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Esophageal and Lung Institute
February 2015, Part II
Esophageal and
Lung Institute
Clinical Updates
Blair Jobe, MD
Director ELI
A Message from the Director
Rodney J. Landreneau, MD
Co-Director ELI
Management of Ipsilateral
Lymph node positive (Stage IIIa)
Non-Small Cell Lung Cancer
ELI surgeons
Toshitaka Hoppo, MD
Mathew VanDeusen, MD
Lana Schumacher, MD
ELI Pulmonary Medicine
Marvin Balaan, MD
Denise Swidwa, MD
Steven Sotos, MD
Giath Shari, MD
Terry Obringer, DO
Regionally Advanced NSCLC Trials
ELI Gastroenterology
Shyam Thakker, MD
Abhijit Kulkarni, MD
Manish Dhawan, MD
Marcia Mitre, MD
Katie Farah, MD
Ricardo Mitre, MD
Suzanne Morrissey, MD
Esophageal & Lung Institute Visiting Lectureship Series
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 Trial
Bernard Dallemagne Lectureship
Esophageal
& Lung
Institute Visiting Lectureship Series
in
Surgical
Innovation
Bernard Dallemagne Lectureship
in Surgical Innovation
Inaugural presentation by Bernard Dallemagne, MD
Saturday, April 11, 2015
Magovern Conference Center
Allegheny
General
Hospital by Bernard Dallemagne, MD
Inaugural
presentation
Pittsburgh, Pennsylvania
Saturday, April 11, 2015
Magovern Conference Center
Allegheny General Hospital
Pittsburgh, Pennsylvania
Participants 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 Cancer
NSCLC 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
©2015 AHN
and assesses the impact on survival outcomes.
An equal opportunity employer.
All rights reserved.
AHN-35077 jz/pt
sponsored by
The Esophageal and Lung Institute
Allegheny Health Network
Pittsburgh, Pennsylvania
Clinical Update
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, 2015
Magovern 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, 2015
Edward Kent Lectureship in Thoracic Oncology
Honored Guest Speaker: James R. Jett, MD
National Jewish Health, Denver, CO
September 19, 2015
Chevalier Jackson General Thoracic Lectureship
Honored Guest Speaker: Nasser K. Altorki, MD
New York-Presbyterian/Weill Cornell Medical College, New York, NY
December 5, 2015
George Liebler Thoracic Oncology Lectureship
Honored Guest Speaker: Wayne Hofstetter, MD
MD Anderson Cancer Center, Houston, TX
Medical Oncology
Eugene Finley, MD
Moses Raj, MD
Scott Long, MD
Casey Moffa, DO
Jane Raymond, MD
Antonios Christou, MD
Dulabh Monga, MD
Larisa Greenberg, MD
Shifeng Mao, MD
Jason Thomas, MD
David Mayernik, MD
Helen Analo, MD
Radiation Oncology
David Parda, MD
Athanasios Colonias, MD
Patrizia Guerrieri, MD
Steven Anolik, MD
Rheumatology
Mary Chester Wasko, MD
Michael Lucke, MD
ELI Research
Ali Zaidi, MD
Emily Lloyd, CCRC
Kelli S. Davis, RN, MSN-CNL, OCN
Lead Physician Extender
Kim Swendsen, CRNP
Blair A. Jobe, MD, FACS,
Director, Esophageal &
Lung Institute
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
PET/ CT of stage IIIa non-small
this particular arena, and identifies the
cell lung cancer
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.
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
Upcoming Topics
March
April May
June
July
Research Edition
Minimally Invasive Esophagectomy
Pulmonary Metastasectomy
Lung Cancer Edition
Esophageal Motility Disorders
August
September
October
November
December
Lung Cancer Staging Today
Swallowing Center Edition
Laryngopharyngeal Reflux
Alternatives to Pneumonectomy
ELI Outcomes by Disease
Swallowing Center
Joan Schrenker, RN, CGRN
Speech Pathology
Paula Tirpak, MS,CCC/SLP
Dietitian
Rachel Harkin, MS, RD, LDN
ELI Clinical Update Mission:
To provide healthcare professionals with focused and timely coverage of important
clinical topics which affect the esophagus and lung.
Management of Ipsilateral Lymph node positive (Stage IIIa)
Non-Small Cell Lung Cancer
Rodney J. Landreneau, MD
Division Chief, General Thoracic Surgery
Co-Director of the Esophageal and Lung Institute
Director 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,
Table 1 Characteristics for favorable results with
combined modality therapy (including surgery)
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 abovementioned work – and
investigations to be discussed,
that there is an important
survival advantage associated
with multimodality therapy
(chemotherapy with possible
radiation therapy) combined
with complete surgical
Figure 1 Bulky mediastinal disease
resection among NSCLC
IIIa– PET/CT
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].
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.
Single level, non-bulky mediastinal node involvement vs.
multi-level bulky/matted mediastinal nodal involvement
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.
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.
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
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]
Figure 6 Chemotherapy / radiation followed by lobectomy vs
non-surgical therapy survival curve – Fig. 10.
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.
References
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.
1. 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;13:18801892.
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;350:351360.
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.
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