherapy plus chemotherapy with oro without surgical resection for stage III non-small-cell lung cancer. A phase III randomized trial. Lancet 2009;374:379-386.11. Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J. International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004;350:351-360.12. Lally BE, Zelterman D, Colasanto JM, Haffty BG, Detterbeck FC, Wilson LD. Postoperative radiotherapy for stage II and III non-small-cell lung cancer using the Surveillance, epidemiology, and end results database. J Clin Oncol 2006;24:2998-3006.13. Pignon JP, Tribodet H, Scagliotti GV, et al. LACE Collaborative Group. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 2008;26:3552-3559.

Table 1 Characteristics for favorable results with combined modality therapy (including surgery)

Single level, non-bulky mediastinal node involvement vs. multi-level bulky/matted mediastinal nodal involvement

Microscopic “surprise” limited, mediastinal node involvement identified on pathologic review of resected clinical stage I disease

Complete surgical resection less than pneumonectomy (lobectomy) after induction chemo-radiation therapy

Pathologic evidence of complete sterilization of mediastinal lymph nodes in pathologic surgical specimen Figure 3 Differences in progression-free survival. Chemo-

radiation/surgery VS. chemo-radiation therapy alone. – Ref. 10.

Figure 4 Differences in Overall survival. Chemo-radiation/surgery VS. chemo-radiation therapy alone. – Ref. 10.

Figure 5 Chemotherapy/radiation followed by pneumonectomy survival vs non-surgical therapy – Ref. 10.

Figure 6 Chemotherapy / radiation followed by lobectomy vs non-surgical therapy survival curve – Fig. 10.

Figure 7 PET /CT image of small paratracheal PET positive node which would not have been suggestive of metastatic involvement by CT scanning alone.

Figure 8 Surgical resection of surprise (stage I –IIIa NSCLC) followed by adjuvant chemotherapy for surprise IIIa disease. Ref. 2