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The role of surgery in the treatment of locally advanced non-small cell lung cancer
Dickhoff, C.
2017
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THE ROLE OF SURGERY
IN THE TREATMENT OF
LOCALLY ADVANCED NON-SMALL CELL
LUNG CANCER
Christian Dickhoff
THE RO
LE OF SU
RGERY IN
THE TREATM
ENT O
F LOCA
LLY AD
VAN
CED N
ON
-SMA
LL CELL LUN
G CA
NCER Christian Dickhoff
UITNODIGING
voor het bijwonen van deopenbare verdediging
van het proefschrift
The role of surgery in the treatment of locally advanced
non-small cell lung cancer
doorChristian Dickhoff
op vrijdag 8 december 2017om 11.45 uur
In de aula van de Vrije UniversiteitDe Boelelaan 1105 te Amsterdam
Paranimfen:
Petr [email protected]
+31 6 29466025
Reinier [email protected]
+31 6 24253208
THE ROLE OF SURGERY
IN THE TREATMENT OF
LOCALLY ADVANCED NON-SMALL CELL
LUNG CANCER
Christian Dickhoff
THE RO
LE OF SU
RGERY IN
THE TREATM
ENT O
F LOCA
LLY AD
VAN
CED N
ON
-SMA
LL CELL LUN
G CA
NCER Christian Dickhoff
UITNODIGING
voor het bijwonen van deopenbare verdediging
van het proefschrift
The role of surgery in the treatment of locally advanced
non-small cell lung cancer
doorChristian Dickhoff
op vrijdag 8 december 2017om 11.45 uur
In de aula van de Vrije UniversiteitDe Boelelaan 1105 te Amsterdam
Paranimfen:
Petr [email protected]
+31 6 29466025
Reinier [email protected]
+31 6 24253208
514237-L-bw-Dickhoff514237-L-bw-Dickhoff514237-L-bw-Dickhoff514237-L-bw-DickhoffProcessed on: 4-10-2017Processed on: 4-10-2017Processed on: 4-10-2017Processed on: 4-10-2017 PDF page: 1PDF page: 1PDF page: 1PDF page: 1
THE ROLE OF SURGERY
IN THE TREATMENT OF LOCALLY ADVANCED
NON-SMALL CELL LUNG CANCER
Christian Dickhoff
VRIJE UNIVERSITEIT AMSTERDAM
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ColofonThe role of surgery in the treatment of locally advanced non-small cell lung cancer
ISBN/EAN: 978-94-028-0803-2
Copyright © 2017 Christian Dickhoff
All rights reserved. No part of this thesis may be reproduced, stored or transmitted in any way or
by any means without the prior permission of the author, or when applicable, of the publishers
of the scientific papers.
Layout and design by Alex Wesselink, persoonlijkproefschrift.nl.
Printed by Ipskamp Printing, proefschriften.net.
Feng
Chiesi
Nederlandse Vereniging voor Longchirurgie
Boehringer Ingelheim
Pfizer
Krijnen Medical Innovations
Nutricia
IKNL
Chipsoft
Netherlandscomprehensivecancer organisation
Printing of this thesis was financially supported by:
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VRIJE UNIVERSITEIT
THE ROLE OF SURGERY
IN THE TREATMENT OF LOCALLY ADVANCED
NON-SMALL CELL LUNG CANCER
ACADEMISCH PROEFSCHRIFT
ter verkrijging van de graad Doctor aan
de Vrije Universiteit Amsterdam
op gezag van de rector magnificus
prof.dr. V. Subramaniam
in het openbaar te verdedigen
ten overstaan van de promotiecommissie
van de Faculteit der Geneeskunde
op vrijdag acht december 2017 om 11.45 uur
in de aula van de universiteit
De Boelelaan 1105
door
Christian Dickhoff
geboren te Helmond
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promotor: prof.dr. E.F. Smit
copromotoren: dr. M. Dahele
dr. K.J. Hartemink
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CONTENTS:
Chapter 1: Introduction and outline of the thesis
PART I Surgery as part of trimodality treatment for locally advanced NSCLC
Chapter 2: Population-based patterns of surgical care for stage IIIA NSCLC in the Netherlands between 2010 and 2013 Journal of Thoracic Oncology 2016
Chapter 3: Patterns of care and outcomes for stage IIIB non-small cell lung cancer in the TNM-7 era: results from the Netherlands Cancer Registry Lung Cancer 2017
Chapter 4: Trimodality therapy for stage IIIA non-small cell lung cancer: benchmarking multi-disciplinary team decision-making and function Lung Cancer 2014
Chapter 5: Is the routine use of trimodality therapy for selected patients with non-small cell lung cancer supported by long-term clinical outcomes? Annals of Oncology 2017
PART II New roles for surgery after chemoradiotherapy: recurrent or persistent disease and complications
Chapter 6: Salvage surgery for loco-regional recurrence or persistent tumor after high dose chemoradiotherapy for locally advanced non-small cell lung cancer Lung Cancer 2016
Chapter 7: Surgical treatment of complications after high-dose chemoradiotherapy for lung cancer Annals of Thoracic Surgery 2017
Chapter 8: Radical-intent treatment of lung cancer after prior thoracic radiotherapy Journal of Thoracic Oncology 2017
Chapter 9: Discussion and future perspectives
Chapter 10: Summary Samenvatting List of publications Curriculum vitae Dankwoord
7
17
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43
57
63
77
93
97
105109 113 117 121
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CHAPTER 1
Introduction and outline of the thesis
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CHAPTER 1
INTRODUCTION AND OUTLINE OF THE THESIS
Lung cancer is the leading cause of cancer related death worldwide [1]. In the Netherlands,
more than 12000 people are diagnosed with lung cancer every year with the majority of these
patients having non-small cell histology (~85%) [2]. In the Western world, the incidence is slowly
stabilizing in both sexes and despite more effective therapies for sub-groups of patients, for lung
cancer patients as a whole, only small improvements in survival have been made during the last
two decades [3].
Table 1. 7th edition of TNM classification of lung cancer
Descriptor DefinitionT – primary tumorTx Primary tumor may not be assessed or detected with sputum or bronchial washings and
is not visualized at imaging or bronchoscopyT0 No evidence of primary tumorTis Carcinoma in situT1 Tumor ≤ 3cm in greatest dimension, surrounded by lung or visceral pleura, without
bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e. not in the main bronchus
T1a Tumor ≤ 2cm in greatest dimensionT1b Tumor > 2cm and ≤ 3 cm in greatest dimensionT2 Tumor > 3cm and ≤ 7 cm; or tumor with any of the following features: involves main
bronchus and is ≥ 2m distal to the carina; invades visceral pleura; associated with atelectasis or obstructive pneumonitis that extends the hilar region but does not involve the entire lung
T2a Tumor > 3cm and ≤ 5cm in greatest dimensionT2b Tumor > 5cm and ≤ 7cm in greatest dimensionT3 Tumor > 7cm or one that directly invades any of the following: chest wall (including
superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium, or tumor in the main bronchus < 2cm distal to the carina; or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe as the primary
T4 Tumor of any size that invades one of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, oesphagus, vertebral body, carina: separate tumor nodule(s) in a different ipsilateral lobe than the primary
N – regional lymph nodesNx Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and
intrapulmonary nodes, including involvement by direct extensionN2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral
scalene, or supraclavicular lymph node(s)M – distant metastasisMx Distant metastasis cannot be assessedM0 No distant metastasisM1 Distant metastasisM1a Separate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or
malignant pleural or pericardial effusionM1b Distant metastasis
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Optimal treatment selection for patients with non-small cell lung cancer (NSCLC) is highly
dependent on the clinical stage at presentation. Like most solid tumors, NSCLC is staged according
to the TNM Classification of Malignant Tumours from the Union for International Cancer Control
(UICC) [4]. The latest edition, the 7th edition of TNM classification of lung cancer, was introduced
in 2009 and has been used in all studies described in this thesis. The TNM-descriptors and the
different stages according to the 7th edition are presented in Table 1 and Table 2, respectively.
Nearly one-third of all patients with lung cancer present with clinical stage III disease, with a five-
year survival of 36% for stage IIIA and 19% for stage IIIB disease [5]. Except potentially resectable
sulcus superior (Pancoast) tumors for whom induction chemoradiotherapy followed by resection
has become the standard of care, the optimal treatment for patients with locally-advanced stage
III NSCLC remains controversial and may vary depending for example on the interpretation of
the data and the expertise within individual multidisciplinary team [6]. In particular, the role
of surgery as part of a multimodal approach is subject to ongoing analysis and debate. Against
this background, the main goal of this thesis was to document and evaluate the evolving role of
surgery for locally advanced NSCLC.
Table 2. Stage grouping in the 7th edition of TNM classification of lung cancer
N0 N1 N2 N3
T1a IA IIA IIIA IIIB
T1b IA IIA IIIA IIIB
T2a IB IIA IIIA IIIB
T2b IIA IIB IIIA IIIB
T3 IIB IIIA IIIA IIIB
T4 IIIA IIIA IIIB IIIB
M1 IV IV IV IV
Trimodality treatment
Whether there is a role for surgery in patients with NSCLC depends on both tumor stage and
patient characteristics. For patients with early stage tumors, surgery is currently the standard of
care, unless patients are medically inoperable, at high risk for surgical complications, or decline
an operation, in which case stereotactic body radiotherapy (SBRT) is an alternative curative
intent treatment option [7]. There is also emerging data suggesting that SBRT may ultimately
have a role in operable patients [8]. In these patients, if SBRT is the primary treatment for early
stage lung cancer, surgery can be reserved for salvage therapy if local failure occurs [9].
More advanced NSCLC represents a wide range of possible T- and N-descriptors, particularly
stage III NSCLC. This results in tumors that may be judged to be resectable up-front (T3N1,
IIIA), potentially resectable after induction therapy (T1-3, single level/non-bulky N2, IIIA-N2) or
(mostly) unresectable (multi-level/bulky N2 or N3, IIIB). Historical trials have shown that single
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CHAPTER 1
modality (monotherapy) treatment of patients with locally advanced NSCLC and mediastinal
nodal involvement (N2/3) results in poor local control and disappointing outcome. In the mid-
nineties, Roth et al. [10] and Le Chevalier et al. [11] reported a 5 year loco-regional recurrence
and distant failure rate of 60% and 65% respectively, with a median overall survival (OS) of 10-
11 months for patients with locally advanced NSCLC treated with single modality surgery, or
radiotherapy. It was at this time that the first phase II trials were published investigating the
role of induction chemoradiotherapy followed by surgery (trimodality therapy) with promising
results [12,13]. Subsequently, van Meerbeeck et al. published the outcomes of a study comparing
chemotherapy followed by surgery or radiotherapy [14]. This randomized controlled study
showed improved survival when two therapies were combined, but there was no difference if
chemotherapy was followed by surgery (median OS 16.4 months) or radiotherapy (median OS
17.5 months). However, 40% of the patients treated with surgery after induction chemotherapy,
received postoperative radiotherapy (PORT), which has been shown to be detrimental to the
survival of certain patients [15]. Then, in 2009, the phase III study (INT0139) from Albain and
co-workers was published [16], in which patients with locally advanced NSCLC were randomized
between two groups: group one had induction chemoradiotherapy (45Gy) followed by surgery
and the group two was treated with induction chemoradiotherapy and additional radiotherapy
up to 61Gy. Both groups received additional chemotherapy. The median OS (23.6 vs 22.2
months respectively) was not statistically different between the two groups. It was only on an
exploratory sub-analysis that patients treated with lobectomy (as opposed to pneumonectomy),
were found to have an improved OS (median OS of 33.6 months and a 5-year survival of 36%)
compared to full-dose radiation. The recently published results from the ESPATUE trial [17],
are consistent with the results of the INT0139 trail as both trimodality therapy and definitive
chemoradiotherapy were found to be good treatments for medically and technically operable
patients with locally advanced (IIIA-N2 and selected IIIB) disease. However, these studies have
been difficult to accrue and have tended to include a few patients from many centers over a long
period of time. As an example, the ESPATUE study closed due to slow accrual after about half
of the target patient number was reached, leaving it under-powered with respect to its primary
end-point of OS. This raises some uncertainties as to the generalizability of the results.
Based on a synthesis of the available evidence, recent guidelines state that both definitive
chemoradiotherapy and induction plus surgery are curative intent treatment options in patients
with clinical stage IIIA disease. For patients with stage IIIB according the 7th edition of TNM,
surgery is largely excluded, as potentially resectable T4N0/1 tumors, which were IIIB in the 6th
TNM edition, have now migrated to stage IIIA. Only as part of a study protocol, surgery might be
considered for stage IIIB [6,18].
The role of surgery in NSCLC is evolving. The introduction of SBRT has provided an alternative
for selected patients with early-stage NSCLC. For those with locally-advanced NSCLC, surgery
is being increasingly confined to selected patients with IIIA and B disease. However, we also
identify growing niche areas for complex, specialized surgical interventions, including recurrent/
persistent disease after chemoradiotherapy and in addressing certain serious complications of
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chemoradiotherapy. These themes form the basis for this thesis. We have evaluated the use
of surgery in contemporary daily practice in the treatment of locally advanced NSCLC in the
Netherlands. We conducted a study on national patterns of care by retrieving data from the
Netherlands Cancer Registry (NCR). The use of surgery for patients with clinical stage IIIA is
discussed in Chapter 2, and for clinical stage IIIB, in Chapter 3.
Although randomized trials have failed to confirm the general superiority of trimodality
treatment compared with definitive chemoradiotherapy, population based studies report
improved survival from the addition of surgery to chemoradiotherapy [19-22]. This further
supports the hypothesis that some patients, carefully selected by an experienced multidisciplinary
tumor board, may be eligible for a trimodality approach outside study protocols. To justify this
approach, outcomes must at least be equal to those after definitive chemoradiotherapy. In
Chapter 4 we studied institutional data of patients with locally advanced NSCLC treated with
trimodality therapy after discussion at our multidisciplinary tumor board, and compared these
with results after definitive chemoradiotherapy. We also present long term results of trimodality
therapy in Chapter 5.
Surgery for recurrent disease, persistent disease and complications after chemoradiotherapy
Although definitive chemoradiotherapy is the preferred treatment for most patients with locally
advanced NSCLC, the 2-year loco-regional and distant failure rates have recently been reported
as 30.7% and 46.6%, respectively [23]. Loco-regional recurrence and persistent disease after
definitive chemoradiotherapy is a difficult clinical situation to manage, and there are only a few
curative intent treatment options. For selected patients, salvage procedures (radical re-irradiation
or surgical resection) can be considered, however available evidence to support these options,
is limited. Re-irradiation, although technically feasible in selected patients, carries the potential
risk of fatal bleeding, especially in larger centrally located recurrent or persistent tumor, and has
a reported median overall survival of 13.5-14.7 months [24,25]. Extensive fibrosis as a result of
high dose radiotherapy and due to prolonged time-interval between last day of radiotherapy and
surgery makes salvage surgery challenging. However, with increasing experience of performing
surgical procedures after chemoradiotherapy and the application of improved surgical techniques,
e.g. bronchial stump enforcement with well-vascularized muscle flaps and the availability of triple-
layer stapling devices, even major resections, including pneumonectomy, can be considered in
highly selected patients with recurrent or persistent disease after definitive chemoradiotherapy.
We report our experience with this type of surgical procedures in Chapter 6.
With the expanding use of chemoradiotherapy in the treatment of NSCLC [3], the incidence
of complications is expected to rise. Some complications are self-limiting, and are treated by
intensive supportive care, e.g. esophagitis, neutropenia. However, structural complications like
bronchial stenosis and parenchymal cavitation may pose a serious threat to life, and surgery is
often the only definitive treatment available. In Chapter 7 we review our institutional results
with this high-risk, complex surgical intervention.
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CHAPTER 1
REFERENCES
1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359-E386
2. http://www.cijfersoverkanker.nl/selecties/Incidentie_long_en_luchtpijpkanker/img54d0ecb34ed7b. Accessed October 10, 2016
3. van der Drift MA, Karim-Kos HE, Siesling S, et al. Progress in standard of care therapy and modest survival benefits in the treatment of non-small cell lung cancer patients in the Netherlands in the last 20 years. J Thorac Oncol 2012;7:291-298
4. Rami-Porta R, Crowley JJ, Goldstraw P. The revised TNM staging system for lung cancer. Ann Thorac Cardiovasc Surg 2009;15:4-9
5. Goldstraw P, Chansky K, Crowley J, et al. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. J Thorac Oncol 2016;11:39-51
6. Eberhardt W, De Ruysscher D, Weder W, et al; Panel Members. 2nd ESMO Consensus Conference in Lung Cancer: locally-advanced stage III non-small-cell lung cancer (NSCLC). Ann Oncol 2015;00:1-16
7. Baker S, Dahele M, Lagerwaard FJ, Senan S. A critical review of recent developments in radiotherapy for non-small cell lung cancer. Radiat Oncol 2016;11:115
8. Louie AV, Chen H, Van Werkhoven E, et al. Quality of Life Following Stereotactic Ablative Radiation Therapy Versus Surgery for Early-Stage Lung Cancer: Results From the ROSEL Randomized Controlled Trial and a Systematic Review. Int J Radiat Oncol Biol Phys 2016;96:S10-S11
9. Verstegen NE, Maat AP, Lagerwaard FJ, et al. Salvage surgery for local failures after stereotactic ablative radiotherapy for early stage non-small cell lung cancer. Radiat Oncol 2016;11:131
10. Roth JA, Fossella F, Komaki R, et al. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA NSCLC. J Natl Cancer Inst 1994;86:673-680
11. Le Chevalier T, Arriagada R, Quoix E, et al. Radiotherapy alone versus combined chemotherapy and radiotherapy in unresectable non-small cell lung carcinoma. Lung cancer 1994;10 Suppl 1:S239-S244
12. Weiden PL, Piantadosi S. Preoperative chemotherapy (cisplatin and fluorouracil) and radiation therapy in stage III non-small-cell lung cancer: a phase II study of the Lung Cancer Study Group. J Natl Cancer Inst 1991;83:266-273
13. Rusch VW, Albain KS, Crowley JJ, et al. Surgical resection of stage IIIA and stage IIIB non-small-cell lung cancer after concurrent induction chemoradiotherapy. A Southwest Oncology Group trial. J Thorac Cardiovasc Surg 1993;105:97-104
14. van Meerbeeck JP, Kramer GW, Van Schil PE, et al; European Organisation for Research and Treatment of Cancer-Lung Cancer Group. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst 2007;99:442-450
15. Burdett S, Rydzewska L, Tierney J, et al; PORT Meta-analysis Trialists Group. Postoperative radiotherapy for non-small cell lung cancer. Cochrane Database Syst Rev 2016;10:CD002142
16. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet 2009;374:379-386
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17. Eberhardt WE, Pöttgen C, Gauler TC, et al. Phase III Study of Surgery Versus Definitive Concurrent Chemoradiotherapy Boost in Patients With Resectable Stage IIIA(N2) and Selected IIIB Non-Small-Cell Lung Cancer After Induction Chemotherapy and Concurrent Chemoradiotherapy (ESPATUE). J Clin Oncol 2015;33:4194-4201
18. Ramnath N, dilling TJ, Harris LJ, et al. Treatment of stage III non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143:e314S-e340S
19. Koshy M, Fedewa SA, Malik R, et al. Improved survival associated with neoadjuvant chemoradiation in patients with clinical stage IIIA(N2) non-small-cell lung cancer. J Thorac Oncol 2013;8:915-922
20. Patel AP, Crabtree TD, Bell JM, et al. National patterns of care and outcomes after combined modality therapy for stage IIIA non-small-cell lung cancer. J Thorac Oncol 2014;9:612-621
21. Vinod SK, Wai E, Alexander C, et al. Stage III non-small-cell lung cancer. Population-based patterns of treatment in British Columbia, Canada. J Thorac Oncol 2012;7:1155-1163
22. Hancock J, Rosen J, Moreno A, et al. Management of clinical stage IIIA primary lung cancers in the National Cancer Database. Ann Thorac Surg 2014;98:424-432
23. Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 2015;16:187-199
24. Tetar S, Dahele M, Griffioen G, Slotman B, Senan S. High-dose conventional thoracic re-irradiation for lung cancer: updated results. Lung Cancer 2015;88:235-236
25. McAvoy S, Ciura K, Wei C, et al. Definitive reirradiation for locoregionally recurrent non-small cell lung cancer with proton beam therapy or intensity modulated radiation therapy: predictors of high-grade toxicity and survival outcomes. Int J Radiat Oncol Biol Phys 2014;90:819-827
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PART I
Surgery as part of trimodality
treatment for locally advanced NSCLC
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CHAPTER 2
Population-based patterns of surgical care for stage IIIA NSCLC
in the Netherlands between 2010 and 2013
C. Dickhoff
M.Dahele
A.J. de Langen
M.A. Paul
E.F. Smit
S. Senan
K.J. Hartemink
R.A. Damhuis
Journal of Thoracic Oncology 2016;11:566-572
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CHAPTER 2
ABSTRACT
Introduction:
Current guidelines include both induction therapy plus an operation and chemoradiotherapy (CRT)
as options for clinical stage IIIA (cIIIA) non-small cell lung cancer (NSCLC) after multidisciplinary
evaluation. We explored the use of operations for cIIIA NSCLC in the Netherlands.
Methods:
Data about the primary treatment of patients with cIIIA NSCLC (according to the seventh edition
of the Tumour, Node, and Metastasis Classification of Malignant Tumours) between 2010 and
2013 were extracted from the Netherlands Cancer Registry. Mortality information was obtained
from the automated civil registry.
Results:
A total of 4816 patients with cIIIA NSCLC (stage cN2, 3240 [67%]; stage T4, 1252 [26%]) were
identified. CRT was used in 45% of patients and an operation was a component of treatment
in 15%, with 28% of the latter having induction therapy. The 4-year survival rate was highest
with induction therapy plus an operation (51%), followed by an operation plus adjuvant therapy
(39%) and CRT (27%). Patients receiving induction therapy plus an operation were younger than
those receiving CRT (median age 60 versus 66 years). The 30- and 90-day postoperative mortality
after induction therapy plus lobectomy were 0.6 and 3.7% compared with 4.2 and 12.5% after
induction therapy plus bilobectomy or pneumonectomy. Factors associated with poorer survival
after induction therapy plus an operation were age older than 69 years, histological findings
of nonsquamous cell carcinoma, and bilobectomy or pneumonectomy. Pathological stage IIIA
NSCLC was present in only 51% of patients with cIIIA NSCLC who underwent an operation with
or without adjuvant therapy, and the disease was of a lower stage in most of the remaining
patients.
Conclusions:
In the Netherlands, between 2010 and 2013, 15% of patients with cIIIA NSCLC received an
operation, with the minority of these patients receiving induction therapy. In those receiving
induction therapy, 90-day mortality after bilobectomy or pneumonectomy was more than three
times higher than that for lobectomy. The discrepancy between clinical and pathological stage in
patients receiving an upfront operation merits further investigation.
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INTRODUCTION
In the Netherlands, which has nearly 17 million inhabitants, lung cancer is diagnosed in
approximately 12,000 patients per year, 85% of whom have non-small cell histological findings
[1]. For patients with clinical stage IIIA (cIIIA) locally-advanced non-small cell lung cancer
(NSCLC), management can vary, in large part owing to the heterogeneity of tumor (T) and
node (N) descriptors included in this particular stage [2,3]. After chemoradiotherapy (CRT),
the reported median survival ranges from 18 to 28.7 months [4-6]. Results from phase III
randomized studies have not demonstrated a clear survival benefit of an operation compared
with that of radiotherapy after induction chemotherapy [7] or CRT followed by surgical resection
[8,9]. Nonetheless, recent nonrandomized and population-based studies continue to report
encouraging survival rates for selected patients treated with strategies involving an operation
[10-15]. These studies report that an operation was part of the treatment in 13.7% of patients
with stage IIIA-N2 disease treated with curative intent [12] and in 17.5 % of a cohort of 1046
patients with any type of stage IIIA disease [14].
In the past 10 years, the number of hospitals in the Netherlands performing pulmonary
operations for lung cancer has declined from 79 in 2005 to 44 in 2014. There are seven high-
volume hospitals performing 50 or more resections a year. In more than half of the hospitals,
pulmonary resections are performed fewer than 20 times a year. Radiotherapy as cancer
treatment is delivered in 21 institutes. We studied the pattern of care of patients with stage IIIA
disease in the Netherlands, with particular focus on surgical treatment using population-based
data extracted from the Netherlands Cancer Registry (NCR).
MATERIALS AND METHODS
For this study, data on patients with stage IIIA NSCLC diagnosed from 2010 through 2013 was
retrieved from the NCR after formal approval by the NCR monitoring committee. Data on all
patients in the Netherlands in whom cancer has been diagnosed are collected by NCR through
notification of newly diagnosed malignancies by the national automated pathological archive
and notification of diagnoses at hospital discharge. Completeness is estimated to be at least 95%
[16]. Information on diagnosis, staging, and treatment is extracted routinely from the medical
records by specially trained NCR personnel. Information on survival status is updated annually
using a computerized link with the automated national civil registry. For the present analysis this
was available up to January 1, 2015.
As of 2010, stage information is recorded according to the seventh edition of the Tumour,
Node, and Metastasis (TNM) Classification of Malignant Tumours from the Union for International
Cancer Control [17]. Analysis was restricted to patients with cIIIA NSCLC. Patients without
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pathological verification of their tumor were excluded from the analysis, as were those with
carcinoid tumours and synchronous or metachronous tumors.
Treatment information comprised coding for thoracic radiotherapy, chemotherapy and
type of surgical procedure. Primary treatment strategies were defined as radiotherapy alone,
chemotherapy alone, CRT involving any combination of chemotherapy and radiotherapy,
an initial operation (with or without adjuvant treatment), induction therapy (chemotherapy
or CRT) followed by surgical resection, and best supportive care. The types of chemotherapy
administered and the radiotherapy dose and fractionation scheme were not recorded in
the NCR during this period. The database contained information on pathological verification
of lymph node metastases but not on the timing of when pathologic confirmation of N2
involvement was performed (i.e. whether it was performed preoperatively, during the operation
or postoperatively). Detailed data concerning the mediastinal assessment were not available
from the NCR database. Data about comorbidity were not available.
Statistical analyses were performed using the STATA software package, version 13 (Stata
Corp, college Station, TX). Overall survival was calculated from date of diagnosis until date of
death or censoring. Maximum follow-up time was 59 months and the median follow-up of
censored cases was 29 months. Differences in survival according to type of treatment were
tested for significance with the log-rank test. Prognostic factors for survival of patients receiving
an operation after induction therapy were identified using multivariable Cox proportional hazard
analysis and included in the final model if the p value of the log likelihood was less than 0.05. The
results were reported as hazard ratios and 95 % confidence intervals.
RESULTS
In the study period, NSCLC was diagnosed in 34,533 patients, with 14% of patients (n=4816)
staged as having cIIIA disease. Patient and tumor characteristics are presented in Table 1. Clinical
suspicion of mediastinal nodal involvement was recorded in 67% of patients (n=3240), and it
was proven by pathological examination in 58% of patients (Table 2). A T4 tumour was clinically
apparent in 26% of patients (n=1252).
CRT was the primary treatment in 45% of patients (n=2180). Treatment involved surgical
resection in 15% of all patients (n=744). In 28% of these patients (n=209), an operation
followed induction therapy, and the remaining 72% (535 of 744) received an operation with or
without adjuvant therapy. Of the patients receiving induction therapy, 19% (n=40) were given
chemotherapy and 81% (n=169) underwent a combination of chemotherapy and radiotherapy.
When patient characteristics and treatment strategy were analyzed, patients treated with
induction therapy plus an operation were considerably younger (median age 60 versus 68
years, p<0.001) [Table 3]. Furthermore, there was a higher proportion of patients with upper
lobe tumours in the group receiving induction plus an operation (73%) when compared to the
whole group treated with operation (57%). Whether this finding could be attributed to a higher
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proportion of tumors of the sulcus superior was not extractable from the NCR. Chemotherapy
alone, radiotherapy alone, or best supportive care was the preferred treatment in 9% of patients
(n=457), 12% (n=555) and 18% (n=880), respectively.
Table 1. General characteristics of patients with clinical stage IIIA NSCLC
n %
Gender MenWomen
31201696
6535
Age 18-5960-6970-7980+
101715711573 655
21333314
Year 2010201120122013
1293123711531133
27262424
Morphology Squamous cellAdenoLarge cell
21791672 965
453520
cTNM T1N2T2N2T3N2T3N1T4N0T4N1TxN2
55914261044 324
1025 227 211
123022 7
21 5 4
Treatment Best supportive careRadiotherapyChemotherapySurgeryInduction+surgeryChemoradiotherapie
880 555 457 535 209
2180
1812 9
11 4
45
Table 2. Pathological confirmation of lymph node metastasis in patients with clinical suspicion of N2-involvement
Treatment n %
Best supportive careRadiotherapyChemotherapySurgery1
Induction+surgeryChemoradiotherapy
601 313 325 225 128
1648
333256547072
Total 3240 58
1= Confirmation may have been established during or after surgery
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Table 3. Median age of patients according to applied treatment
Treatment Age (years)
Best supportive careRadiotherapyChemotherapySurgeryInduction+surgeryChemoradiotherapy
767770666066
In patients with clinical stage IIIA who underwent an operation without induction therapy,
pathological examination revealed a lower stage in 45% of cases. Clinical N2 disease had the
highest probability of being overstaged (54%), followed by T3N1 (50%) and T4 tumors (30%).
Tumors initially staged as cIIIA were subsequently classified as pathological TNM (pTNM) stage I
in 13% of patients (n=71) and stage II in 32% (n=171). A higher pTNM stage (IIIB or IV) was found
in 4% of patients (n=19). Agreement between clinical TNM and pTNM stage was found in 51%
of patients (n=274) undergoing surgical resection with or without adjuvant therapy. Of those
patients with pathological stage IIIA (pIIIA) disease and upfront surgical resection, 34% (n=181)
received adjuvant chemotherapy and 8% (n=42) received CRT. Survival curves for the different
primary treatment scenarios based on patients with cIIIA NSCLC are presented in Figure 1.
The 4-year survival rates were 51% for patients receiving induction treatment and an
operation, 39% for those treated with an operation with or without adjuvant therapy, and 27%
for those receiving CRT. The median survival times for an operation, CRT, radiotherapy and
chemotherapy were 33, 22, 11, and 8 months, respectively. Median survival for the patients
treated with induction therapy and an operation was not reached. The 4-year survival rate in
patients managed with an operation with or without adjuvant therapy ranged from 47% for
pathological stages I and II combined to 34% for pIIIA and 0% for pathological stage IIIB/IV
(Figure 2).
Analysis of survival in patients according to induction treatment revealed no benefit of
the addition of radiotherapy to chemotherapy. Pathological examination showed complete
pathological response in 36% of patients (n=75) and downstaging in 41% (n=87). The 30- and
90-day postoperative mortality rates after induction therapy plus lobectomy was 0.6% and 3.7%
compared with 4.2% and 12.5% after induction therapy plus bilobectomy or pneumonectomy. On
multivariate analysis, factors associated with poorer survival in patients treated with induction
therapy were higher age (>69 years), histological findings of nonsquamous cell carcinoma and
bilobectomy or pneumonectomy (Table 4).
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Figure 1: Kaplan-Meier survival estimates for patients with clinical stage IIIA NSCLC, stratified by type of
treatment.
Figure 2: Kaplan-Meier survival estimates for patients with clinical stage IIIA NSCLC, treated with upfront
surgery, stratified by pTNM stage.
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Table 4. Multivariate analysis of prognostic factors in patients who received induction treatment before surgery
n % HR1 95% CI2
Gender MenWomen
135 74
6535
ns3
Age 18-5960-6970+
102 82 25
493912
10.83.6
-0.5-1.32.9-6.7
Year 2010201120122013
54 50 43 62
26242130
ns
Morphology Squamous cellAdenoLarge cell
81103 25
394912
12.03.4
-1.2-3.51.7-6.8
ypTNM 0/XIIIIII
75 53 34 47
36251622
ns
Neoadjuvant ChemotherapyChemoradiotherapy
40169
1981
ns
Surgery LobectomyBilobectomyPneumonectomy
161 16 32
77 8
15
12.43.0
-1.1-5.31.6-5.4
1= Hazard Ratio, 2= Confidence Interval, 3=not significant
DISCUSSION
The NCR covers at least 95% of all patients in whom cancer has been diagnosed and shows that
in the Netherlands, multiple treatment strategies are currently being used in the management
of patients with cIIIA NSCLC. Between 2010 and 2013, 15% of patients with cIIIA NSCLC received
an operation, with the minority of these patients receiving induction therapy. The 4-year
survival rate was highest in patients selected to receive induction therapy plus an operation
(51%), followed by an operation with or without adjuvant therapy (39%) and CRT (27%). Factors
associated with poorer survival after induction therapy plus an operation were age older than
69 years and histological findings of nonsquamous cell carcinoma. In patients receiving induction
therapy, the 90-day mortality rate after bilobectomy or pneumonectomy was 12.5%, which is
more than three times higher than that for lobectomy and four times higher than that reported
by Weder et al. for pneumonectomy after induction therapy [18]. The limited data available in
the NCR do not allow us to speculate on the reasons for this.
Definitive CRT was performed in 45% of patients, a finding broadly consistent with other
nationwide reports on treatment of stage III NSCLC [13-15]. Almost 40% of patients received
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chemotherapy or radiotherapy alone, or best supportive care. Owing to the nature of
observational retrospective studies, it is impossible to determine whether the decision for a
certain treatment was biased by, for example, the following: patient factors such as performance
status, comorbidity and patient preference; local policy; or other factors. For example, in a
recent systematic review/meta-analysis, lower socioeconomic status was found to be associated
with a reduced chance of receiving any treatment, an operation, or chemotherapy (but not
radiotherapy) [19]. In addition, treatment in an academic center or high volume institute has
been associated with use of a operation in patients with stage IIIA disease [13,20]. It was beyond
the scope of the present study to analyze outcomes by socioeconomic status or by individual or
type of center, which would require the data to be corrected for case mix and prognostic factors.
The overall survival of the entire study group compared favorably with other studies reporting
data obtained in the era of the sixth edition of the TNM staging system. In this edition, stage
IIIA included only T3-tumors based on local invasion and not T4 tumors (which were formerly
stage IIIB). In the seventh edition, T4N0/1 tumors are also classified as stage IIIA (formerly as
stage IIIB) [17]. This means that the portion of N2 disease in stage IIIA is expected to be lower
when the seventh TNM is used. Consistent with this, the percentage of patients with clinical
mediastinal nodal involvement in our study (67%) was lower than that in other reports, which
may contribute to a favorable overall survival.
The use of an operation as the initial treatment in 15% of patients with stage IIIA disease and
the favorable survival after treatment that included an operation compared with after CRT are
consistent with recent cohort studies from Canada and the United States [13,15], retrospective
studies [21] and a sub-group analysis of RTOG 0139 [8]. Unfortunately, the present study cannot
allow for a direct comparison of between treatments that included an operation as a component
and CRT because we do not have data on factors such as performance status or comorbidity.
In patients treated with induction therapy and an operation, younger age, squamous cell
carcinoma, and lobectomy were identified as prognostic factors for improved survival. We found
no difference in survival for patients treated with induction CRT when compared with induction
chemotherapy, which is consistent with a recent multi-institutional phase III randomized trial
of induction chemotherapy or induction sequential CRT [22]. It is noteworthy that only 7% of
patients in each arm of this study had a mediastinal bulk of 5cm or larger, a group that some
might consider to have the most to gain from radiotherapy. In addition to bulk, a recent analysis
suggests subdivision of N1 and N2 nodes into different groups [23]. Neither bulkiness nor
detailed nodal information was available from the NCR.
When pathological staging (pIIIA) was used as the benchmark, in those patients treated
with an upfront operation with or without adjuvant therapy, only 51% of patients with cIIIA
disease were subsequently shown to have been correctly staged as having stage IIIA disease.
Most incorrectly staged patients turned out to have a lower stage (I or II), and this fact is
assumed to be at least partly responsible for the better survival in this group. Inevitably, what
these numbers were for patients treated with definitive CRT and those treated with induction
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therapy plus an operation is not known. The extent of the discordance between cIIIA and pIIIA
in this contemporary cohort with national access to fludeoxyglucose F 18 positron emission
tomography/computed tomography (PET/CT) staging was unexpected. A report by Jakobsen et
al. showed 83 to 91% agreement between clinical TNM stage and pTNM for all stages determined
between 2010 and 2012 [24]. However, Muehling et al. report an agreement between clinical
and pathological Union for International Cancer Control stage IIIA of only 36.7%, even with PET/
CT being used in 42 of 49 patients [25]. Although in our study survival rate after an operation
for ‘true’ (pathological) stage IIIA was similar to the survival rate seen for patients treated by
CRT, the accuracy of pretreatment staging in the CRT group truly is not known. If N2 disease is
found on pathological examination after an upfront operation, adjuvant chemotherapy is the
standard of care. The role of postoperative radiotherapy (PORT) was evaluated by the Adjuvant
Navelbine International Trialist Association trial subgroup in an unplanned subgroup analysis
[26,27]. It reported that PORT improved median survival in patients with pN2 disease regardless
of whether they received adjuvant chemotherapy (47.4 versus 23.8 months) or observation
(22.7 versus 12.7 months). An analysis based on the Surveillance, Epidemiology, and End Results
database also reported benefits for PORT in N2 disease [28]. The role of PORT is currently being
investigated in the randomized phase III Lung Adjuvant Radiotherapy Trial [29]. Currently, an
upfront operation followed by the appropriate adjuvant therapy remains an important treatment
option, including for patients in whom the extent of disease cannot be pathologically confirmed
before an operation.
We acknowledge that this study has important limitations. These include the retrospective
nature of the analysis, the fact that the accuracy of the staging data in the NCR has not been
verified, and the lack of patient-specific data (including performance status and comorbidity).
With the nationwide introduction of the Dutch Lung Surgery Audit (DLSA) in 2012, some of the
limitations we encountered during this study may be overcome in future analyses. The DLSA is
a prospective database that collects detailed information on preoperative staging, nodal status,
patient characteristics such as comorbidities and pulmonary function, and tumor and treatment
characteristics. In 2016, the DLSA will be replaced by the Dutch Lung Cancer Audit (DLCA), a
database which will include data on operations, systemic therapy, and radiotherapy collected
from all patients with lung cancer in the Netherlands. Nonetheless, this study has for the first
time provided a clear picture of the current use of operations in stage IIIA locally-advanced
NSCLC in the Netherlands, and it corroborates previous reports on encouraging survival for
selected patients receiving treatment strategies involving an operation. Furthermore, it shows
that accuracy of clinical staging remains poor despite widespread implementation of PET/CT
scanning in the diagnostic work-up for patients with locally advanced NSCLC and easily accessible
European guidelines for mediastinal staging [30]. Because properly powered clinical trials may
not be conducted, prospective dedicated clinical registries such as the DLSA that include robust
and sufficiently detailed data are needed to help define the parameters that predict which
patients are likely to benefit most from trimodality therapy, and which patients should receive
definitive CRT alone.
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CHAPTER 3
Patterns of care and outcomes for stage IIIB
non-small cell lung cancer in the TNM-7 era:
results from the Netherlands Cancer Registry
C. Dickhoff
M.Dahele
E.F. Smit
S. Senan
K.J. Hartemink
R.A. Damhuis
Lung Cancer 2017:110;10-14
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ABSTRACT
Objectives:
There is limited data on the pattern of care for locally advanced, clinical (c) IIIB non-small cell
lung cancer (NSCLC) in the TNM-7 staging era. The primary aim of this study was to investigate
national patterns of care and outcomes in the Netherlands, with a secondary focus on the use
of surgery.
Material and Methods:
Data from patients treated for TNM-7 cIIIB NSCLC between 2010-2014, was extracted from
the Netherlands Cancer Registry (NCR). Survival data was obtained from the automated Civil
Registry.
Results:
43.762 patients with NSCLC were recorded in the NCR during this 5-year period, with cIIIB
accounting for 10% (n=4.401). Clinical N2 (37%) and N3 (63%) nodal involvement was
pathologically confirmed in 50.8%. The use of endobronchial ultrasound (EBUS) increased with
time from 9% to 29% (p<0.001), while the rate of pathological confirmation of N2 or N3 nodes
increased from 44% to 54% (p<0.001). 48% of patients received chemoradiotherapy (CRT), 19%
chemotherapy (CT), RT in 10% and surgery in 2.2%. 22% received best supportive care (BSC). The
percentage of patients treated with CRT decreased from 65% for patients aged <60 years to 13%
for patients aged 80 years or older. Overall survival for surgery was 28 months, followed by CRT
(19mths), CT (9mths), RT (8mths) and BSC (3mths).
Conclusion:
In the Netherlands, CRT is the most frequent treatment for cIIIB NSCLC in the TNM-7 era. The use
of surgery is limited. Accurate staging requires specific attention and the scarce use of radical
treatment in elderly patients merits further evaluation.
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INTRODUCTION
The current guideline recommended radical treatment for fit patients with stage IIIB non-small
cell lung cancer (NSCLC) consists of concurrent or sequential chemoradiotherapy [1,2], with a
reported 5-year survival in the region of 20% [3]. For patients with a poor performance status,
excessive comorbidity, or substantially impaired pulmonary function, palliative treatment with
radiotherapy, chemotherapy or best supportive care may be appropriate. The role of surgery in
stage IIIB non-small cell cancer is controversial, with primary surgery often not feasible due to
tumor extent (T4) or multi-level/bulky nodal involvement (N2-3). Recent data from the United
States suggests that the use of surgery for advanced stage (IIIA-IV) NSCLC is decreasing, despite
being associated with longer survival, for as yet undetermined reasons [4]. Although several
studies have investigated surgical resection for patients with stage IIIB NSCLC, most used the
6th edition of the American Joint Committee on Cancer (AJCC) system to define the stage. These
studies included patients with T4N0 and T4N1 subsets, which are re-classified as stage IIIA in the
7th edition of the TNM classification of malignant tumors [5,6]. Other modifications in TNM-7 are
the re-classification of: nodules in the same lobe as T3, malignant pleural or pericardial effusion
as M1a, and nodules in another ipsilateral lobe as T4.
Against this background, our primary aim was to explore contemporary patterns of care
and outcomes for patients with clinical stage IIIB NSCLC in the Netherlands, with a secondary
focus on the utilization of surgery. We analysed population-based data extracted from the
Netherlands Cancer Registry (NCR) from 2010 until 2014, a period in which the 7th edition of the
TNM classification for the staging of NSCLC was applied nationally.
MATERIAL AND METHODS
Anonymous data on patients diagnosed with clinical stage IIIB NSCLC between January 2010 and
December 2014, were retrieved from the NCR, after formal approval by the NCR Monitoring
Committee. Information on the NCR and completeness of data collection has been previously
published in detail [7]. In brief, completeness of the registration of newly diagnosed malignancies
in the Netherlands by the NCR is estimated to be at least 95% [8], and data is extracted and
recorded by specially trained NCR personnel. A computerized link with the automated national
civil registry was used to obtain survival data, which was complete up to February 1, 2016.
From the year 2010, the stage of patients with NSCLC was recorded using the 7th edition of
the Tumour, Node, and Metastasis (TNM) Classification of Malignant Tumours from the Union
for International Cancer Control [9]. Excluded from the analysis were patients younger than 18
years, those with a pathological diagnosis of carcinoid tumor, sarcomatoid, salivary or large cell
neuroendocrine carcinoma, those without pathological confirmation of disease, and patients
with reported metachronous tumors.
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Recorded patient, and tumor characteristics included age, sex, year of registration,
morphology and TNM-subset. Data on whether lymph node involvement was pathologically
confirmed was available from the NCR, however, information on timing and type of invasive
staging techniques was limited. Patient related comorbidity and performance score, and data on
treatment related morbidity is not available.
The type of primary treatment strategy was categorized as radiotherapy alone (RT),
chemotherapy alone (CT), chemoradiotherapy (CRT) in any combination (sequential, concurrent),
surgery or induction therapy (CT or CRT) followed by surgery (SURG), and best supportive
care (BSC). Information on type of chemotherapy, and the dose and fractionation scheme of
radiotherapy was not available.
Statistical analyses were performed with the STATA software package, version 14.1 (Stata
Corp, College Station, TX). General characteristics were tabulated or cross tabulated. The use
of staging diagnostics was tabulated by year of diagnosis and the significance of trends was
evaluated by univariate logistic regression. Survival was calculated from day of diagnosis with
actuarial analysis and is represented by Kaplan-Meier curves. Variation between subgroups
was assessed by the log-rank test. Median survival (in months) and 5-year survival are reported
with 95% confidence intervals (95% CI). Prognostic factors for survival of patients treated with
chemoradiotherapy were evaluated with multivariable proportional hazards analysis. Statistical
significance was assessed by the likelihood ratio test and significant factors are represented by
the hazard ratio (HR) and a 95% confidence interval.
RESULTS
During the period January 2010 to December 2014, 43.762 patients with NSCLC were recorded in
the NCR, with clinical stage IIIB accounting for 10% (n=4.401). Patient and tumor characteristics
are presented in Table 1. Nearly 60% of patients presenting with stage IIIB NSCLC were younger
than 70 years. Annual patient numbers remained fairly stable during the study period. There
were 1647 (37%) patients with clinical N2 and 2754 (63%) with clinical N3 nodal involvement.
Nodal involvement was pathologically confirmed in half (50.8%) of these patients (Table 2). The
use of endobronchial ultrasound (EBUS) increased with time from 9% to 29% (p<0.001), while
the rate of pathological confirmation of N2 or N3 nodes increased from 44% to 54% (p<0.001).
In addition, the rates of pathological confirmation drops from 60% in patients of 18-59 to 55%
in those with age 60-69, 47% in those 70-79 years and to 32% in patients 80 years and older,
respectively (data not shown).
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Tabel 1. Patient and tumor characteristics of patients with clinical stage IIIB non-small cell lung cancer.
n %
Gender MenWomen
27731628
63,037,0
Age 18-5960-6970-7980+
103015231328
520
23,434,630,211,8
Year 20102011201220132014
905897856875868
20,620,419,519,919,7
Morphology SquamousAdenocarcinomaLarge cell
17511711
939
39,838,921,3
cTNM T4 N2TX N3T1 N3T2 N3T3 N3T4 N3
1647196448757552801
37,44,5
10,217,212,518,2
Treatment ChemoradiotherapyChemotherapyRadiotherapyBest supportive careSurgeryInduction + surgery
2100813439953
5838
47,718,510,021,7
1,30,9
Table 2. Trends in the use of staging diagnostics in patients with clinical stage IIIB non-small cell lung cancer
2010 2011 2012 2013 2014 p trend
% % % % %
Pathology confirmation of nodal metastasis
43,9 50,5 52,3 53,9 53,6 <0.001
Endoscopicultrasound
11,7 16,7 14,0 16,1 14,9 0.13
Endobronchialultrasound
8,6 14,5 21,4 24,1 28,8 <0.001
Mediastinoscopy 5,6 5,9 5,7 4,9 5,3 0.49
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Surgery was performed in only 96 patients (2.2%). Induction therapy prior to resection was
used in 38 patients (0.9%). The other 58 patients (1.3%) had initial surgery, of whom only 9
had stage IIIB disease established on postoperative pathological examination. The majority of
patients with stage IIIB disease underwent CRT (48%), followed by BSC (22%), CT (19%), and
RT (10%). The percentage of patients treated with CRT rapidly decreased with increasing age,
from 65% for patients aged <60 years to 13% for patients aged 80 years or older (Figure 1). The
reverse trend can be observed for BSC. RT was more common in patients with T4-disease (12%)
than in patients with lower T-stage (7%) (data not shown).
Median follow-up of censored patients was 31 months. Median overall survival following
surgery was 28 months (95%CI 23-46) (Figure 2). Of the non-surgical therapies, CRT was
associated with a median survival of 19 months (95%CI 18-20), followed by 9 months for CT
(95%CI 7,9-9,5), 8 months for RT (95%CI 7,5-9,3) and 3 months for BSC (95%CI 2,4-3,1). Five-year
overall survival for surgery, CRT, CT, RT and BSC was 25% (95%CI 13-39), 20% (95%CI 18-22), 2,8%
(95%CI 1,5-4,8), 1,7% (95%CI 0,4-4,6), and 0,7% (95%CI 0,2-2,0), respectively.
Figure 1: Association between age and treatment in patients with clinical stage IIIB non-small cell lung cancer
In the subgroup of patients treated with CRT, survival was better for patients with T1N3
or TXN3 and worse for patients with T3N3 or T4N3 (Figure 3). This finding was confirmed in
multivariable analysis (Table 3) but the differences appeared to be marginal with hazard ratios
ranging from 0.83 to 1.24. Survival was better for adenocarcinoma (HR=0.83) and worse for
elderly patients; HR=1.20 for patients 70-79 years and HR=1.46 for patients 80 years and older.
Pathology confirmation of nodal status did not influence survival. For surgery, there were too
few events to perform detailed analyses.
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Figure 2: Overall survival in patients with clinical stage IIIB non-small cell lung cancer by type of treatment.
Figure 3: Overall survival by TNM subgroup in patients with clinical stage IIIB non-small cell lung cancer treated with chemoradiotherapy.
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Table 3. Univariable and multivariate analysis of prognostic factors in patients with stage IIIB non-small cell lung cancer treated with chemoradiotherapy
n 5-year survival
p HR 95%CI
Gender MenWomen
1325775
1724
0.01 ns -
Age 18-5960-6970-7980+
673840521
66
24201511
<0.001 11.071.201.46
0.95-1.211.05-1.381.09-1.94
Morphology SquamousAdenocarcinomaLarge cell
818831451
142423
<0.001 10.830.96
0.73-0.930.84-1.11
TNM T4 N2TX N3T1 N3T2 N3T3 N3T4 N3
81989
233375245339
192730221415
<0.001 10.830.871.031.151.24
0.62-1.110.72-1.050.89-1.200.97-1.361.07-1.44
Pathology confirmation of nodal status
YesNo
1254846
2118
0.23 ns -
DISCUSSION
These 5 years of data from the Netherlands Cancer Registry show that CRT is the most commonly
applied treatment for clinical stage IIIB NSCLC (48% of patients). Surgery was performed in only
2.2% of patients and the favourable survival observed in patients undergoing upfront surgery,
of whom only 9/58 patients had stage IIIB disease pathologically confirmed after surgery, may
be largely attributable to over-staging and selection-bias. A recent study from the USA analyzing
data from the National Cancer Database (NCDB) reported favourable survival for clinically
staged IIIB patients treated with a trimodality approach, involving surgery in any order [10].
Median survival was similar to our study (25.2 months for surgery and 16.3 months for CRT).
A survival benefit was seen in patients with both cN3 and cT4 disease who received surgery,
suggesting a possible role for trimodality treatment in carefully selected patients with stage IIIB
NSCLC. However, as the definition of T4 disease has changed from the TNM edition 6 to 7, new
studies will be required to demonstrate this in the TNM-7 era. Such studies may prove difficult to
complete because although several phase II and III studies have been conducted to explore the
role of surgery in stage IIIB disease [5,11-13], slow accrual resulted in small numbers of patients
[5,12] or premature closure [12,13].
Adequate staging remains important for the determination of true IIIB disease, and for
accurate treatment decision making. Endoscopic bronchial endosonography with fine-needle
aspiration is available in many centers and can be combined with endoscopic oesophageal
endosonography [14]. However, our findings suggest that a substantial proportion of patients are
not staged according to current guidelines and/or the state of the art [15]. Both under-staging and
over-staging may occur in real-world practice [16,17] and may limit the ability to compare results.
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Although CRT was the most commonly applied treatment for patients with stage IIIB NSCLC,
the NCR did not contain accurate information on whether CRT was sequential or concurrent, and
elucidating the criteria on which the treatment selection was based, was not possible. However,
Driessen et al [18] identified comorbidity, poor performance score and patient refusal as the
most common motives for omitting CRT. Older patients appeared to have inferior survival, which
might be influenced by the decreased use of CRT with increasing age, a finding consistent with
previous data [19]. A recent systematic review and meta-analysis has highlighted the importance
of not excluding fit patients from more aggressive treatment on the basis of age alone [20].
Squamous cell morphology predicted worse survival when compared with adenocarcinoma, a
finding which agrees with a recent report on patients with advanced squamous cell carcinoma
by Langer et al., who suggested that more advanced disease, higher incidence of comorbidities,
and a lack of targeted first line treatment options in patients with squamous cell carcinoma,
were responsible for this finding [21]. The precise reason for worse survival for squamous cell
morphology in our cohort of patients treated with chemoradiotherapy, is as yet unclear and
cannot be deduced from the data in the NCR. The introduction of the Dutch Lung Surgery Audit
(DLSA) in 2011, and more recently of the Dutch Lung Cancer Audit (DLCA), with more detailed
information on diagnosis and treatment of patients with lung cancer, recorded by pulmonary
physicians, radiation oncologists and surgeons, will provide more detailed information on
diagnosis and treatment, such as radiotherapy dose and fractionation, type of induction
chemotherapy and the patients performance status.
Regarding overall survival, the TNM subgroup was a statistically significant predictive
factor. Patients treated with CRT for T3N3 and T4N3 tumours had a worse survival than other
subgroups in stage IIIB. This is in line with the results from the high-volume dataset used for the
proposal of the 8th edition of the TNM classification for lung cancer [22]. In this 8th edition of
the TNM classification, stage IIIC was introduced, containing T3-4N3 tumors, with a reported
5-year survival of 13% and 12% for clinical and pathological stage IIIC, respectively, compared
with 26% and 24% for patients with clinical and pathological stage IIIB [22]. This change in stage
III NSCLC will not automatically result in different treatment protocols for specific subsets of
patients, but should allow for a better prediction of the patient’s prognosis. It is noteworthy
that the TNM classification itself is mainly based on results from surgical treatment and that in
the 8th edition the nodal classification will remain unchanged [23], and will still not distinguish
between mediastinal, supraclavicular and scalene nodes.
The use of surgery for clinical stage IIIB NSCLC in the Netherlands in the TNM-7 era has been
very limited. Nonetheless, this should not prevent attempts to identify those patients that might
gain from a resection. The data also raise some questions about the accuracy of mediastinal
staging in daily practice in the Netherlands. Accurate staging is important for treatment selection
and to avoid inappropriate exclusion of patients from radical therapy. The decreased use of CRT
in elderly patients suggests that the evaluation of these patients for radical treatment requires
specific attention and strategies to maximize potential benefits [24,25].
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REFERENCES
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2. Ramnath N, dilling TJ, Harris LJ, et al. Treatment of stage III non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143:e314S-e340S
3. Goldstraw P, Chansky K, Crowley J, et al. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. J Thorac Oncol 2016;11:39-51
4. David EA, Canter RJ, Chen Y, et al. Surgical Management of Advanced Non-Small Cell Lung Cancer Is Decreasing But Is Associated With Improved Survival. Ann Thorac Surg 2016;102:1101-1109
5. Stupp R, Mayer M, Kann R, et al. Neoadjuvant chemotherapy and radiotherapy followed by surgery in selected patients with stage IIIB non-small-cell lung cancer: a multicentre phase II trial. Lancet Oncol 2009;10:785-793
6. Ichinose Y, Fukuyama Y, Asoh H, et al. Induction chemoradiotherapy and surgical resection for selected stage IIIB non-small-cell lung cancer. Ann Thorac Surg 2003;76:1810-1814
7. Dickhoff C, Dahele M, de Langen AJ, et al. Population-Based Patterns of Surgical Care for Stage IIIA NSCLC in the Netherlands between 2010 and 2013. J Thorac Oncol 2016;11:566-572
8. Schouten LJ, Höppener P, van den Brandt PA, et al. Completeness of cancer registration in Limburg, The Netherlands. Int J Epidemiol 1993;22:369-376
9. Rami-Porta R, Crowley JJ, Goldstraw P. The revised TNM staging system for lung cancer. Ann Thorac Cardiovasc Surg 2009;15:4-9
10. Bott MJ, Patel AP, Crabtree TD, et al. Role for surgical resection in the multidisciplinary treatment of stage IIIB non-small cell lung cancer. Ann Thor Surg 2016;99:1921-1928
11. Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by 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
12. Surmont V, van Klaveren RJ, Goor C, et al. Lessons to learn from EORTC study 08981: a feasibility study of induction chemoradiotherapy followed by surgical resection for stage IIIB non-small cell lung cancer. Lung Cancer 2007;55:95-99
13. Eberhardt WE, Pöttgen C, Gauler TC, et al. Phase III Study of Surgery Versus Definitive Concurrent Chemoradiotherapy Boost in Patients With Resectable Stage IIIA(N2) and Selected IIIB Non-Small-Cell Lung Cancer After Induction Chemotherapy and Concurrent Chemoradiotherapy (ESPATUE). J Clin Oncol 2015;33:4194-4201
14. Korevaar DA, Crombag LM, Cohen JF, et al. Added value of combined endobronchial and oesophageal endosonography for mediastinal nodal staging in lung cancer: a systematic review and meta-analysis. Lancet Respir Med 2016;4:960-968
15. Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods for staging non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143:e211S-e250S
16. Muehling B, Wehrmann C, Oberhuber A, et al. Comparison of clinical and surgical-pathological staging in IIIA non-small cell lung cancer patients. Ann Surg Oncol 2012;19:89-93
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17. Heineman DJ, Ten Berge MG, Daniels JM, et al. The Quality of Staging Non-Small Cell Lung Cancer in the Netherlands: Data From the Dutch Lung Surgery Audit. Ann Thorac Surg 2016;102:1622-1629
18. Driessen EJ, Bootsma GP, Hendriks LE, et al. Stage III Non-Small Cell Lung Cancer in the elderly: Patient characteristics predictive for tolerance and survival of chemoradiation in daily clinical practice. Radiother Oncol 2016;121:26-31
19. De Ruysscher D, Botterweck A, Dirx M, et al. Eligibility for concurrent chemotherapy and radiotherapy of locally advanced lung cancer patients: a prospective, population-based study. Ann Oncol 2009;20:98-102
20. Dawe DE, Christiansen D, Swaminath A, et al. Chemoradiotherapy versus radiotherapy alone in elderly patients with stage III non-small cell lung cancer: A systematic review and meta-analysis. Lung Cancer 2016;99:180-185
21. Langer CJ, Obasaju C, Bunn P, et al. Incremental Innovation and Progress in Advanced Squamous Cell Lung Cancer: Current Status and Future Impact of Treatment. J Thorac Oncol 2016;11:2066-2081
22. Goldstraw P, Chansky K, Crowley J, et al. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TMN Stage Groupings in the Forthcoming (Eight) Edition of the TNM Classification for Lung Cancer. J Thorac Oncol 2016;11:39-51
23. Asamura H, Chansky K, Crowley J, et al. The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for the Revision of the N Descriptors in the Forthcoming 8th Edition of the TNM Classification for Lung Cancer. J Thorac Oncol 2015;10:1675-1684
24. Walko CM, McLeod HL. Personalizing medicine in geriatric oncology. J Clin Oncol 2014;32:2581-2586
25. Smith GL, Smith BD. Radiation treatment in older patients: a framework for clinical decision making. J Clin Oncol 2014;32:2669-2678
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CHAPTER 4
Trimodality therapy for stage IIIA non-small cell lung
cancer: benchmarking multi-disciplinary
team decision-making and function
C. Dickhoff
K.J. Hartemink
P.M. van de Ven
E.J.F. van Reij
S. Senan
M.A. Paul
E.F. Smit
M. Dahele
Lung Cancer 2014;85:218-223
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ABSTRACT
Objectives:
Although the standard treatment for patients with stage IIIA non-small cell lung cancer
(NSCLC) is chemoradiotherapy, some patients are considered for trimodality therapy [TT]. We
analysed outcomes for stage IIIA NSCLC, treated with TT and compared them with concurrent
chemoradiotherapy [con-CRT].
Materials and Methods:
Patients treated between Jan 2007-Dec 2011 were retrospectively analysed. Not included were
patients with sulcus superior tumors, unknown T/N-status, or recurrent disease after con-CRT
followed by surgery. All patients were discussed at our multidisciplinary thoracic tumor board
(MTB).
Results:
Mean Charlson Comorbidity Index was 2 for TT and con-CRT patients. TT patients were younger
(median TT=56yrs vs. con-CRT=62yrs; p=0.001) and had less advanced cN-stage (TT cN2=41% vs.
83% for CRT; p<0.001). 44% of TT patients had T4-stage vs. 12% of con-CRT patients. Median RT
dose was lower for TT (50Gy vs. 66Gy; p=0.001) and median RT planning target volume (PTV) in
TT and con-CRT patients was 525cm3 and 655cm3 (p=0.010), respectively. The majority of TT
patients had a lobectomy (23/32). Median follow-up was 30.3 months (95%CI=18.7-41.9) for TT
and 51 months (95%CI=24.9-77.4) for con-CRT. Median overall survival was not reached for TT
and was 18.6 months (95% CI=12.8-24.4) for con-CRT (p=0.001). For PTV</≥500cm3, median
OS for TT was not reached/33.9 months and 29.1/17.1 months for con-CRT. TT patients with
cN0/1 had better survival than those receiving con-CRT (p=0.015), but those with cN2 did not
(p=0.158). The 90-day mortality from start of RT was 0% (0/32) for TT and 1.7% (1/58) for con-
CRT. 90-day post-operative mortality for TT was 3.1% (1/32, event unrelated to TT).
Conclusions:
Selected patients with IIIA NSCLC treated with TT had favorable long-term survival with acceptable
short-term mortality. These outcomes support the decision-making and function of our MTB/
treatment team. The role of TT in cN2 disease and large tumors merits further evaluation.
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INTRODUCTION
About a quarter of patients diagnosed with non-small cell lung carcinoma (NSCLC) have stage
IIIA disease [1]. For these patients, radical concurrent chemoradiotherapy (con-CRT) has been
considered to be the standard treatment [2,3]. However, there has also been a view that
selected patients may benefit from trimodality therapy [TT], consisting of induction con-CRT
followed by surgical resection [4-6]. Our current institutional policy is to treat patients with
superior sulcus tumors (SST) with TT whenever possible [7]. Selected patients with potentially
resectable stage IIIA non-SST NSCLC are also managed with TT. Trimodality therapy exposes
patients to the additional risks of an operation, its benefits have been widely debated and it
remains controversial. We therefore performed this retrospective study to analyze patient
characteristics and outcomes for stage IIIA non-SST NSCLC patients treated with TT or con-CRT
and to benchmark the clinical outcome for TT patients, including early mortality rates, against
con-CRT. A worse clinical outcome or high early-mortality rate would both call into question the
role of TT.
MATERIAL AND METHODS
Study design and population
We are a tertiary academic hospital with an established multidisciplinary thoracic tumor board
(MTB) consisting of surgeons, pulmonary oncologists, radiation oncologists, radiologists, nuclear
medicine specialists and pathologists. This retrospective cohort analysis was performed with
permission of the institutional ethics board. Two separate databases were used containing
information about consecutive patients treated by TT or radical con-CRT. Patients with stage
IIIA NSCLC who received TT between January 2007 and December 2011 and con-CRT between
January 2007 and October 2010, were included in the analysis. Patients with SST were excluded,
as were patients with unknown T- or N-status. Patients who experienced a local recurrence
after radical con-CRT and underwent subsequent salvage surgery (defined as surgery more
than 100 days after last radiotherapy) were considered a separate clinical group and excluded
from this analysis. Patients treated with sequential CRT (either as radical or induction therapy),
were not included. Overall survival (OS) and 90-day mortality were calculated from the start of
radiotherapy, the date of which was available for all patients. We also report post-resection 90-
day mortality, calculated from the day of resection. Date of death was obtained from a national
registry.
Treatment
During the period under evaluation, the 7th edition of the TNM staging system replaced the
6th edition. Therefore, for this analysis all patients were re-staged using the 7th edition of the
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TNM staging system [8], based on information from bronchoscopy/endobronchial ultrasound
(EBUS)/esophageal ultrasound (EUS), computed tomography (CT) scan, fluorodeoxyglucose
(FDG) positron emission tomography (PET) scan and an MRI or CT of the brain [9]. The decision
between TT and con-CRT was made in a dedicated lung cancer MTB.
All TT patients underwent surgery at our institute. Chemotherapy was delivered in our
own institute or in a referring hospital and typically comprised 1 cycle of cisplatin and either
gemcitabine in patients with squamous histology or pemetrexed in non-squamous histology,
followed by 2 cycles of cisplatin and etoposide given concurrently with radiotherapy. All patients
in the con-CRT-group, but not in the TT group, received radiotherapy in our institute. We used
a 4-dimensional CT scan; daily on-line image-guidance was introduced in 2007, and inverse-
planned intensity-modulated radiotherapy was available from 2009 [10]. Patients with disease
considered resectable at presentation, were typically treated with induction radiotherapy up to a
total dose of 50Gy in fractions of 2Gy/day, starting on day 2 of the second cycle of chemotherapy.
Patients considered candidates for TT, but in whom there was some uncertainty about the
likelihood of a complete resection, were initially treated with higher doses of radiotherapy
(60-66Gy). Patients recommended for con-CRT received 60-66Gy of radiotherapy, also in 2Gy
fractions. We have previously identified the radiotherapy planning target volume (PTV) as being
correlated with OS in patients treated with radiotherapy, including con-CRT [10]. We therefore
included this as a factor in the outcome analysis for this study.
The recommendation for con-CRT or TT by the MTB is typically based on patient factors
such as medical fitness for surgery and lung resection and tumor characteristics such as primary
tumor resectability and extent and bulkiness of mediastinal lymphadenopathy. When patients
were scheduled for TT, referral to a physiotherapist and a dietician was typically part of the
preoperative work-up, which also included an anesthetic assessment. Patients were usually
restaged by CT (n=11) and/or FDG-PET/CT-scan (n=21) after completing induction CRT. If there
was no pre-induction brain MRI, one was performed after induction. Patients proceeded to
resection only if there was a high probability of complete resection based on imaging. Surgery
was planned approximately 6 weeks after the last day of radiotherapy and an anatomical
pulmonary resection was performed whenever possible. Mediastinal lymph node dissection
was routinely performed and the bronchial stump or sleeve-anastomosis was buttressed with a
vascularized muscle-flap (n=28) or pericardial fat (n=4).
Statistical analysis
Statistical analyses were performed using the SPSS software package (SPSS, version 20, SPSS
Inc, Chicago, IL, USA). Differences in patient and treatment characteristics between TT and
CRT were assessed by means of chi-square test or Fisher’s exact test for characteristics that
were categorical and by means of independent samples t-test and Mann Whitney test for
characteristics measured on a continuous scale. The Mann-Whitney test was also used to
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compare characteristics measured on an ordinal scale. Curves for OS and 2- and 5-years survival
probabilities were calculated using Kaplan-Meier analyses, OS is compared between TT and
CRT using the log-rank test. Median follow-up times were estimated using the inverse Kaplan-
Meier method. The 95% confidence intervals for the survival probabilities were computed using
the normal approximation and standard errors reported in the survival table (i.e. estimated
probability ± 1.96 times the standard error) and, if necessary, truncating lower limits at 0 and
upper limits at 100%. There were too few events to perform multivariate survival analyses for TT
and CRT. Statistical significance was defined as p<0.05.
RESULTS
Patient and treatment characteristics
In total, 90 patients with stage IIIA NSCLC who were treated with con-CRT (n=58, 64%) or TT
(n=32, 36%) were included in this analysis. The characteristics of all patients are summarized in
Table 1. The mean Charlson Comorbidity Index (CCI) was 2 in both groups. However, TT patients
were younger (median TT=56yrs vs. con-CRT=62yrs; p=0.001), had less advanced cN-stage
(cN2=41% for TT vs. 83% for CRT; p<0.001) and consisted of a larger proportion of T4 tumors
(44% T4 for TT patients [14/32] vs. 12% in the con-CRT group [7/58]; p<0.001).
Consistent with the induction protocol, median RT dose was lower for TT (50Gy vs. 66Gy;
p=0.001). PTV was available for all but 7 patients (all in the TT group), who had their radiotherapy
in another institution. The median PTV in the con-CRT group was significantly larger at 665cm3
(range540-890) versus 525cm3 (range 344-690) in the TT group (p=0.010).
Lobectomy, with (n=4) or without (n=19) resection of the thoracic wall, was performed in
the majority of TT patients (23/32). In some patients a pneumonectomy (n=4) or bilobectomy
(n=4, including one patient who had partial resection of thoracic wall) was necessary to achieve
a macroscopically radical resection. A wedge resection was performed in 1 patient because of
unexpected metastatic disease found at the time of thoracotomy. The median American Society
of Anesthesiology-score (ASA-score) was 2 (range 1-3) and the median total duration of stay on
a medium care or intensive care unit at any point in the post-operative period was 1 day (range
0-69). Surgical resection was complete (R0) in 84% (27/32) of the patients. Complete response
(pCR) on pathological examination was found in 31% (12/32) of TT patients.
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Table 1: Patient-, tumor- and treatment characteristics
Con-CRT (n=58) TT (n=32) p-value
Patients and tumor characteristics
Age at diagnosis (mean, sd) 62.4 (9.24) 56.1 (7.73) 0.0011
Male patients (n, %) 42 (72.4%) 17 (53.1%) 0.0652
CCI 2 (0.75-3) 2 (1 – 3) 0.5873
cTNM (7th TNM)T4N0T3N1T4N1T1N2T2N2T3N2
5/58 (8.6%)3/58 (5.2%)2/58 (3.4%)11/58 (19.0%)18/58 (31.0%)19/58 (32.8%)
12/32 (37.5%)5/32 (15.6%)2/32 (6.2%)2/32 (5.0%)5/32 (15.6%)6/32 (18.8%)
cN2 (n, %)pN2 (n, %)
48/58 (82.8)*
13/32 (40.6)11/32 (34.4)
< 0.0012
PTV (cm3)** 665 (540-890) 525 (344-690) 0.0103
Treatment characteristics
RT dose (Gy) 66.0 (60.0 – 66.0) 50.0 (46.5 – 66.0) 0.0013
Completed CRT (% yes) 100% 100%
Sublobar resection (Bi-) Lobectomy Pneumonectomy
NANANA
1(4) 234
R0 resection NA 27/32 (84%)
pCR NA 12/32 (31%)1Independent samples t-test 2Chi-square test 3Mann Whitney U-test* Data not available** 58 (100%) and 25 (78.1%) patients with known PTV in the concurrent and trimodality groups, respectivelysd=standard deviation; n=number of patients; CCI=Charlson Comorbidity Index; Con-CRT=Concurrent Chemoradiotherapy; CRT=Chemoradiotherapy; NA=Not Applicable; PTV=Planning Target Volume; RT=Radiotherapy; TT=Trimodality Therapy; pCR=pathological complete response
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Follow-up and survival
The follow-up and survival data for both groups is presented in Table 2 and Figures 1-3.
Figure 1: Kaplan-Meier estimates for overall survival of patients with stage IIIA NSCLC treated with TT or
con-CRT (NAR= number at risk, TT= trimodality therapy, con-CRT= concurrent chemoradiotherapy)
Median follow-up in con-CRT and TT groups was 51 (95% CI: 24.5-77.4 months) and 30.3 months
(95% CI: 18.7-41.9 months), respectively. The median overall survival (OS) was not reached for
TT and was 18.6 months (95% CI: 12.8–24.4 months) for patients treated with radical con-CRT
(p=0.001). In patients with a PTV<500cm3, the median OS was not reached in those undergoing
TT, and it was 29.1 months (95% CI: 15.5-42.7 months) following CRT (p=0.150). For patients with
a PTV≥500cm3, median OS was 33.9 months (95% CI: 7.9-59.9 months) after TT, and 17.1 months
following con-CRT (95% CI: 12.4-21.7 months) (p=0.052), as presented in Figures 2A and 2B.
Table 2: Follow-up, early mortality and survival after concurrent chemoradiotherapy and trimodality
therapy
Con-CRT(n=58)
TT(n=32)
p-value
Follow-up (months) 51.0 (95% CI: 24.5 – 77.4) 30.3 (95% CI: 18.7 – 41.9)90-day mortality 1.7% (1/58) 0% (0/32)Post-resection 90-day mortality
NA 3.1 (1/32)
Overall survival (months) 18.6 (95% CI: 12.8 – 24.4) Not reached 0.001(log rank)n=number of patients; con-CRT=concurrent chemoradiotherapy; TT=trimodality therapy; NA=not applicable
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Figure 2: Kaplan-Meier estimates for overall survival of patients with stage IIIA NSCLC treated with TT or con-CRT, with (A) PTV<500cm3 or (B) PTV≥500cm3 (NAR= number at risk, TT= trimodality therapy, con-CRT= concurrent chemoradiotherapy, PTV= planning target volume)
TT patients with cN0/1 had better survival than those receiving con-CRT (p=0.015), but this
was not observed with cN2 (p=0.158) (Figures 3A and 3B). The 90-day-mortality for TT was 0%
(0/32) and 1.7% (1/58) for con-CRT. Post-resection 90-day mortality was 3.1% (1/32) due to a
ruptured abdominal aneurysm on day 24 after surgery. One patient, who developed a post-
operative empyema, subsequently underwent multiple thoracotomies and spent a total of 69
days on the ICU, died more than 4 months post-TT from sepsis and hemorrhage.
Figure 3: Kaplan-Meier estimates for overall survival of patients treated with TT or con-CRT, for (A) stage
IIIA-N0/1 and (B) stage IIIA-N2 (NAR= number at risk, TT= trimodality therapy, con-CRT= concurrent
chemoradiotherapy)
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DISCUSSION
Outcome data for institutional TT and con-CRT is rarely presented side-by-side as it has been in
this analysis. However, for benchmarking and quality assurance, this is important. We audited
our MTB-based management of stage IIIA NSCLC treated with TT or con-CRT. For the groups as
a whole, overall survival after TT was better than after con-CRT. Patients selected by our MTB
for TT were younger, had less advanced nodal disease and smaller radiotherapy target volumes.
The data suggest that in such patients, surgery can potentially be added to induction CRT with
acceptable early overall mortality, and result in good OS. These data support the decision-
making of our institutional MTB and the function of the multidisciplinary team that is necessary
to provide trimodality therapy.
Although there was 1 patient in the TT group who died within 90 days of surgery, the survival
curves (Figure 1) signified no excess in early overall mortality for TT compared to con-CRT. We
reported on 90-day post-operative mortality, rather than the conventional 30-days, since the
latter might underestimate risk [11]. Nonetheless, causal relationships cannot be assumed and
in this case the ruptured abdominal aneurysm was considered unrelated to TT. One patient was
considered to have died from complications of TT, more than 4 months after the date of surgery,
and so even 90-day post-operative data would have been inadequate to capture this. Identifying
the contribution that TT and con-CRT make to mortality is important to clarify ‘trade-offs’
between treatment-related mortality and OS, and to facilitate decision-making with patients.
Looking at our data in more detail, we found no significant differences in survival between
the sub-group of cN2 patients treated with TT and those who received con-CRT, despite the
fact that patients with more advanced cN2 disease (e.g. bulky and multi-level) are likely to be
treated with con-CRT. Based on these data, any possible advantage for TT in N2 disease, even
when it is considered resectable at presentation, remains uncertain. We tried to compare TT
and con-CRT in patients with similar baseline characteristics, but the numbers were too small
and prevented a robust analysis. Several reports have shown that the addition of surgery to CRT
can be associated with favorable survival [6,12], even with persistent single level N2 disease [13]
or when pneumonectomy is required [14]. Nonetheless, the use of TT in N2 disease is widely
debated, highlighting ongoing uncertainty about the role of TT in this patient group. In addition,
there are strong arguments that N2 disease should not be considered a single patient group.
In line with this, recent guidelines by the American College of Chest Physicians (ACCP) have
argued for subdivision of stage IIIA-N2 into single level, non-bulky/non-fixed N2 disease and
bulky, multi-station, bulky/fixed N2 disease [4,5], with the first group more likely to benefit from
surgery after induction therapy [15,16]. Some reports highlight that persisting N2 (yN) status is
an independent prognostic factor [17,18], and that patients with persistent N2/3 disease after
induction therapy followed by resection, seem to have an OS little different from what has been
reported for con-CRT [16]. Complete responders to induction CRT may also have better survival
than patients with persistent vital tumor cells in the resected specimen [19]. In the present
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study, the proportion of complete responders to induction CRT using doses of RT in the order of
50Gy was 31% (12/32). However, predicting this in advance of surgery is currently problematic.
Although our numbers were small, we also found that the radiotherapy target volume may be a
relevant prognostic factor in TT. This parameter is not usually presented in TT reports, however
it is available before surgery and should be further evaluated as a (simple) prognostic factor in
larger TT datasets.
The results of TT in this study are consistent with previous reports, where induction CRT
followed by surgical resection was effective for selected patients with locally advanced NSCLC. In
the intergroup 0139 study [6], patients were randomized between induction chemoradiotherapy
(45Gy) followed , in the absence of progression, by either resection or continuation up to a
radiation dose of ≤61Gy. The study enrolled patients with T1-3pN2 disease and found no
significant difference in median OS between TT (23.6 months) and CRT (22.2 months; HR 0.87,
p=0.24). Our observation of no difference in survival between TT and con-CRT in N2 patients
(despite our median OS for con-CRT being slightly lower at 18.6 months) is therefore in keeping
with these results. Our favorable results with TT are also in keeping a large analysis from the
National Cancer Database [12], in which patient outcomes after a variety of treatments for
clinical stage IIIA-N2 NSCLC were compared. Over 11,000 patients were included, but median
follow-up was short (11.8 months). Nonetheless, the authors found that the best outcomes
were associated with induction chemoradiotherapy followed by lobectomy (5 year OS 33.5%
versus 10.9% for con-CRT). Our current OS data after TT in highly selected patients compares
favorably with this and with other studies reporting for example 5 year OS results of 61% and
44% for patients with T3-4/N0 locally advanced NSCLC [20,21]. The finding that radical con-
CRT compared less favorably with TT in patients with cN0-1 disease can be contrasted with the
excellent local control rates possible with short duration, hypo-fractionated stereotactic body
radiotherapy (SBRT) in T1-2 NSCLC [22,23]. This suggests that other radiotherapy strategies
merit testing as an alternative to modest dose, highly fractionated con-CRT in selected patients
with locally advanced NSCLC (e.g. those with nodal status N0-1).
There are some limitations in this study. It is retrospective and although the results of TT
in patients with stage IIIA are favorable, this group is relatively small, and the proportion of N2
disease was low. Furthermore, due to the retrospective nature of the study, we do not know how
many patients were still considered unresectable after induction therapy or did not have surgery
for other reasons. We acknowledge that the TT group only consists of those who completed
induction therapy and remained fit enough for surgery and those patients who were initially
considered unresectable, who were subsequently rendered resectable. Similarly, the con-CRT
only includes those patients who completed con-CRT. Both groups are therefore highly selected.
Because of limitations such as these, conclusions should be drawn with caution. Chemotherapy
alone has also been shown to be an effective induction therapy [24,25]. Our report does not
include this treatment approach only because it is not standard in our institution. We also
acknowledge that it did not include patient-reported outcomes (PRO), which are not usually
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available in a retrospective chart analysis. Several authors have reported quality of life after con-
CRT [26,27], but less is known about PRO in TT [26].
In conclusion, for certain patients with IIIA NSCLC, TT resulted in similar short-term all-cause
mortality and favorable long-term survival, when compared with con-CRT. However the role of
TT for cN2 disease and large tumors in particular, merits further evaluation. Acknowledging the
limitations, these results provide support for our selective use of TT and are consistent with the
view that acceptable results can be achieved in institutions with experienced multidisciplinary
tumor boards and treatment teams [28,29].
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12. Koshy M, Fedewa SA, Malik R, et al. Improved survival associated with neoadjuvant chemoradiation in patients with clinical stage IIIA(N2) non-small-cell lung cancer. J Thorac Oncol 2013;8:915-922
13. Decaluwe H, de Leyn P, Vansteenkiste J, et al. Surgical multimodality treatment for baseline resectable stage IIIA-N2 non-small cell lung cancer. Degree of mediastinal lymph node involvement and impact on survival. Eur J Cardiothorac Surg 2009;36:433-439
14. Krasna MJ, Gamliel Z, Burrows WM, et al. Pneumonectomy for lung cancer after preoperative concurrent chemotherapy and high-dose radiation. Ann Thorac Surg 2010;89:200-206
15. Cerfolio RJ, Maniscalco L, Bryant AS. The treatment of patients with stage IIIA non-small cell lung cancer from N2 disease: who returns to the surgical arena and who survives. Ann Thorac Surg 2008;86:912-920
16. Steger V, Walker T, Mustafi M, et al. Surgery on unfavourable persistent N2/N3 non-small-cell lung cancer after trimodal therapy: do the results justify the risk? Interact Cardiovasc Thorac Surg 2012;15:948-953
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17. Shintani Y, Funakoshi Y, Inoue M, et al. Pathological status of mediastinal lymph nodes after preoperative concurrent chemoradiotherapy determines prognosis in patients with non-small cell lung cancer. Ann Thorac Cardiovasc Surg 2012;18:530-535
18. Bueno R, Richards WG, Swanson SJ, et al. Nodal stage after induction therapy for stage IIIA lung cancer determines patient survival. Ann Thorac Surg 2000;70:1826-1831
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20. Daly BD, Ebright MI, Walkey AJ, et al. Impact of neoadjuvant chemoradiotherapy followed by surgical resection on node-negative T3 and T4 non-small cell lung cancer. J Thorac Cardiovasc Surg 2011;141:1392-1397
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22. Verstegen NE, Oosterhuis JW, Palma DA, et al. Stage I-II non-small-cell lung cancer treated using either stereotactic ablative radiotherapy (SABR) or lobectomy by video-assisted thoracoscopic surgery (VATS): outcomes of a propensity score-matched analysis. Ann Oncol 2013;24:1543-1548
23. Senan S, Lagerwaard FJ. The role of radiotherapy in non-small-cell lung cancer. Ann Oncol 2005:16;ii223-ii228
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28. Boxer MM, Vinot SK, Shafiq J, Duggan KJ. Do multidisciplinary team meetings make a difference in the management of lung cancer? Cancer 2011;117:5112-5120
29. Freeman RK, Van Woerkom JM, Vyverberg A, Ascioti AJ. The effect of a multidisciplinary thoracic malignancy conference on the treatment of patients with lung cancer. Eur J Cardiothorac Surg 2010;38:1-5
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CHAPTER 5
Is the routine use of trimodality therapy for
selected patients with non-small cell lung cancer
supported by long-term clinical outcomes?
C. Dickhoff
K.J. Hartemink
J. Kooij
P.M. van de Ven
M.A. Paul
E.F. Smit
M. Dahele
Letter to the Editor in Annals of Oncology 2017;28:185
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To the Editor:
Induction chemo-radiotherapy followed by surgical resection (trimodality therapy, TT) in
patients with non-small cell lung cancer (NSCLC) remains controversial, in particular for non-
Pancoast tumors. Studies comparing TT with definitive chemo-radiotherapy have failed to show
an advantage for either strategy [1,2]. As a result, TT continues to be used outside clinical trials
for patients with stage IIB (chest wall invasion) and stage III (locally advanced, node positive)
NSCLC [3,4,5]. However, randomized studies have been challenging to conduct. For example,
the recently published ESPATUE study closed early due to poor accrual and outcomes in the
trimodality arm were based on 80 patients enrolled in multiple centers over a decade [1]. This
raises uncertainties in the extrapolation of such data to routine practice. It is therefore necessary
to ensure that results of TT in routine clinical practice are not worse than expected.
We audited long-term outcomes after TT for non-Pancoast tumors in 54 consecutive patients
treated over 5 years starting in 2007. All surgery was performed in one center. 13 patients
(24.1%) had stage IIB disease (all T3N0), 37 (68.5%) IIIA and 4 (7.4%) IIIB (7th edition TNM).
Median age was 57 years (40-72), 33/54 (61.1%) and 16/54 (29.6%) were American Society of
Anesthesiologists II and III respectively, and 33 were male (61.6%). 19/54 had clinical N2 (14
confirmed). 48/54 (88.9%) received concurrent chemo-radiotherapy, and 32/54 (59.3%) <50Gy
of radiation (87.5% of whom had <cN2 disease). Surgery was an average of 47 days after final day
of radiotherapy and comprised 38 lobectomies (6 bronchial sleeve resections), 7 bi-lobectomies,
5 pneumonectomies and 4 sub-lobar resections. 10 patients underwent chest wall resection, 7
pulmonary artery sleeve resection, 2 superior vena cava, 1 subclavian artery, and 1 complete
vertebral resection. 44/54 (81.5%) had bronchial stump coverage. Complete (R0) resection was
achieved in 48/54 (88.9%) and 21/54 (38.9%) had a pathologic complete response. Post-surgical
mortality at 30/90 days was 1.9/5.5% respectively (none after pneumonectomy).
Median follow-up was 80.4 months (95% CI: 66.6–94.1) during which 27/54 (50.0%)
experienced recurrent disease of whom 20 died of disease. Median overall and event-free
survival (OS, EFS) were 75.9 and 58.7 months respectively. 18 patients (33.3%) had distant
recurrence (brain in 9/18, of whom 7/9 diagnosed within 14 months of surgery), 6 (11.1%) loco-
regional, and 3 both (5.6%). Of the 6 patients without a radical resection, 4 had loco-regional
recurrence/persistent disease. Median survival after loco-regional and distant relapse was 5.1
months (95%CI: 3.2-7.0) and 11.8 months (95%CI: 0.0–32.3) respectively. Univariate predictors
for improved OS and EFS included radical resection and the absence of pre-induction mediastinal
metastasis.
Accepting that there will be differences in tumor stage and patient characteristics between
the population presented here and published studies, the median OS >6 years, low peri-operative
mortality, and high R0 resection rate after trimodality therapy compare favorably with what has
been reported in trials and support the careful use of TT for selected patients [1-3]. Clinical audit
is essential to ensure that outcomes in routine practice are acceptable.
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REFERENCES
1. Eberhardt WE, Pöttgen C, Gauler TC, et al. Phase III Study of Surgery Versus Definitive Concurrent Chemoradiotherapy Boost in Patients With Resectable Stage IIIA(N2) and Selected IIIB Non-Small-Cell Lung Cancer After Induction Chemotherapy and Concurrent Chemoradiotherapy (ESPATUE). J Clin Oncol 2015;33:4194-4201
2. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet 2009;374:379-386
3. Kawaguchi K, Yokoi K, Niwa H, et al. Trimodality therapy for lung cancer with chest wall invasion: initial results of a phase II study. Ann Thorac Surg 2014;98:1184-1191
4. Koshy M, Fedewa SA, Malik R, et al. Improved survival associated with neoadjuvant chemoradiation in patients with clinical stage IIIA(N2) non-small-cell lung cancer. J Thorac Oncol 2013;8:915-922
5. Dickhoff C, Dahele M, de Langen AJ, et al. Population-based patterns of surgical care for stage IIIA NSCLC in the Netherlands between 2010 and 2013. J Thorac Oncol 2016;11:566-572
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PART II
New roles for surgery after chemoradiotherapy:
recurrent or persistent disease and complications
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CHAPTER 6
Salvage surgery for locoregional recurrence or
persistent tumor after high dose chemoradiotherapy
for locally advanced non-small cell lung cancer
C. Dickhoff
M.Dahele
M.A. Paul
P.M. van de Ven
A.J. de Langen
S. Senan
E.F. Smit
K.J. Hartemink
Lung Cancer 2016;94:108-113
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CHAPTER 6
ABSTRACT
Objectives:
Curative intent treatment options for locoregional recurrence or persistent tumor after radical
chemoradiotherapy for locally-advanced non-small cell lung cancer (NSCLC) are limited.
In selected patients, surgery can be technically feasible, although it is widely believed to be
hazardous. As data regarding the outcome of this approach is sparse, we evaluated our
institutional experience with salvage surgery.
Materials and methods:
Patients with a pulmonary resection for in-field locoregional recurrence or persistent tumor
after high dose chemoradiotherapy (≥60 Gy) for the treatment of non-small cell lung cancer,
were identified and retrospectively analyzed.
Results:
A total of 15 patients treated between January 2007 and August 2015 were eligible for
evaluation. In 13 patients (87%), the indication for surgery was a locoregional recurrence, while
2 patients had persistent tumor. The prior median radiotherapy dose was 66 Gy (range 60 - 70).
All patients underwent an anatomical resection, with 8 patients having a pneumonectomy, and
all pathological specimens revealed the presence of viable tumor. The in-hospital morbidity rate
was 40% (6 patients), and the 90-day mortality rate was 6.7% (1 patient). Median follow-up was
12.1 months. The estimated median overall and event-free survivals were 46 months and 43.6
months, respectively.
Conclusion:
Salvage surgery for locoregional recurrence or persistent tumor after high dose chemoradio-
therapy, resulted in acceptable morbidity, mortality and promising outcome. It should be
considered as a treatment option for selected patients.
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INTRODUCTION
The recommended treatment for fit patients with locally advanced non-small cell lung
cancer (NSCLC) is a combination of chemotherapy and radiotherapy [1-3]. A median survival
of 28.7 months has recently been reported for selected patients treated with concurrent
chemoradiotherapy [4]. However, there was a local failure rate of 39% at 2 years in a sub-group
of protocol compliant patients [4].
Once locoregional recurrence or persistent tumor is diagnosed after chemoradiotherapy,
curative intent treatment options are limited and therapy is often palliative. However, selected
patients might be candidates for radical re-irradiation or resection. Due to fibrosis as a result
of the interval between chemoradiotherapy and surgery, so-called salvage resections are
technically demanding, and associated with higher risks.
There are relatively few reports presenting outcome data after salvage surgery following
chemoradiotherapy [5-8], and a lack of a uniform definition has hampered proper comparison
of outcome data. We audited our institutional experience with salvage surgery, defined as a
pulmonary resection for locoregional recurrence or persistent tumor in the previously irradiated
area, ≥12 weeks after the last day of curative intent high dose (>60Gy) chemoradiotherapy.
MATERIAL AND METHODS
This retrospective cohort analysis was conducted with Institutional Review Board approval.
Patients who underwent salvage pulmonary resection at the VU University medical center
between January 2007 and August 2015, after prior curative intent chemoradiotherapy for
primary NSCLC, were identified. Before planning surgery, patients had been discussed in our
weekly institutional multidisciplinary tumor board (MTB) consisting of surgeons, pulmonary
oncologists, radiation oncologists, radiologists, nuclear medicine specialists and pathologists.
MTB decisions are based on the patient’s physical and medical status, as well as radiological and
pathological findings. Patients were considered candidates for salvage surgery when physical
status and objective cardiopulmonary function (e.g. lung function tests, exercise testing, cardiac
evaluation) were sufficient to undergo surgical resection and, radiological and endobronchial
findings showed that complete resection of all suspicious/proven disease was technically
feasible. The absence of pathological confirmation of viable tumor was not a strict exclusion
criteria, since percutaneous post-chemoradiotherapy pathology may be unreliable with lower
sensitivity and negative predictive value [5]. Patients were excluded from the present analysis
if they had 1) surgery as part of a planned trimodality protocol, 2) surgery for complications
of definitive chemoradiotherapy, 3) prior single modality treatment, 4) histology other than
NSCLC, and 5) stage IV disease prior to chemoradiotherapy. Salvage surgery was defined as a
pulmonary resection for locoregional recurrence or persistent tumor in the previously irradiated
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CHAPTER 6
area, ≥12 weeks after the last day of curative intent high dose (>60Gy) chemoradiotherapy for
the treatment of NSCLC.
Data was retrieved from our institutional database and individual patient records, including
age, sex, comorbidity, physical status, stage of the index tumor, prior treatment and staging
modalities. If data were missing, the patient’s general practitioner or referring hospital were
contacted. As the 7th edition of the TNM classification for lung cancer replaced the 6th edition
during the study period, both the index tumor and the locoregional recurrence or persistent
tumor of all patients was re-staged using the 7th edition. Surgical factors that were evaluated
included the type of resection, lymph node dissection, complications, length of intensive
care unit (ICU) and in-hospital stay and pathology. The date of surgery was used for survival
measures. During follow-up, a CT-scan was routinely performed every 3 months in the first year,
every 6 months in the 2nd and 3rd year and thereafter every year, or more frequent when there
was clinical suspicion of disease progression. Statistical analyses were performed using the SPSS
software package (SPSS, version 20, SPSS Inc, Chicago, IL, USA). Median follow-up times were
estimated using the inverse Kaplan-Meier method. Overall survival (OS) and event free survival
(EFS) distributions were analyzed using Kaplan-Meier analyses. For event free survival we
considered the following events: death from any cause, locoregional recurrence or progression
of disease.
RESULTS
Between January 2007 and August 2015, a total of 183 patients underwent pulmonary resection
at our institution after chemoradiotherapy. In total, 21/183 patients were not included in a
trimodality protocol, and were operated on more than 12 weeks after the last day of high dose
chemoradiotherapy, for either loco-regional recurrence or persistent tumor within the irradiated
area. Four patients had a pathological diagnosis of small cell lung cancer, 1 patient had previous
resection and a recurrence treated with chemotherapy with low-dose radiotherapy (30Gy) and
1 patient had stage IV disease based on a solitary brain metastasis developed during initial
treatment, leaving 15 patients eligible for analysis. Between 2007 and 2012, 1 or 2 operations
were performed per year for this indication, increasing to 3 in 2014, and 5 in the first 8 months
of 2015. The majority of patients (12/15) had their primary treatment with chemoradiotherapy
in other hospitals and were referred to our center after being diagnosed with locoregional
recurrence or persistent tumor. Detailed patient characteristics are presented in Table 1. The
median age at the time of chemoradiotherapy was 59 years (range 41-70) and 73% of patients
were male. Median body-mass-index (BMI) was 25.7 (range 20.6-32.8), and median FEV1 was
78% of predicted (range 59%-138%). Median Charlson comorbidity score was 4 (range 2-6).
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67
Tabl
e 1:
Pati
ent,
tum
or a
nd tr
eatm
ent c
hara
cter
istic
s of
pati
ents
trea
ted
with
sal
vage
sur
gery
bet
wee
n 20
07 a
nd 2
015
Pati
ent
Year
of
rese
ction
Sex
Age
at
trea
tmen
t of
in
dex
tum
or
CCI
cTN
MH
isto
logy
Radi
ation
do
se (G
y)Re
ason
fo
r sa
lvag
e su
rger
y
Tim
e la
st R
T to
sur
gery
(m
onth
s)
Att
empt
ed
PA/P
A-
prov
en
Pre-
salv
age
med
iasti
nal
eval
uati
on(N
aruk
e st
ation
)
r-cT
NM
r-pT
NM
120
07m
492
T4N
0sst
scc
60*
PD29
-/-
noT3
N0
T2bN
02
2007
m51
3T4
N2
scc
60R
48+/
+no
T2bN
0T3
N1
320
08f
563
T1N
3ad
eno
60R
13+/
+M
edia
stino
scop
y (4
R, 4
L, 7
, 2R)
T2aN
0T1
bN0
420
09f
412
T2aN
2ad
eno
66R
22-/
-no
T2aN
0T2
aN0
520
10m
645
T2N
3N
SCLC
60R
95+/
-no
T2aN
0T4
N2
620
12m
536
T2aN
2ad
eno
66R
15+/
-no
T2aN
0T1
bN0
720
12f
433
T2N
2N
SCLC
66*
R75
+/+
noT4
N0
T3N
08
2014
f70
6T3
N2
aden
o70
*R
22-/
-no
T1bN
0T2
aN0
920
14m
606
T2N
2sc
c66
R20
+/+
EUS
(7)
T2aN
0T2
bN0
1020
14m
563
T2bN
2ad
eno
66PD
3-/
-no
T2aN
2T2
aN2
1120
15m
605
T4N
0sc
c66
R21
+/+
EBU
S (4
R)T2
aN0
T2aN
012
2015
m64
4T4
N2
scc
66R
11+/
+no
T3N
0T3
N0
1320
15m
604
T4N
0ad
eno
66R
38+/
+no
T3N
0T3
N0
1420
15m
593
T2bN
3sc
c66
R11
+/+
noT2
aN0
T2aN
015
2015
m69
5T3
N2
aden
o66
R7
+/+
noT2
aN0
T2aN
0m
= m
ale,
f =
fem
ale,
CCI
= C
harl
son
com
orbi
dity
Inde
x, c
-TN
M =
clin
ical
TN
M s
tage
of
inde
x tu
mor
, sst
= s
uper
ior
sulc
us t
umor
, EBU
S =
endo
bron
chia
l ul
tras
ound
, EU
S =
esop
hage
al u
ltras
ound
, RT
= ra
diot
hera
py, *
= s
eque
ntial
, PD
= p
ersi
sten
t dis
ease
, R =
recu
rren
ce, P
A =
pat
holo
gy, r
-cTN
M =
recu
rren
ce-
clin
ical
TN
M, r
-pTN
M =
recu
rren
ce-p
atho
logi
cal T
NM
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CHAPTER 6
Before starting their initial treatment with chemoradiotherapy, 10 patients were staged as
IIIA, and 5 patients as IIIB (according to the 7th edition of the TNM), and 10/12 patients with
clinical suspicion of mediastinal/supraclavicular nodal involvement had pathologically proven
N2 or N3 disease. The median radiotherapy dose was 66 Gy (range 60 - 70); 80% of patients
had concurrent chemotherapy, and 20% sequential. In the majority of patients (n=13; 87%),
the reason for salvage surgery was locoregional recurrence and the remaining 2 patients had
persistent tumor. One of the latter had persistent disease after definitive chemoradiotherapy,
and was subsequently treated with erlotinib resulting in stable disease, before a decision
was made to perform salvage surgery. The other patient had a high suspicion of persistent
tumor on follow-up CT and subsequent metabolic imaging soon after finishing curative intent
chemoradiotherapy.
Before surgery, all patients were staged with a fluorodeoxyglucose (FDG) PET-CT scan to
confirm the absence of distant metastases, and 13 patients had a preoperative MRI or CT-scan of
the brain, which was negative in all cases. Preoperative confirmation of disease was attempted
in 11 of the 15 patients and confirmed in 9 patients. PET-CT identified possible involvement of N2
nodes in 2 patients. Three patients had invasive mediastinal staging with mediastinoscopy (n=1),
esophageal ultrasound (n=1) or endobronchial ultrasound (n=1) because of clinical suspicion
of N2 involvement (n=2) or central localization of the recurrent tumor (n=1). One patient
had unforeseen N2-disease on postoperative pathological examination and in one patient an
invasive diagnostic mediastinal intervention was omitted because of high suspicion of persistent
N2 nodal involvement on PET-CT. The clinical stage of the locoregional recurrence or persistent
tumor was IA in 1, IB in 9, IIB in 3 and IIIA in 2 patients. Of the patients with IIIA The median time
between the last day of radiotherapy and surgery was 21 months (range 3–95).
Surgical data are summarized in Table 2. All patients underwent an anatomical surgical
resection consisting of a segmentectomy in 1, lobectomy in 4, bilobectomy in 2 and
pneumonectomy in 8 patients (right sided 3/8). The resection was extended with an additional
parenchymal resection (e.g. en-bloc wedge resection) in 4 patients. One patient had a superior
sulcus tumor and underwent a chest wall resection. Six patients had an intrapericardial
dissection of the central structures due to extensive fibrosis of the hilum or because of centrally
located tumor. The median number of lymph node stations that were dissected and submitted
for pathological examination was 4 (range 1-8). Median duration of surgery was 225 minutes
(range 124-387). In all patients, pathological examination of the resected specimen revealed the
presence of tumor. This was invading the resection margin (R1 resection) in 2 patients. Median
length of stay on the ICU was 1 day (range 0-4) and median total in-hospital stay was 7 days
(range 5-12).
Complications were encountered in 6 patients (in hospital morbidity rate: 40%), with 2 events
requiring re-thoracotomy, both after a left-sided pneumonectomy. One patient had an empyema
and was re-operated on 4 weeks after resection. The second patient, who underwent an
intrapericardial resection of the left lung, developed severe arrhythmias with acute hypotension
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69
Tabl
e 2:
Sur
gica
l det
ails
, mor
bidi
ty a
nd s
urvi
val o
f pati
ents
trea
ted
with
sal
vage
pul
mon
ary
rese
ction
Patie
ntTy
pe o
f re
secti
on#
Ope
ratin
g tim
e (m
ins)
Intr
aper
icar
dial
di
ssec
tion
Add
ition
al
rese
ction
Bron
chia
l st
ump
cove
r
Sepa
rate
dis
sect
ed
LN-s
tatio
ns (+
in
dica
tes
posi
tive)
In-h
ospi
tal
com
plic
ation
Rein
ter-
venti
on
<30
days
ICU
/MCU
st
ay (d
ays)
Hos
pita
l st
ay
(day
s)
Rese
ction
m
argi
nLo
cal (
LF)
or d
ista
nt
prog
ress
ion
(DP)
aft
er
surg
ery
Surv
ival
(m
onth
s)
1L
+ W
+ T
245
+rib
s 1-
4,
phre
nic
nerv
e,
pulm
onar
y ar
tery
peric
ard
5,7,
8,10
,11
--
15
R0-
≥96
2RP
387
+-
omen
tum
7, 1
0(+)
--
27
R1LF
, DP
221
3BL
200
--
IMF
4,7,
8,10
,11,
12-
-0
7R0
-≥9
0
4RP
174
--
diap
hrag
m4,
7,8,
9,10
--
110
R0D
P46
1
5LP
164
+-
IMF
4,5(
+),6
,7,9
luxa
tion
hear
tth
orac
otom
y4
5R1
-02
6L
124
--
IMF
4,7,
8,11
pneu
mon
iaan
tibio
tics
17
R0-
≥37
7LP
142
--
peric
ard
4,5,
7,9,
10,1
1-
-1
7R0
DP
51
8S
+ W
226
--
peric
ard
5-
-2
6R0
-≥1
9
9LP
298
+-
ASM
4,7
--
08
R0-
≥12
10L
+ S
219
-re
curr
ent
nerv
eIM
F4(
+),5
,6,7
,8,9
,10,
11-
-0
8R0
-≥1
1
11RP
355
+-
ASM
4,7
FUO
antib
iotic
s4
12R0
-≥8
12BL
338
--
IMF
4,7,
11FU
O-
09
R0-
≥6
13LP
225
+-
IMF
9,10
atria
l flutt
er-
17
R0-
≥4
14L
+ W
272
--
IMF
2,4,
10-
-0
6R0
-≥3
15LP
214
--
IMF
5,6,
7,10
,11
empy
ema
thor
acot
omy
06
R0-
≥2
RP =
righ
t pne
umon
ecto
my,
LP
= le
ft p
neum
onec
tom
y, B
L =
bilo
bect
omy,
L =
lobe
ctom
y, S
= s
egm
ente
ctom
y, W
= w
edge
rese
ction
, T =
thor
acic
wal
l res
ectio
n,
IMF
= pe
dicl
ed
inte
rcos
tal
mus
clefl
ap,
ASM
=
ante
rior
se
rrat
us
mus
cle,
FU
O
= fe
ver
of
unkn
own
orig
in,
ICU
=
inte
nsiv
e ca
re
unit,
MCU
= m
ediu
m c
are
unit,
1 = d
ied
of d
isea
se p
rogr
essi
on 2 =
die
d of
ARD
S 6
days
aft
er s
urge
ry
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immediately after closure of the thorax. After prompt re-thoracotomy, the heart was found
to be herniated through the pericardium. The heart was replaced in its anatomical position,
the pericardial defect was closed, and after cardioversion, there was normal sinus rhythm and
blood pressure recovered. Unfortunately, this patient died 4 days after surgery because of acute
respiratory distress syndrome (ARDS). This case represents the only patient who died within 90
days of surgery (90-day mortality rate: 6.7%).
No patient received adjuvant therapy. One patient with N2 disease died in the perioperative
period (Patient 5, Table 1 and 2). One patient with N1 disease (patient 2) and one patient with
N2 disease (patient 10) underwent close follow-up.
Median follow-up was 12.1 months (95% CI: 0 – 27.1) and estimated median overall and
event-free survival was 46 months and 43.6 months respectively (Figures 1 and 2).
Figure 1: Kaplan-Meier estimates for overall survival (OS) of patients treated with salvage surgery
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Figure 2: Kaplan-Meier estimates for event-free survival (EFS) of patients treated with salvage surgery
DISCUSSION
In this highly selected group of patients undergoing salvage surgery for recurrent or persistent
tumor after high dose chemoradiotherapy for NSCLC, we have shown that surgery can be
performed with acceptable risks and encouraging survival can be achieved. Although the study is
retrospective, the cohort is homogeneous in terms of prior treatment, pathology, and indication
for surgery. All patients received prior high-dose chemoradiotherapy (minimum dose 60Gy),
were staged with PET-CT +/- invasive mediastinal intervention and an MRI of the brain, and had
viable tumor in the resected specimen. Furthermore, when compared to other reports [5,6], the
median interval between chemoradiotherapy and salvage surgery was considerable, indicating
that resections were truly salvage and not part of a (delayed) trimodality approach. This is also a
contemporary series, with all surgery carried out in one large tertiary referral thoracic oncology
center over the last decade.
Based on our limited data, it appears that patients whose disease can be removed with
a lobectomy have a good prognosis. Despite the fact that all patients who were deceased at
the time of the current analysis had undergone a pneumonectomy, appreciable survival can
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be still be achieved in this group. This is illustrated by two patients who lived for 22 and 46
months, even after an incomplete (R1) resection. We acknowledge that our overall follow-up
is relatively short, and longer follow-up could identify additional data to help guide patient
selection, including the optimal selection of patients for pneumonectomy. Despite the large
number of pneumonectomies in a group treated with prior high dose chemoradiotherapy, no
patients developed a postoperative bronchopleural fistula. This might be attributable to the
strict application of vascularized flaps for bronchial stump coverage. In addition, the incidence
of postoperative empyema was low, which might be at least partly explained by our routine
application of intravenous antibiotics during the first 5 days after surgery.
The evidence regarding salvage surgery remains limited: a recent review identified 4 studies,
with a total of only 47 patients, and of these 2 studies (9 patients) were related to salvage
surgery after prior stereotactic body radiotherapy (SBRT), which is a different clinical scenario
(for example, the mediastinum is typically not irradiated to a significant dose with lung SBRT)
[9]. Furthermore, there is currently no uniform definition of salvage surgery. In our study we
used a definition pulmonary resection of locoregional recurrence or persistent tumor in the
irradiated area, ≥12 weeks after radical chemoradiotherapy (≥60Gy) for NSCLC. Bauman et
al. reported on 24 patients who underwent resection for evidence of treatment failure after
high dose of radiotherapy (>59Gy), with or without chemotherapy [5]. However, the interval
between the end of radiotherapy and surgery was variable, with the shortest being 5.4 weeks
and their median time from radiotherapy to surgery was 21 weeks (compared with 21 months
in our cohort). Furthermore, Bauman et al. reported on a more heterogeneous patient group
which included 1 patient with bronchopleural fistula, and 4 were treated in a trimodality
protocol. In addition, only 79% of their operated patients had malignancy confirmed in the
resection specimen. Uramoto and Tanaka reported on salvage thoracic operations for 8 patients,
but their cohort is heterogeneous and included patients with stage IV disease [7]. Kuzmik et
al. analyzed outcomes for 14 patients undergoing resection for recurrence after definitive
chemoradiotherapy. However, they included patients treated with radiotherapy doses as low as
30Gy (median 57Gy), patients with SCLC as the index tumor, and nearly 50% of patients received
a resection for a non-local recurrence (including in a contralateral lobe) [8]. The report on
salvage surgery for NSCLC by Yang et al. described 31 patients who were operated at a median
of 17.7 weeks after chemoradiotherapy to a median dose of 60 Gy [6]. However, all decisions to
proceed to surgery were based solely on imaging with the final pathological examination of the
resected specimen revealing no vital tumor in nearly 40% (12/31) of patients. Their patients with
a pathological complete response had a significantly better survival than those without, and no
patients underwent pneumonectomy, in comparison with 8/15 in our study. The features of the
abovementioned studies must be taken into account when studies are compared.
A number of potential alternative interventions and specific considerations are relevant
to MTB discussions for patients with recurrent or persistent loco-regional disease. High-dose
thoracic re-irradiation has been used in selected patients. We have previously reported our
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institutional results with re-irradiation in this setting [10] and found it to be technically feasible
with a median overall survival of 13.5 months. However, we have observed a considerable rate
of fatal bleeding (to which tumor and treatment related factors may be contributing) in patients
who have high dose overlap of the first and second radiation courses in the hilar/central regions.
In a study by McAvoy et al. [11], median survival after re-irradiation was 14.7 months (range
10.3-20.6) with grade ≥3 esophageal toxicity of 7% and grade ≥3 pulmonary toxicity of 10%. Both
groups found smaller tumors to be associated with better survival. Another treatment approach
is palliative chemotherapy, although it has been observed that response rates to carboplatin-
gemcitabine chemotherapy in patients with recurrent NSCLC who had been formerly treated
with platinum-based chemoradiotherapy were low (10%) [12], and this cannot be considered a
curative intent treatment option.
CONCLUSION
We report that selected patients with locoregional recurrence or persistent tumor after
high dose chemoradiotherapy, can undergo salvage surgery with acceptable morbidity and
mortality, even when a pneumonectomy is required. Factors that might have contributed to
these favorable results include adequate pre-operative staging, ability to obtain an R0 resection
and a good performance status. Medically operable patients presenting with (high suspicion
of) locoregional recurrence or persistent tumor after definitive chemoradiotherapy for NSCLC,
should have all treatment options reviewed in an experienced MTB.
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CHAPTER 6
REFERENCES
1. Eberhardt WE, De Ruysscher D, Weder W, et al; Panel Members. 2nd ESMO Consensus Conference in Lung Cancer: locally-advanced stage III non-small-cell lung cancer. Ann Oncol 2015;26:1573-1588
2. Kozower BD, Larner JM, Detterbeck FC, Jones DR. Special treatment issues in non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143:e369S-e399S
3. O’Rourke N, Roqué I Figuls M, Farré Bernadó N, Macbeth F. Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev 2010 16;CD002140
4. Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 2015;16:187-199
5. Bauman JE, Mulligan MS, Martins RG, Kurland BF, Eaton KD, Wood DE. Salvage lung resection after definitive radiation (>59Gy) for non-small cell lung cancer: surgical and oncologic outcomes. Ann Thor Surg 2008;86:1632-1638
6. Yang CF, Meyerhoff RR, Stephens SJ, et al. Long-Term Outcomes of Lobectomy for Non-Small Cell Lung Cancer After Definitive Radiation Treatment. Ann Thorac Surg 2015;99:1914-1920
7. Uramoto H, Tanaka F. Salvage thoracic surgery in patients with primary lung cancer. Lung Cancer 2014;84:151-155
8. Kuzmik GA, Detterbeck FC, Decker RH, et al. Pulmonary resections following prior definitive chemoradiation therapy are associated with acceptable survival. Eur J Cardiothorac Surg 2013;44:e66-e70
9. Schreiner W, Dudek W, Sirbu H. Is salvage surgery for recurrent non-small-cell lung cancer after definitive non-operative therapy associated with reasonable survival? Interact Cardiovasc Thorac Surg 2015;21:682-684
10. Tetar S, Dahele M, Griffioen G, Slotman B, Senan S. High-dose conventional thoracic re-irradiation for lung cancer: updated results. Lung Cancer 2015;88:235-236
11. McAvoy S, Ciura K, Wei C, et al. Definitive reirradiation for locoregionally recurrent non-small cell lung cancer with proton beam therapy or intensity modulated radiation therapy: predictors of high-grade toxicity and survival outcomes. Int J Radiat Oncol Biol Phys 2014;90:819-827
12. Paramanathan A, Solomon B, Collins M, et al. Patients treated with platinum-doublet chemotherapy for advanced non-small-cell lung cancer have inferior outcomes if previously treated with platinum-based chemoradiation. Clin Lung Cancer 2013;14:508-512
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CHAPTER 7
Surgical treatment of complications after high-dose chemoradiotherapy for lung cancer
C. Dickhoff
M. Dahele
S.M. Hashemi
S. Senan
E.F. Smit
K.J. Hartemink
M.A. Paul
Annals of Thoracic Surgery 2017;104:436-442
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ABSTRACT
Background:
There are limited published reports on the indications for, and outcomes of, a surgical intervention
for complications arising after high dose chemoradiotherapy (CRT) for locally advanced non-
small cell lung cancer (NSCLC). We report on our institutional experience with such cases.
Methods:
Patients who underwent operations for any complication after CRT (≥60Gy) for NSCLC between
2009 and 2015 were identified. All operations were performed at a tertiary referral center.
Results:
In the 15 patients identified, the median time between the last day of radiotherapy and first
radiologic confirmation of the complication was 8 months (range, 0-102 months). Complicated
pulmonary cavitation was the most frequent indication for surgical intervention (n=11 in 9
patients), followed by esophagorespiratory fistula (n=3), hemorrhage (n=3), bronchial stenosis
(n=2), esophageal stenosis (n=1), and bronchiectasis (n=1). Four patients had more than two
complications diagnosed, and 9 patients underwent more than one surgical intervention. Surgical
procedures performed included thoracostomy (n=11 in 9 patients) with 7 vascularized muscle
flaps used in 6 patients, pulmonary resection (n=5 in 4 patients) and esophageal resection with
gastric tube reconstruction (n=3). The 30- and 90-day mortality rates were 20% (n=3) and 27%
(n=4), respectively. Median survival was 19 months (95% confidence interval [CI]: 3.9 to 34.1
months).
Conclusions:
An operation is often the only treatment option when irreversible complications arise after high
dose chemoradiotherapy for NSCLC. It is infrequently performed, technically challenging and
associated with high peri-operative risk and even death. Therefore, we suggest that such patients
should be managed by a multidisciplinary team, including experienced thoracic surgeons.
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INTRODUCTION
Both local control and overall survival rates in patients with locally-advanced NSCLC remain
modest [1]. A meta-analysis found that definitive concurrent chemoradiotherapy (CRT)
was superior to the sequential administration of both modalities [2] and this strategy is one
of the guideline-recommended treatments for fit patients with an acceptable target volume
[1,3]. Although acute toxicities of CRT such as esophagitis, pneumonitis and neutropenia are
well recognized, irreversible complications such as bronchial stenosis, parenchymal cavitation
or fistula formation are less well so. Such structural complications often respond poorly to
nonsurgical interventions, and surgical treatment may represent the only definitive treatment.
To date, however, the frequency with which such operations are performed and the results of
operations for serious structural complications of CRT are not well characterized [4].
Patients who experience complications such as esophagorespiratory fistula (ERF) or
pulmonary cavitation (PC) with infection or bronchopleural fistula formation are often in a poor
physical condition, which can increase the risks of surgical intervention. These risks are further
increased by the impaired quality and wound healing capacity of tissues previously treated
with CRT. In this report, we describe our experience with the use of surgery in patients with
complications from high dose CRT for locally advanced NSCLC.
PATIENTS AND METHODS
With Institutional Review Board approval, patients who underwent operation at the VU
University medical center between 2009 and 2015, for complications after high-dose (≥60Gy)
CRT for NSCLC, were identified in an institutional lung cancer surgery database. Patients who
were initially treated with high-dose CRT as part of a trimodality approach were excluded.
Patient and treatment data were extracted from individual patient records, and referring
physicians or general practitioners were contacted. Patient and tumor characteristics analyzed
included age at first diagnosis of NSCLC, sex, comorbidity (age-adjusted Charlson Comorbidity
Index [AA-CCI], American Society of Anesthesiologists score [ASA] and Body Mass Index [BMI])
before operation, tumor histologic examination, and stage (seventh edition TNM). Treatment-
specific details including the initial CRT, type of complications, preoperative feeding policy
and surgical interventions for the treatment of complications were recorded. Peri-operative
microbiological cultures and pathology reports of resected tissue, were extracted.
Complications of CRT were categorized as (1) complicated PC (with or without infection,
with or without bronchopleural fistula): a non-bronchial air-containing cavity located within the
area of the treated primary tumor, as defined in a previous publication on tumor cavitation
which included 2 patients described in this study [5]; (2) hemorrhage: both acute or chronic (eg.
because of persistent infection in a pulmonary cavity); (3) bronchial stenosis; (4) esophageal
stenosis; and (5) ERF.
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CHAPTER 7
In patients not requiring urgent intervention, the decision to operate was made by a
multidisciplinary team, including thoracic surgery, pulmonary oncology, radiation oncology,
radiology and nuclear medicine.
The time from last day of radiotherapy to the date of first diagnosis of a complication
treated with an operation, and time from diagnosis of these complications and subsequent
surgical intervention were recorded in months. Complications were confirmed by radiologic
examination except for acute hemorrhage necessitating immediate intervention. The 30- and
90-day mortality rates were counted from the day of the primary surgical procedure planned
to resolve the complication. Overall survival was calculated from the date of diagnosis of the
complication to last day of follow-up or death.
RESULTS
Between January 2009 and December 2015, 15 patients underwent an operation for
complications after definitive CRT. Nine of the 15 patients had undergone CRT in our hospital.
All operations were performed at the VU University medical center, which is a tertiary
referral hospital for thoracic surgical oncology. Patient, tumor and initial CRT characteristics are
presented in Table 1. The median age at initial diagnosis of NSCLC was 56 years (range, 44 to
65 years) and patients were predominantly men (67%). Initial tumor stage was IIIA in 9 patients
(60%), IIIB in 5 patients (33%), or IV in 1 patient (7%). The reason that trimodality therapy was
not used in the initial treatment of patients with stage IIIA disease was multi-level mediastinal
nodal involvement in 3 patients, insufficient pulmonary function in 2 patients, prior malignancy
in 2 patients, prior pulmonary resection in 1 patient, and a major cerebrovascular accident in 1
patient. All patients received platinum-based chemotherapy and 66-Gy radiotherapy, which was
concurrent in 14 patients (93%), and sequential in 1 patient. The median time between last day
of radiotherapy and first radiologic confirmation of a complication was 8 months (range, 0 to
102 months), but this varied widely from fistula formation during therapy to the development
of an infected PC with hemorrhage 102 months after finishing radiotherapy. The median time
between clinical confirmation of a complication and first surgical procedure was 3 months
(range, 0 to 16 months).
The complications and the details of the subsequent surgical procedures are presented in
Table 2. Before the operation, the median AA-CCI was 5 (range, 3 to 7), median ASA score was
3 (range, 2 to 4), BMI was less than 18kg/m2 in 4 patients (27%), 5 patients (33%) required
oral protein-enriched nutritional support, and 6 patients (40%) had enteral nutrition. Four
patients (27%) experienced two or more complications, and more than one surgical procedure
was performed in 9 patients (60%), with a median of 2 procedures per patient (range, 1 to 10
procedures per patient).
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81
Tabl
e 1:
Pati
ent,
tum
or a
nd tr
eatm
ent c
hara
cter
istic
s of
pati
ents
trea
ted
with
sur
gery
for
late
com
plic
ation
s aft
er c
hem
orad
ioth
erap
y fo
r N
SCLC
Patie
ntSe
xA
ge a
t di
agno
sis
inde
x tu
mor
cTN
M(+
= p
atho
logy
pro
ven
N-in
volv
emen
t )
Stag
e (T
NM
7)H
isto
logi
c ex
amin
tion
CRT
sche
me
RT dose
(Gy)
Tim
e la
st R
T to
com
plic
ation
(m
ths)
Tim
e co
mpl
icati
on
to o
pera
tion
(mth
s)
1M
63T2
N2(
+)III
AAC
conc
urre
nt66
312
2M
55T4
N3(
+)III
BAC
conc
urre
nt66
03
3M
58T2
N2
IIIA
NSC
LCco
ncur
rent
666
4
4M
65Tx
N2(
+)III
ASC
Cco
ncur
rent
668
1
5M
49T2
N2(
+)III
AN
SCLC
conc
urre
nt66
97
6M
56T1
N2(
+)III
AAC
conc
urre
nt66
160
7M
58T4
N2(
+)III
BSC
Cco
ncur
rent
664
0
8F
44T2
N2(
+)III
AAC
conc
urre
nt66
98
9F
50T2
N2
IIIA
ACco
ncur
rent
665
16
10F
50T4
N2
IIIB
SCC
conc
urre
nt66
102
4
11M
48T4
N0
IIIA
ACco
ncur
rent
664
6
12M
60T4
N2(
+)III
BSC
Cco
ncur
rent
662
0
13M
59T2
N2
IIIA
NSC
LCco
ncur
rent
6601
9
14M
45T1
N2M
12 (+)
IVAC
conc
urre
nt66
771
15F
57T2
N3
(+)
IIIB
NSC
LCse
quen
tial
6691
01 C
avity
was
alre
ady
pres
ent d
urin
g in
itial
pre
sent
ation
, 2 Bra
in m
etas
tasi
s (r
esec
ted)
AC =
ade
noca
rcin
oma,
CRT
= c
hem
orad
ioth
erap
y, C
T =
chem
othe
rapy
, cTN
M =
clin
ical
TN
M, M
= m
ale,
F =
fem
ale,
NSC
LC =
non
-sm
all c
ell l
ung
canc
er,
RT =
radi
othe
rapy
, SCC
= s
quam
ous
cell
carc
inom
a, +
= p
atho
logy
pro
ven
N-in
volv
emen
t
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CHAPTER 7
Tabl
e 2:
Sur
gica
l cha
ract
eris
tics,
sur
viva
l aft
er d
iagn
osis
of t
he c
ompl
icati
on, a
nd c
ause
of d
eath
of p
atien
ts t
reat
ed fo
r la
te c
ompl
icati
ons
after
hig
h do
se C
RT
for
NSC
LCPa
tien
tCo
mpl
icati
on
of C
RTBM
IA
A-
CCI
ASA
Surg
ical
proc
edur
esPr
inci
pal
oper
ation
Com
plic
ation
of
oper
ation
Add
ition
al
inte
rven
tion
sH
ospi
tal
stay
(ICU
), da
ys
Surv
ival
aft
er c
ompl
icati
on
(CRT
)/ a
fter
ope
rati
on,
mon
ths
Caus
e of
de
ath
1PC
22.0
42
2Th
orac
osto
my
Pers
iste
nt
infe
ction
2n th
orac
osto
my
17 (1
)2/
0*M
OF
2ER
F23
.25
25
Esop
hage
ctom
ySC
V-sy
ndro
me
+ is
chem
ic
jeju
num
Re-t
hora
coto
my
+ re
-lapa
roto
my
with
en
tera
l res
ectio
n +
trac
heos
tom
y
78 (5
7)11
/8*
MO
F
3PC
25.2
62
1G
PM-p
last
y0
07
(2)
47/4
3*SC
LC
4PC
15.4
53
1Th
orac
osto
my
00
7 (0
)2/
1*RF
5PC
+ B
PF16
.03
310
Thor
acop
last
y +
clos
ure
BPF
with
A
SM-p
last
y
Nec
rosi
s A
SM-
flap
+ pe
rsis
tent
BP
F +
blee
ding
br
achi
ocep
halic
ar
tery
Om
ento
plas
ty
+ sp
lene
ctom
y +G
PM-p
last
y +
brac
hioc
epha
lic a
rter
y st
ent +
trac
heos
tom
y
143
(46)
18/1
1*CR
F
6BS
24.8
44
3Sl
eeve
lo
bect
omy
BPF
Com
pleti
on
pneu
mec
tom
y +
trac
heos
tom
y
74 (6
2)44
/44*
PCa
7PC
+ B
PF30
.37
34
Thor
acos
tom
y +
clos
ure
BPF
Cost
al p
ain
2 tim
es re
visi
on
thor
acos
tom
y +
thor
acop
last
y w
ith
ICM
-pla
sty
51 (2
9)27
/27*
RF
8PC
+ B
S +
BPF
+ H
20.4
32
3Th
orac
osto
my
0A
SM-p
last
y +
scar
tis
sue
corr
ectio
n20
(0)
67/5
9-
9ES
+ E
RF21
.54
24
Esop
hage
ctom
yD
ynam
ic a
irw
ay
colla
pse
Trac
heos
tom
y +
re-
trac
heos
tom
y98
(24)
24/8
*RF
10PC
+ H
24.0
53
1Th
orac
osto
my
+ LD
M-p
last
y0
09
(1)
32/2
8-
11ER
F17
.53
34
Pneu
mon
ecto
my
+ esop
hage
ctom
y
Blee
ding
Re-t
hora
com
y +
gast
ric
tube
+
trac
heos
tom
y
67 (4
3)19
/13*
RF
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83
Pati
ent
Com
plic
ation
of
CRT
BMI
AA
-CC
IA
SASu
rgic
alpr
oced
ures
Prin
cipa
lop
erati
onCo
mpl
icati
on o
f op
erati
onA
dditi
onal
in
terv
enti
ons
Hos
pita
l st
ay (I
CU),
days
Surv
ival
aft
er c
ompl
icati
on
(CRT
)/ a
fter
ope
rati
on,
mon
ths
Caus
e of
de
ath
12PC
17.9
73
1Th
orac
osto
my
00
37 (0
)9/
9*Bl
13PC
24.6
43
2Th
orac
osto
my
+ A
SM-p
last
yPe
rsis
tent
in
fecti
on2nd
thor
acos
tom
y +
LDM
-pla
sty
32 (1
)12
/3*
RF
14B
25.8
62
1Pu
lmon
ary
wed
ge re
secti
on0
015
(0)
27/2
6-
15H
25.2
54
1Bi
lobe
ctom
yCo
ma
06
(5)
0/0*
Com
a * =
Dec
ease
dA
A-CC
I =
age
adju
sted
Cha
rlso
n Co
mor
bidi
ty I
ndex
, A
SA =
Am
eric
an S
ocie
ty A
nest
hesi
olog
ists
, A
SM =
ant
erio
r se
rrat
us m
uscl
e, B
= b
ronc
hiec
tasi
s,
Bl =
ble
edin
g BM
I =
Body
Mas
s In
dex,
BPF
= b
ronc
hopl
eura
l fist
ula,
BS
= br
onch
ial s
teno
sis,
CRF
= c
ardi
o-re
spira
tory
fai
lure
, CR
T =
chem
orad
ioth
erap
y,
ERF
= oe
soph
agor
espi
rato
ry fi
stul
a, E
S =
esop
hage
al s
teno
sis,
GPM
= g
reat
er p
ecto
ral m
uscl
e, H
= h
emor
rhag
e, IC
M =
inte
rcos
tal m
uscl
e, IC
U =
inte
nsiv
e ca
re u
nit,
LD
M =
latis
sim
us d
orsi
mus
cle,
MO
F =
mul
tiorg
an fa
ilure
, NSC
LC =
non
-sm
all c
ell l
ung
canc
er, P
C =
pulm
onar
y ca
vita
tion,
PCa
= p
rost
ate
canc
er,
RF =
resp
irato
ry fa
ilure
, SCV
= s
uper
ior
cava
l vei
n, S
CLC
= sm
all-c
ell l
ung
canc
er
Tabl
e 2:
con
tinue
d
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Pulmonary cavitation
The most frequent complication was PC (9 patients, 60%). The reason to operate on these
patients was infection in 8 patients, with (3 patients) or without (5 patients) a bronchopulmonary
fistula, resulting in severe cachexia or cough. Another reason was hemoptysis due to ongoing
infection in an irradiated infected area adjacent to pulmonary or bronchial vessels that was
interpreted as signifying a high risk of possible severe hemorrhage (2 patients, one of which
also had a bronchopleural fistula). To relieve symptoms, patients with PC were treated by partial
resection of one or more ribs, resulting in a thoracostomy and drainage of infected contents
(n=11 in 9 patients). Seven vascularized muscle flaps were used in 6 patients to fill the cavity,
to cover a bronchopleural fistula (n=3), or both. In 4 patients, 5 muscle flap transpositions were
done at the initial thoracostomy procedure (one-step) and 2 patients had a multistep procedure
(Table 2). In patients without direct muscle transposition, the cavity was managed with daily
dressing changes.
Esophagorespiratory fistula
Operations were performed for an ERF in 3 patients (20%), 1 of whom also had complete
occlusion of the esophageal lumen. All 3 patients underwent esophagectomy. Same procedure
gastric tube reconstruction was performed in 2 patients. One patient, who had a concomitant
pneumonectomy, had a delayed reconstruction with a gastric tube. There was considerable
morbidity (e.g. jejunal ischemia in 1 patient and bleeding in another patient) necessitating
multiple operations in every patient with an ERF (Table 2).
Hemorrhage
Acute hemorrhage warranting surgical intervention occurred in 2 patients (13%). One patient had
a fistula from the central pulmonary artery to the intermediate bronchus requiring an emergency
bilobectomy 67 months after CRT. The second patient, who underwent a thoracostomy 3 months
earlier because of PC 16 months after CRT, was treated with an anterior serratus muscle flap to
cover a bleeding branch of a segmental pulmonary artery.
Bronchial stenosis
Bronchial stenosis (n=2, 13%), was accompanied by PC in 1 patient, who underwent a
thoracostomy. A right upper lobe sleeve lobectomy was performed for a second patient with
bronchial stenosis, however, a completion pneumonectomy and thoracostomy were needed
because of dehiscence of the sleeve anastomosis. One patient with bronchiectasis was
successfully treated in a single operation by two parenchymal wedge resections. Although
not directly related to complications of CRT, in 5 patients (33%), the physical condition and
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pulmonary status during admission to the intensive care unit precluded adequate weaning, as a
result of which a surgical tracheostomy was performed.
During the operation, tissue sampling with postoperative pathologic examination was
performed in 12 patients (80%), but no evidence of persistent tumor was observed in any patient.
Per-operative cultures of intrathoracic tissue, debris or fluid were sent for microbiological
investigation in 12 patients (80%), which revealed micro-organisms in 5 patients, fungal infection
in 2 patients, or both in 1 patient. In 7 patients with PC, cultures were positive for bacteria in 4,
fungus (Aspergillus) in 2, and both in 1 patient. In 1 patient with PC, cultures remained negative,
and in 1 patient with PC no cultures were taken during the operation.
Median duration of postoperative stay on the intensive care unit or medium care unit was
2 days (range, 0 to 62 days) and median total hospital stay related to treatment of the CRT
complication was 32 days (range, 6 to 143 days). Readmission between first and last surgical
procedure was necessary 15 times in 6 patients. With a median follow-up of 71 months (range, 10
to 85 months), 12 patients died. The median overall survival after diagnosis of the complication
was 19 months (95% CI: 3.9 to 34.1 months) (Figure 1), and 11 months (95% CI: 4.7 to 17.3
months) after the principal operation.
Figure 1: Kaplan-Meier estimate for overall survival after diagnosis of the complication, of patients with
non-small cell lung cancer undergoing operation for complications of chemoradiotherapy. (NAR = number
at risk)
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The 30- day mortality rate was 20% (n=3) and the 90-day mortality rate was 27% (n=4). Of the
4 patients who died within 90 days of their operation, 3 patients died in the hospital because of
infection and multi-organ failure 16 days, coma 4 days, and respiratory failure 20 days after the
(principal) surgical procedure. Of the remaining patients who were dead at time of the present
analysis (n=8, 53%), none was reported to have died of disease progression or recurrent NSCLC.
In these patients, respiratory failure was reported to be the cause of death in 4, multiorgan
failure in 1, progressive prostate cancer in 1, massive bleeding from a branch of the pulmonary
artery in 1 patient with a thoracostomy, and a second primary small cell lung cancer in 1 patient.
DISCUSSION
There are limited published studies available on the surgical treatment of complications after
high-dose CRT for NSCLC. The incidence of serious structural complications requiring surgical
intervention is hard to determine. There are several reasons for this, including the retrospective
nature of this series and the fact that patients were referred from multiple institutions. In
addition, we do not have information on the proportion of patients initially considered for a
surgical procedure, but who were ultimately not operated on for varying reasons. Nonetheless,
a crude estimate is possible. Over the 7-year period of this analysis, 9 patients who received
high-dose CRT at our center were operated on for complications. We estimate that about
50 patients per year undergo definitive concurrent or sequential CRT for stage III NSCLC [3],
which suggest that about 2.5% of patients (9 of 350) have undergone surgical intervention
for serious structural complications. This indicates that the estimated incidence of operation
for complications after high dose CRT is likely to be low. Although these complications do not
preclude the use of standard CRT to a radiation dose of 60 to 66Gy and standard chemotherapy
agents, it is important that treating teams are aware of their existence and to acknowledge that
attempts to escalate the radiation dose, or to alter the systemic component of CRT, may lead to
an increase in the risk of structural complications. In the future, more accurate estimates of the
frequency and outcomes of complications are desirable and may be available from initiatives
such as the prospective national lung cancer registry (Dutch Lung Cancer Audit).
Infected pulmonary cavities and ERF may have a clinically aggressive course leading to a
debilitated and weakened patient, and some of the complications encountered after CRT were
potentially life threatening. The combination of the complication, comorbidity, and limited
condition of the patient (as indicated by the AA-CCI, ASA score and BMI) undoubtedly contributed
to the high-risk nature of these operations, with a 90-day mortality rate of 27%, and 20% in-
hospital mortality rate. The time between the onset of a complication and operation varied
considerably, and might reflect several factors, including a patient’s poor physical condition,
requirement for prior nutritional support or antibiotics before the operation, and uncertainty
in external centers about whether to refer their patient. If the patient’s condition deteriorates
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during the period between the onset of the complication and the operation, this might increase
the perioperative risks.
Despite the risks accompanying the operation, several patients achieved a prolonged
survival. To put the median overall survival of 19 months from diagnosis of the CRT complication
and 11 months after operation into some kind of context, we have previously reported a median
overall survival after the start of radiotherapy for locally advanced NSCLC treated with CRT of
18.6 months [3], and a median overall survival of 75.9 months after a median follow-up of 80.4
months (with 5.5% 90-day mortality) after up-front trimodality therapy for non-Pancoast NSCLC
[6]. Any comparisons with a salvage operation for recurrent or persistent tumor following CRT
are limited by our median follow-up in this cohort of 12.1 months with a 90-day mortality of
6.7% [7]. Determining the cause of patient death during follow-up is not straightforward and we
cannot exclude that the overall procedure-related mortality may have been even higher. Twelve
(of 15) patients operated on in the present series had pathologic examination of the resected
material performed. None had evidence of persistent tumor, and none died subsequently from
persistent or recurrent NSCLC. However, we acknowledge that we cannot definitively exclude
the presence of tumor at the time of death without an autopsy.
The risks of these interventions makes critical multidisciplinary discussion and patient
counselling regarding the risks and outcomes of an operation mandatory. In general, the
decision to operate on a patient with these kinds of complications was only made when
symptoms were severely debilitating or potentially life threatening. Except when there was an
urgent indication to operate, all decisions were made in a weekly institutional multidisciplinary
tumor board and after appropriate patient counselling. Factors that our multidisciplinary
tumor board considered in the decision-making process included the likelihood of improving
debilitating or life-threatening complaints, (e.g. continuous coughing or massive hemoptysis),
life-expectancy with or without an operation, the presence of (recurrent) tumor, co-morbidity,
and clinical condition. Although no patient in this report had a diagnosis of tumor recurrence,
late surgical resection in patients with recurrent or persistent NSCLC can achieve good results,
suggesting that a recurrence should not preclude surgery if a coexisting complication merits that
approach [6]. Although a lower BMI and higher AA-CCI were not clearly related to outcome, we
recommend preoperative involvement of a dietician, because the outcome of the operation
after CRT is negatively influenced by malnutrition [8]. Therefore, we believe that in patients
who are malnourished, with low BMI or low serum albumin, operation is preferably preceded
by nutritional support, and a multistep surgical approach may be favored to restore physical
reserves before the major surgical intervention (eg. esophageal resection in ERF).
Our experience suggests that detailed preoperative planning is necessary, with careful
attention to technical details. For example, perioperative damage of a useful muscle flap such
as the anterior serratus muscle or latissimus dorsi muscle must be avoided by an appropriate
choice of incision. This means that each complication and patient requires a tailored treatment
approach. An irradiated area with cavitation is often infected by microorganisms, fungus or
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both, and antibiotics and antifungal medication should precede surgical intervention in such
patients. In general, for PC with infection or bronchopleural fistula, we prefer to perform an
initial thoracic wall fenestration (thoracostomy) to remove the infection and debris. Once the
patient’s physical condition improves, a second operation can be undertaken to fill the cavity
with either a pedicled muscle flap (serratus anterior, latissimus dorsi, pectoralis muscle) or
omentum, depending on the size and location of the cavity. A vital muscle flap can also be used
to close a bronchopleural fistula [9]. A (partial) thoracoplasty might be added, a procedure
historically used in the treatment of tuberculosis [10], but in this context facilitates muscular
filling by reducing the size of the cavity. The interval between the 2 operations should be limited
if the cavity extends towards the pulmonary hilum, because erosion of a major vessel may cause
fatal hemorrhage. A one-step procedure with concomitant introduction of omentum or an
extrathoracic muscle (e.g. latissimus dorsi flap) can be considered, especially in patients who are
in relatively good physical condition [11].
Bronchial stenosis that contributes to recurrent infection due to sputum stasis peripheral of
the narrowed airway may require pulmonary or airway resection. Because of the previous high-
dose CRT, there is an increased risk of dehiscence of the bronchial stump or sleeve anastomosis.
To try to minimize the risk of this complication, we buttress the transected airway with a
vascularized muscle flap. In some patients, the central airway can be stented endobronchially, but
in general we prefer to reserve this for patients who are not candidates for surgical interventions
because of their physical condition or presence of disseminated tumor [12].
An ERF after CRT presents a therapeutic challenge. Published studies on this topic are
scarce, with most studies reporting on esophageal malignancy as the main cause of such
fistulae [13,14]. From our limited experience with the three patients described in this series our
preferred approach for ERF has been primary closure of the airway with muscular or pericardial
reinforcement and one- or two-stage esophageal resection and gastric tube reconstruction. The
main reason that primary closure of the esophagus was not performed, was because extended
fibrosis or stenosis of the esophagus was encountered during the operation, and at that moment
the option of a vascularized muscle flap between airway and esophagus was considered to be
insufficient.
There are a number of limitations of this study, perhaps the most considerable of which
are the retrospective analysis, the limited number of patients and the heterogeneity of the
cohort. This limits the detail that can be presented about clinical decision-making, the strength
of some of the conclusions, and the possibility of more detailed statistical and prognostic
analysis. Also important is that we do not know the outcome of such complications if they are
not operated on, and so a quantitative estimate of the benefit of an operation is not possible.
The retrospective methodology precludes formal patient-reported outcomes and quality-
of-life analysis, which may be of particular interest in this patient group. Nonetheless, and in
conclusion, our institutional experience with operations for serious structural complications
after CRT for locally advanced NSCLC indicates that these procedures are high-risk interventions.
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Given the high postoperative mortality rate, operation in this high-risk patient group can only
be justified if there are sufficiently serious complications. Each patient needs careful discussion
in an experienced multidisciplinary team and requires a high level of perioperative support
and resources. Knowledge of traditional surgical techniques such as thoracoplasty and muscle
flaps and an experienced care team before and after the operation are mandatory. Future work
should include the identification of risk factors for serious complications after CRT, the natural
history of such complications, the optimal selection of patients for surgical intervention, and
treatment strategies and techniques to minimize the risk of post-operative/intervention death.
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REFERENCES
1. Eberhardt W, De Ruysscher D, Weder W, et al; Panel Members. 2nd ESMO Consensus Conference in Lung Cancer: locally-advanced stage III non-small-cell lung cancer (NSCLC). Ann Oncol 2015;00:1-16
2. Aupérin A, Le Péchoux C, Rolland E, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol 2010;28:2181-2190
3. van Reij EJ, Dahele M, van de Ven PM, et al. Changes in non-surgical management of stage III non-small cell lung cancer at a single institution between 2003 and 2010. Acta Oncol 2014;53:316-323
4. Lee CB, Stinchcombe TE, Moore DT, et al. Late complications of high-dose (>/=66 Gy) thoracic conformal radiation therapy in combined modality trials in unresectable stage III non-small cell lung cancer. J Thorac Oncol 2009;4:74-79
5. Phernambucq EC, Hartemink KJ, Smit EF, et al. Tumor cavitation in patients with stage III non-small-cell lung cancer undergoing concurrent chemoradiotherapy: incidence and outcomes. J Thorac Oncol 2012;7:1271-1275
6. Dickhoff C, Hartemink KJ, Kooij J, et al. Is the routine use of trimodality therapy for selected patients with non-small cell lung cancer supported by long-term clinical outcomes? Ann Oncol 2017;28:185
7. Dickhoff C, Dahele M, Paul MA, et al. Salvage surgery for locoregional recurrence or persistent tumor after high dose chemoradiotherapy for locally advanced non-small cell lung cancer. Lung Cancer 2016;94:108-113
8. van der Meij BS, Phernambucq EC, Fieten GM, et al. Nutrition during trimodality treatment in stage III non-small cell lung cancer: not only important for underweight patients. J Thorac Oncol 2011;6:1563-1568
9. Meyer AJ, Krueger T, Lepori D, et al. Closure of large intrathoracic airway defects using extrathoracic muscle flaps. Ann Thorac Surg 2004;77:397-404
10. Dewan RK, Moodley L. Resurgence of therapeutically destitute tuberculosis: amalgamation of old and newer techniques. J Thorac Dis 2014;6:196-201
11. Hata Y, Otsuka H, Makino T, et al. Surgical treatment of chronic pulmonary aspergillosis using preventive latissimus dorsi muscle flaps. J Cardiothorac Surg 2015;10:151
12. Murgu S, Egressy K, Laxmanan B, et al. Central airway obstruction: benign strictures, tracheobronchomalacia and malignancy-related. Chest 2016;150:426-441
13. Hürtgen M, Herber SC. Treatment of malignant tracheoesophageal fistula. Thorac Surg Clin 2014;24:117-127
14. Ke M, Wu X, Zeng J. The treatment strategy for tracheoesophageal fistula. J Thorac Dis 2015;7(Suppl4):S389-S397
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CHAPTER 8
Radical-intent treatment of lung cancer
after prior thoracic radiotherapy
C. Dickhoff
S. Senan
M. Dahele
Letter to the Editor in Journal of Thoracic Oncology 2017;12:e26-e27
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To the Editor:
Radical retreatment in the thorax, for patients with locoregionally recurrent or new primary non-
small cell lung cancer is a challenging problem. We therefore read with interest the findings of
a prospective 3-institution study of proton reirradiation by Chao et al [1]. With a median follow-
up (FU) of 7.8 months, the authors report a median overall survival (OS) of 14.9 months, with
6 grade 5 toxicities in 57 patients. A significantly higher rate of grade ≥3 toxicity was associated
with increased central airway overlap region, mean esophagus and heart doses, and concurrent
chemotherapy.
These findings are consistent with our published institutional experience of high-dose
thoracic photon reirradiation for locoregionally recurrent, or second primary lung tumors, in 24
patients who had received 2 high dose treatments, many with substantial dosimetric overlap
[2]. In particular, the median OS of 13.5 months (95% CI 5.7-21.2) in our series was comparable
to of Chao et al, but after a notably longer median FU of 19.3 months. We also concluded that
smaller tumors had better outcomes and observed a median OS of 17.4 months in patients with
a planning target volume <300cm3. In an updated report of 30 such patients after a median FU
of 25 months, the median OS remained unchanged [3]. Six patients who underwent a central
retreatment died of hemorrhage, at a median of 7 months after treatment. The currently
available results do not suggest a clear difference between photon and proton reirradiation, and
for the patients with the highest risks, centrally located organs like large airways and vessels are
typically in contact with the tumor and inside the volume to be retreated, limiting the high-dose
sparing that can be expected, even with the use of protons.
The patients receiving high-dose reirradiation at our center are highly selected, and it is
not uncommon for patients to decline reirradiation for central tumors once they realize the
potential for life-threatening toxicity. The relatively early occurrence of severe toxicity in patients
undergoing central reirradiation means that alternative treatments, including salvage surgery,
should be considered in fit patients with technically resectable tumors. We have also published
our experience with salvage surgery following prior high-dose (≥60Gy) (chemo)radiotherapy [4],
with the limited number of patients (15) again indicating that they were highly selected. With a
median FU of 12.1 months, the estimated median OS was 46 months and the 90-day mortality
was 6.7%. We concluded that salvage surgery was a valuable treatment option with acceptable
risks for selected patients.
While it is important to optimize reirradiation and salvage surgery, it is also important that
patients fit for a radical-intent intervention are reviewed by a multi-disciplinary team that
includes a thoracic surgeon and radiation oncologist with the relevant experience, or that they
are referred to an appropriate center for an opinion.
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REFERENCES
1. Chao HH, Berman AT, Simone CB 2nd, et al. Multi-institutional Prospective Study of Reirradiation with Proton Beam Radiotherapy for Locoregionally Recurrent Non-Small Cell Lung Cancer. J Thorac Oncol 2016;12:281-292
2. Griffioen GH, Dahele M, de Haan PF, van de Ven PM, Slotman BJ, Senan S. High-dose, conventionally fractionated thoracic reirradiation for lung tumors. Lung Cancer 2014;83:356-362
3. Tetar S, Dahele M, Griffioen G, Slotman B, Senan S. High-dose conventional thoracic re-irradiation for lung cancer: updated results. Lung Cancer 2015;88:235-236
4. Dickhoff C, Dahele M, Paul MA, et al. Salvage surgery for locoregional recurrence or persistent tumor after high dose chemoradiotherapy for locally advanced non-small cell lung cancer. Lung Cancer 2016;94:108-113
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CHAPTER 9
Discussion and future perspectives
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DISCUSSION AND FUTURE PERSPECTIVES
This thesis has explored the role of surgery as part of the multimodality treatment strategy
for locally-advanced non-small cell lung cancer (NSCLC). This includes its role in patients with
IIIA and IIIB disease, recurrent tumor or persistent disease after definitive chemoradiotherapy
(CRT) and in patients suffering from serious complications following CRT that are resistant to
conservative therapies. Both institutional data and data extracted from the Netherlands Cancer
Registry (NCR) were analyzed.
The optimal therapeutic approach for patients with locally-advanced NSCLC is a subject
of ongoing debate. The value of surgery as part of multimodality treatment has not yet been
fully defined. Although several attempts have been made during the last decade, prospective,
randomized trials have so far failed to prove the superiority of treatments including surgery over
other therapeutic strategies in terms of overall survival [1-3]. In addition, the heterogeneity of
patient- and tumor characteristics, the difficulty accruing patients, lack of statistical power and
the application of varying induction regimens, make the results from these studies difficult to
translate into daily practice. In contrast, some studies exploring data from large population-
based registries, perhaps more reliably reflecting daily practice, do report favorable survival
when surgery is part of the multimodality treatment for selected patient groups, however
the contribution of selection bias is hard to quantify [4-7]. Based on the available evidence,
current guidelines state that after multidisciplinary tumor board discussion, both definitive CRT
and induction therapy followed by surgery can be considered radical options for appropriately
selected patients [8,9].
To explore the contemporary use of surgery in patients with stage III NSCLC in the Netherlands,
and its role in daily practice, we analyzed data from the NCR. For stage IIIA and IIIB, surgery was
used in 15% and 2.2%, of patients respectively. For clinical stage IIIA NSCLC, although the patients
receiving surgery as part of their treatment (in particular those treated with induction therapy
followed by surgery) had better survival than those treated with CRT, patient characteristics
were not matched. Although we could see that the patients receiving surgery were younger,
other details like performance status or co-morbidity are not contained in the NCR. We did not
find different survival rates between patients treated with induction chemotherapy or induction
chemoradiotherapy, which is in line with the results of a recent phase III trial [11]. However, in
patients with tumors involving surrounding structures, e.g. the thoracic wall, our team prefers
to use induction CRT to maximize resectability and local control. This is the same strategy that is
used in our institution for superior sulcus (Pancoast) tumors [12]. With the introduction of the
7th edition of the UICC TNM classification of lung cancer [10], potentially resectable T4N0-1 has
migrated from stage IIIB to IIIA, explaining the near absence of surgery for stage IIIB when using
this classification, compared with the period when the TNM 6th edition was being used. We also
found that older patients with stage IIIB disease were less likely to have curative intent CRT or
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surgery. Since age alone is often not the deciding factor for treatment selection [13], the reasons
for this are uncertain.
Selecting the optimal treatment strategy for patients with NSCLC, starts with adequate
staging. After correct TNM staging and after taking the patient’s physical condition and personal
considerations into account, a treatment proposal is constructed during multidisciplinary
discussion. To evaluate the accuracy of the staging process, the clinical TNM (cTNM) can be
compared with the pathological TNM (pTNM), with the latter considered to be the gold standard.
In our analysis of the NCR cIIIA data in patients whose tumor was resected up-front, without
induction, we only found a 51% agreement of cTNM and pTNM. For stage IIIB, this was even
less, and only 17% of the patients with up-front surgery were correctly staged as IIIB (although
the numbers were small). In clinical stage IIIA, the majority of the patients had a lower pTNM,
and mediastinal nodal overstaging (N2) was largely responsible for this finding. For patients with
induction therapy and patients treated with definitive CRT, determining staging accuracy was
not possible, but it is plausible that a considerable number patients in these groups were also
incorrectly staged, meaning that survival data needs to be interpreted with caution.
New clinical registries, in particular the Dutch Lung Cancer Audit (DLCA), including data from
radiation oncologists, pulmonary oncologists and surgeons, may help to identify which patient
and tumor characteristics are most important for selecting different treatments and maximizing
outcomes. In addition, further information about the accuracy of clinical staging could stimulate
treating physicians and tumor boards to improve their staging strategy, and help to prevent
under-or over-treatment.
If the exact role of surgery in the primary treatment of patients with locally advanced
NSCLC has not yet been fully worked out, then even less is known about its use in patients
with complications of definitive CRT and recurrent or persistent disease after CRT. The current
literature does not clearly state how to approach these complex clinical situations. With
concurrent CRT increasingly being used for patients with stage III NSCLC [14], the incidence of
treatment related complications is expected to increase. Some complications are self-limiting
(e.g. esophagitis), or can be medically treated, but other, more structural complications (e.g.
bronchial stenosis, pulmonary cavitation), will not spontaneously resolve and may result in
severe morbidity, and even mortality. In our institutional analysis of complications after high
dose CRT, we observed surgery in these patients to be complex and high risk, with a 30-day and
90-day mortality of 20% and 27% respectively, however, untreated, these complications have a
high morbidity, or can be a serious threat to life (e.g. hemorrhage). In the absence of alternative
treatment options for these complications, we believe that surgery can be justified in selected
patients. The balance between debilitating symptoms and potentially life-threatening conditions
and the risks of surgery, needs to be debated in a multidisciplinary team, and discussed with the
patient.
Clinicians treating NSCLC patients with CRT will at some point be confronted with patients in
whom the tumor, or lymph nodes, are not completely sterilized (persistent disease) or in whom it
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recurs after completion of chemoradiotherapy. The approach to these patients is challenging and
also incompletely addressed in the available literature, preventing definitive conclusions from
being drawn. Several treatment options are described, from curative intent salvage radiotherapy
or surgery, to palliative care with chemotherapy, radiotherapy and best supportive care. There
are a few reports on salvage surgery, however, no uniform definition for this is used, hampering
the comparison of results. We defined salvage surgery as pulmonary resection of locoregional
recurrence or persistent tumor in the irradiated area, ≥12 weeks after radical CRT (≥60Gy) for
NSCLC. This definition excludes patients with recurrence of early stage tumors, treated with
(stereotactic) radiotherapy, and patients treated for complications after CRT, without evidence
of tumor. To justify surgery in a region that has been irradiated to a high-dose, an attempt should
be made by the treating team to try and prove the presence of vital tumor. In addition, the
presence of metastases, particularly in the brain, should be excluded before surgery is planned.
Although in our retrospective series describing salvage surgery not all patients had pathological
proven tumor before surgery, all patients had vital tumor at pathological examination of the
resected specimen. The interpretation of CT-scans and PET-scans during follow-up after CRT,
is challenging, as it can be hard to distinguish between post-radiotherapy tissue damage and
recurrent/persistent tumor [15]. Therefore, all patients with suspected recurrent or persistent
disease, should be discussed in a multidisciplinary tumor board, attended by experienced
radiologists, nuclear physicians, pulmonary oncologists, radiation oncologists and surgeons.
Pulmonary surgery in irradiated tissue is associated with a higher risk of impaired tissue
healing and perioperative bleeding, making greater demands on the surgeon. The potential
risks, together with the finding that nearly 40% of patients had a distant relapse after trimodality
treatment, of which a considerable number occurred within a year after surgery, raises the
question of whether we should treat patients with stage III NSCLC with radical intent CRT alone,
instead of a trimodality protocol. Surgery can then be reserved for those patients suffering
from isolated local recurrence or persistent disease, without distant spread. This strategy might
prevent a surgical procedure for those patients who are going to relapse quickly after initial
bimodality treatment. We have shown that surgery in patients receiving high dose radiotherapy
(>60Gy), can be performed safely, in both patients undergoing surgery as part of trimodality
treatment and in those patients operated on for recurrent or persistent disease. In addition, we
also found that patients with larger planning target volume tumor (PTV>500cm3) had better
survival when treated with trimodality therapy than with definitive CRT, possibly reflecting the
inability of radiotherapy to completely sterilize these larger volume tumors. Tumor volume
should therefore be included in studies comparing these two treatment strategies.
It is likely that in the future, surgery will be increasingly used for recurrent or persistent
disease after curative intent CRT, failure after stereotactic radiotherapy and complications
resulting from these therapies. The exact additional value of surgery, over CRT alone, in the
planned treatment of resectable locally advanced disease has still to be established. Possible
factors predicting complete response to chemoradiotherapy, e.g. tumor volume, tumor biology,
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and parameters allowing treating physicians to differentiate between necrosis, fibrosis, ongoing
radiotherapy effect and vital tumor tissue on imaging after chemoradiotherapy, are issues to be
addressed in future studies.
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REFERENCES
1. van Meerbeeck JP, Kramer GW, Van Schil PE, et al. European Organisation for Research and Treatment of Cancer-Lung Cancer Group. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst 2007;99:442-450
2. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet 2009;374:379-386
3. Eberhardt WE, Pöttgen C, Gauler TC, et al. Phase III Study of Surgery Versus Definitive Concurrent Chemoradiotherapy Boost in Patients With Resectable Stage IIIA(N2) and Selected IIIB Non-Small-Cell Lung Cancer After Induction Chemotherapy and Concurrent Chemoradiotherapy (ESPATUE). J Clin Oncol 2015;33:4194-4201
4. Koshy M, Fedewa SA, Malik R, et al. Improved survival associated with neoadjuvant chemoradiation in patients with clinical stage IIIA(N2) non-small-cell lung cancer. J Thorac Oncol 2013;8:915-922
5. Patel AP, Crabtree TD, Bell JM, et al. National patterns of care and outcomes after combined modality therapy for stage IIIA non-small-cell lung cancer. J Thorac Oncol 2014;9:612-621
6. Vinod SK, Wai E, Alexander C, et al. Stage III non-small-cell lung cancer. Population-based patterns of treatment in British Columbia, Canada. J Thorac Oncol 2012;7:1155-1163
7. Hancock J, Rosen J, Moreno A, et al. Management of clinical stage IIIA primary lung cancers in the National Cancer Database. Ann Thorac Surg 2014;98:424-432
8. Eberhardt W, De Ruysscher D, Weder W, et al; Panel Members. 2nd ESMO Consensus Conference in Lung Cancer: locally-advanced stage III non-small-cell lung cancer (NSCLC). Ann Oncol 2015;00:1-16
9. Ramnath N, dilling TJ, Harris LJ, et al. Treatment of stage III non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143: e314S-e340S
10. Rami-Porta R, Crowley JJ, Goldstraw P. The revised TNM staging system for lung cancer. Ann Thorac Cardiovasc Surg 2009;15:4-9
11. Pless M, Stupp R, Ris HB, et al; SAKK Lung Cancer Project Group. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet 2015;386:1049-1056
12. Vos CG, Hartemink KJ, Blaauwgeers JL, et al. Trimodality therapy for superior sulcus tumours: evolution and evaluation of a treatment protocol. Eur J Surg Oncol 2013;39:197-203
13. Dawe DE, Christiansen D, Swaminath A, et al. Chemoradiotherapy versus radiotherapy alone in elderly patients with stage III non-small cell lung cancer: A systematic review and meta-analysis. Lung Cancer 2016;99:180-185
14. van der Drift MA, Karim-Kos HE, Siesling S, et al. Progress in standard of care therapy and modest survival benefits in the treatment of non-small cell lung cancer patients in the Netherlands in the last 20 years. J Thorac Oncol 2012;7:291-298
15. Ryu JS, Choi NC, Fischman AJ, Lynch TJ, Mathisen DJ. FDG-PET in staging and restaging non-small cell lung cancer after neoadjuvant chemoradiotherapy: correlation with histopathology. Lung Cancer 2002;35:179-187
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CHAPTER 10
Summary
Samenvatting
List of publications
Curriculum Vitae
Dankwoord
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SUMMARY
This thesis comprises two parts, in which the evolving role of surgery in the multimodality
treatment of locally-advanced non-small cell lung cancer treatment is studied. In the first part,
the role of surgery as part of planned trimodality treatment is explored. In the second part, its
role in the treatment of persistent or recurrent disease is analyzed.
PART I Surgery as part of trimodality treatment for locally advanced NSCLC
There are several national and international guidelines recommending radical intent
chemoradiotherapy or treatment approaches that include surgery for patients with clinical
stage IIIA NSCLC. However, thus far it has been unclear how these guidelines are applied in daily
practice in the Netherlands. Chapter 2 describes the current use of several treatment strategies
for patients with clinical stage IIIA NSCLC in the Netherlands, using data from the Netherlands
Cancer Registry (NCR) during the period 2010 until 2013. In this national cohort, including
nearly 5000 patients, chemoradiotherapy was used in 45% of patients, and 15% were treated
with surgery was part of the treatment. The 4-year survival was 51% in patients treated with
induction therapy and surgery, compared with 39% for patients receiving chemoradiotherapy.
Patients treated with surgery were younger (median 60 vs 66 yrs), and those with induction
treatment prior to surgery did best when aged under 69, had squamous histology and
underwent lobectomy instead of a bilobectomy or pneumonectomy. An unexpected finding
was the poor agreement of only 51% between clinical and pathological TNM stage in those
patients treated with upfront surgical resection ± adjuvant therapy, with a majority of the
patients being clinically over-staged. For clinical stage IIIB NSCLC, we explored national patterns
of care between 2010 and 2014, a period in which the TNM 7th edition was used nationally.
Results are described in Chapter 3, which has a secondary focus on the use of surgery for these
patients. In this period, 4401 patients were diagnosed with clinical stage IIIB, of which clinical
N2 (37%) or N3 nodal disease (63%) was pathologically confirmed in only 50.8%. Radical intent
treatment consisted of chemoradiotherapy in 48% of patients and surgery in 2.2% of patients,
with a decrease of the use of chemoradiotherapy from 65% for patients aged <60 years to 13%
for patients aged 80 years or older. Overall survival for surgery was 28 months, followed by
chemoradiotherapy (19 months), chemotherapy (9 months), radiotherapy (8 months) and best
supportive care (3 months). In Chapter 4, our institutional outcome of chemoradiotherapy and
trimodality treatment for locally advanced NSCLC is described and discussed. Patients treated
with trimodality therapy were younger and were more likely to have T4 tumors rather than
N2-disease determining their clinical stage IIIA. With a median follow-up of 30 months, median
survival was not reached for the trimodality group. Patients with N0-1, and larger volume tumors
(represented by a radiotherapy planning target volume >500cm3) had superior survival when
treated with trimodality therapy compared with chemoradiotherapy. In Chapter 5, we showed
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surgery after induction chemoradiotherapy can be performed safely, with a 90-day mortality
of 5.5%, and has promising long term overall and event-free survival of 75.9 and 58.7 months,
respectively (median follow-up 80.4 months).
PART II New roles for surgery after chemoradiotherapy: recurrent or persistent disease and
complications
For patients with recurrent or persistent tumor after radical chemoradiotherapy, therapeutic
options with curative intent are limited. For selected patients, surgery or re-irradiation (Chapter
8) can be considered. Results from the surgical approach, are outlined and discussed in Chapter
6. All patients had high dose chemoradiotherapy (>60Gy), as their initial treatment for locally
advanced NSCLC (10 patients stage IIIA, 5 stage IIIB). The median time of surgery was 21 months
after the last day of radiotherapy. Although surgery in an area long after completion of high dose
radiotherapy is believed to be hazardous, we report that selected patients with locoregional
recurrence or persistent tumor after high dose chemoradiotherapy, can undergo salvage surgery
with acceptable morbidity and mortality, even when a pneumonectomy is required. For patients
who do not have recurrent or persistent disease after high dose chemoradiotherapy, but suffer
from severe complications after such therapy, such as bronchial stenosis, hemorrhage and
esophageal-respiratory fistula, we show that surgical procedures are high risk interventions, as
described in Chapter 7. For the majority of patients, operated on for structural complications
after chemoradiotherapy, all formerly treated with 60 Gy or more, pulmonary cavitation was
the indication for surgical intervention. Other complications for which surgery was performed
were esophago-respiratory fistulae, hemorrhage, bronchial stenosis, esophageal stenosis and
bronchiectasis. The 30- and 90-day mortality was 20% and 27%, respectively, reflecting that
this is a high risk patient group. Therefore, surgery is only justified in those patients with highly
debilitating or life threatening complications.
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CHAPTER 10
Summary
Samenvatting
List of publications
Curriculum Vitae
Dankwoord
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SAMENVATTING
In deze thesis, bestaande uit twee delen, wordt de rol van chirurgie in de multimodaliteit
behandeling van het lokaal gevorderd niet-kleincellig long carcinoom bestudeerd. In het eerste
deel wordt de rol van chirurgie als onderdeel van geplande trimodaliteit therapie uitgediept.
In het tweede deel wordt de rol van chirurgie in de behandeling van persisterende tumor of
terugkerende ziekte geanalyseerd.
DEEL I Chirurgie als onderdeel van trimodaliteit therapie voor het lokaal gevorderd niet-
kleincellig longcarcinoom
Voor patiënten met klinisch stadium IIIA niet-kleincellig longcarcinoom, adviseren verschillende
nationale en internationale richtlijnen in opzet radicale chemoradiotherapie, of een behandeling
welke chirurgie bevat. Het is echter onduidelijk in hoeverre deze richtlijnen in Nederland worden
toegepast in de dagelijkse praktijk. In Hoofdstuk 2 wordt met gebruik van data uit de Nederlandse
Kanker Registratie, voor de periode van 2010 tot en met 2013, het gebruik van verschillende
behandel strategieën voor patiënten met stadium IIIA niet-kleincellig longcarcinoom beschreven.
In dit nationale cohort van bijna 5000 patiënten, werd chemoradiotherapie gebruikt in 45%
van de patiënten, en in 15% van de patiënten was chirurgie onderdeel van de behandeling. De
4-jaars overleving bedroeg 51% voor de patiënten behandeld met inductie therapie en chirurgie,
en 39% voor hen die werden behandeld met chemoradiotherapie. De patiënten die chirurgie
ondergingen waren jonger (mediaan 60 vs. 66 jaar), en de patiënten die inductietherapie
ondergingen voorafgaand aan chirurgie hadden hier het meeste baat bij als ze jonger dan 69
jaar waren, in het geval van een plaveiselcelcarcinoom, en een lobectomie in plaats van bi-
lobectomie of pneumectomie ondergingen. Een onverwachte bevinding was het feit dat voor
patiënten behandeld met chirurgie ± adjuvante therapie, het klinische TNM stadium slechts in
51% overeenkwam met het pathologische TNM stadium, waarbij in het grootste deel van de
patiënten het klinisch stadium te hoger was dan het pathologisch stadium. De nationale zorg,
met een secundair focus op de rol van de chirurgische behandeling, voor het klinisch stadium
IIIB niet-kleincellig longcarcinoom in de periode van 2010 tot en met 2014, waarin de 7e editie
van de TNM nationaal werd toegepast voor het stadiëren van patiënten met het niet-kleincellig
longcarcinoom, wordt beschreven in Hoofdstuk 3. In deze periode werden 4401 patiënten
gediagnosticeerd met klinisch stadium IIIB niet-kleincellig longcarcinoom, waarvan klinisch N2
(37%) of N3 nodale ziekte (63%) in slechts 50.8% van de patiënten pathologisch werd bevestigd. In
opzet curatieve behandeling bestond uit chemoradiotherapie in 48% en chirurgie in 2.2% van de
patiënten. Het gebruik van chemoradiotherapie daalde met de leeftijd, van 65% voor patiënten
onder de 60 jaar, tot 13% voor mensen van 80 jaar en ouder. De overleving na chirurgie was 28
maanden, gevolgd door 19 maanden na chemoradiotherapie, 9 maanden na chemotherapie,
8 maanden na radiotherapie en 3 maanden na ondersteunende therapie. In Hoofdstuk 4
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beschrijven en bediscussiëren we de institutionele resultaten van definitieve chemoradiotherapie
en trimodaliteit therapie for het lokaal gevorderd niet-kleincellig longcarcinoom. De patiënten
behandeld met trimodaliteit therapie waren jonger, en hadden vaker een T4 tumor dan N2
ziekte wat maakte dat ze een klinisch stadium IIIA niet-kleincellig longcarcinoom hadden. Voor
de trimodaliteit groep werd de mediane overleving niet bereikt bij een mediane follow-up
van 30 maanden. Patiënten met N0-1 en patiënten met tumoren van een groter volume (een
radiotherapie planning doelvolume van >500cm3) hadden een betere overleving als behandeld
met trimodaliteit therapie vergeleken met chemoradiotherapie. In Hoofdstuk 5 laten we zien
dat chirurgie na chemoradiotherapie veilig kan, met een 90 dagen mortaliteit van 5.5%, en een
veelbelovende lange termijn overleving en ziekte vrije overleving van respectievelijk 75.9 en
58.7 maanden kan bewerkstelligen (mediane follow-up 80.4 maanden).
DEEL II Nieuwe rol voor chirurgie na chemoradiotherapie: recidief, persisterende ziekte en
complicaties
Therapeutische opties voor patiënten met recidief tumor of persisterende ziekte na
chemoradiotherapie zijn beperkt. Voor geselecteerde patiënten kan chirurgie of re-irradiatie
worden overwogen (Hoofstuk 8). Resultaten van deze chirurgische behandeling (salvage
chirurgie) worden uiteengezet en besproken in hoofdstuk 6. Alle patiënten hebben initieel een
behandeling met hoge dosis chemoradiotherapie (≥60Gy) ondergaan voor een lokaal gevorderd
niet-kleincellig longcarcinoom (10 patiënten stadium IIIA, 5 patiënten stadium IIIB). De mediane
duur van de laatste dag radiotherapie tot chirurgie bedroeg 21 maanden. Hoewel chirurgie in
een eerder met hoge dosis bestraald gebied wordt gezien als potentieel risicovol, rapporteren
wij dat geselecteerde patiënten met locoregionaal recidief of persisterend tumor na hoge dosis
chemoradiotherapie, salvage chirurgie kunnen ondergaan met acceptabele morbiditeit en
mortaliteit, zelfs na pneumectomie. Voor patiënten die geen recidief tumor of persisterende
ziekte hebben na hoge dosis chemoradiotherapie, maar wel problemen hebben veroorzaakt
door complicaties van deze therapie, zoals een bronchusstenose, bloeding of fistel tussen
luchtweg en slokdarm, laten we in hoofdstuk 7 zien dat chirurgie een hoog risico behandeling
is. Het merendeel van deze patiënten werd geopereerd vanwege cavitatie in de long. Overige
complicaties waarvoor een operatie volgde waren slokdarm-luchtweg fistel, bloeding,
bronchusstenose, slokdarm stenose en bronchiëctasien. De hoge 30- en 90 dagen mortaliteit
van respectievelijk 20% en 27%, laten zien dat dit een hoog risico patiëntengroep is. Derhalve
is chirurgie alleen te rechtvaardigen in die patiënten met zeer ernstige of levensbedreigende
complicaties.
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CHAPTER 10
Summary
Samenvatting
List of publications
Curriculum Vitae
Dankwoord
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LIST OF PUBLICATIONS
This thesis (in order of appearance):
1. C. Dickhoff, M. Dahele, A.J. de Langen, M.A. Paul, E.F. Smit, S. Senan, K.J. Hartemink, R.A. Damhuis. Population-based patterns of surgical care for stage IIIA NSCLC in the Netherlands between 2010 and 2013. J Thoracic Oncol 2016;11:566-572
2. C. Dickhoff, M. Dahele, E.F. Smit, S. Senan, K.J. Hartemink, R.A. Damhuis. Patterns of care and outcomes for stage IIIB non-small cell lung cancer in the TNM-7 era: results from the Netherlands Cancer Registry. Lung Cancer 2017;110:14-18
3. C. Dickhoff, K.J. Hartemink, P.M. van de Ven, E.J.F. van Reij, S. Senan, M.A. Paul, E.F. Smit, M. Dahele. Trimodality therapy for stage IIIA non-small cell lung cancer: benchmarking multidisciplinary team decision-making and function. Lung Cancer 2014;85:218-223
4. C. Dickhoff, K.J. Hartemink, J. Kooij, P.M. van de Ven, M.A. Paul, E.F. Smit, M. Dahele. Is the routine use of trimodality therapy for selected patients with non-small cell lung cancer supported by long-term clinical outcomes? Ann Oncol 2017;28:185
5. C. Dickhoff, M. Dahele, M.A. Paul, P.M. van de Ven, A.J. de Langen, S. Senan, E.F. Smit, K.J. Hartemink. Salvage surgery for locoregional recurrence or persistent tumor after high dose chemoradiotherapy for locally advanced non-small cell lung cancer. Lung Cancer 2016;94:108-113
6. C. Dickhoff, M. Dahele, S.M. Hashemi, S. Senan, E.F. Smit, K.J. Hartemink, M.A. Paul. Surgical treatment of complications following high dose chemoradiotherapy for lung cancer. Ann Thorac Surg 2017;104:436-442
7. C. Dickhoff, S. Senan, M. Dahele. Radical-intent treatment of lung cancer after prior thoracic radiotherapy. J Thorac Oncol 2017;12:e26-e27
Other
1. E.M.B.P. Reuling, C. Dickhoff, J.M.A. Daniels. Treatment of bronchial carcinoid tumors: is surgery really necessary. J Thorac Oncol 2017;12:e57-e58
2. T. Schuurs, E. Vandewalle, C. Dickhoff. Zeldzame complicatie van endometriose. Ned Tijdschr Geneeskd 2017;161:D950
3. M.J. Disselhorst, C. Dickhoff, C. Alhan. Good’s syndrome: an uncommon cause of therapy resistant diarrhea. Neth J Med 2016;74:309-312
4. J.E. Oor, J.M Daniels, Y.J Debets-Ossenkopp, E.S. de Lange-de Klerk, J.W. Oosterhuis, C. Dickhoff, K.J. Hartemink. Bronchial colonization and complications after lung cancer surgery. Langenbecks Arch Surg 2016;401:885-892
5. R. Szulcek, C.M. Happé, N. Rol, R.D. Fontijn, C. Dickhoff, K.J. Hartemink, K. Grünberg, L. Tu, W. Timens, G.D. Nossent, M.A. Paul, T.A. Leyen, A.J. Horrevoets, F.S. de Man, C. Guignabert, P.B. Yu, A. Vonk-Noordegraaf, G.P. van Nieuw Amerongen, H.J. Bogaard. Delayed Microvascular Shear-adaptation in Pulmonary Arterial Hypertension: Role of PECAM-1 Cleavage. Am J Respir Crit Care Med 2016;193:1410-1420
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6. Dickhoff C, Li WW, Symersky P, Hartemink KJ. Feasibility of 3-dimensional video-assisted thoracic surgery (3D-VATS) for pulmonary resection. Ann Surg Innov Res 2015;9:8
7. J.E. Oor, B.A. Nijsse, J.M. Ultee, C.Dickhoff. Take a deep breath... Neth J Med 2015;73:90-93
8. A.A.C. Heitkamp, C. Dickhoff, J.H. Nederhoed, J.I.P. de Vries. Saved from a fatal flight: rupture of a splenic artery aneurysm. Int J Surg Case Rep 2015;8C:32-34
9. C. Dickhoff; J.H. Daniels, A. van den Brink, M.A. Paul, A.F.T.M. Verhagen. Does hyperbaric oxygen prevent airway anastomosis from breakdown? Ann Thorac Surg 2015;99:682-685
10. M. Groenedijk, K.J. Hartemink, C. Dickhoff, M. Terra, P. Thoral, K.J. Hartemink, S. Hashemi. Pneumomediastinum and/or bilateral pneumothorax after a high energy trauma is an indication for emergency bronchoscopy. Respir Med Case Rep 2014;13:9-11
11. I. Bahce, C.G. Vos, C. Dickhoff, K.J. Hartemink, M. Dahele, E.F. Smit, R. Boellaard, O.S. Hoekstra, E. Thunnissen. Metabolic activity measured by FDG-PET predicts pathological response in locally advanced NSCLC undergoing trimodality treatment. Lung Cancer 2014;85:205-212
12. P.E. Hooijman, A. Beishuizen, M.C. de Waard, F.S. de Man, J. Vermeijden, A. Bouwman, W. Lommen, H.W.H. van Hees, C. Dickhoff, A.R. Girbes, J.R. Jasper, F.L. Malik, G.J.M. Stienen, K.J. Hartemink, M.A. Paul, C.A.C. Ottenheijm. Diaphragm muscle fiber strength is severely reduced in mechanically ventilated ICU patients and is restored by a fast troponin activator. Am J Respir Crit Care Med 2014;189:863-865
13. C. Dickhoff, K.J. Hartemink, D.J. Slebos, P. Symersky, A. Vonk-Noordegraaf. Extra-thoracic proof of intra-thoracic trouble. Thorax 2014;69:785
14. C. Dickhoff, J.E.L. Cremers, D.A. Legemate, M.J.W. Koelemay. Medical liability insurance claims after treatment of varicose veins. Phlebology 2014;29:293-297
15. C. Dickhoff, K.J. Hartemink. ACNES: operatie indicatie? Ned Tijdschr Geneeskd 2013;157:A6309
16. C.G. Vos, M. Dahele, C. Dickhoff, S. Senan, E. Thunnissen, K.J. Hartemink. Tumor size and pathological complete response rates after chemoradiotherapy for non-small cell lung cancer. Acta Oncol 2013;52:676-678
17. C.G. Vos, C. Dickhoff, M.A. Paul, K.J. Hartemink. Treatment and prognosis of superior sulcus tumours. Ned Tijdschr Geneeskd 2012;156:A5419
18. F. Polat, P.P.C. Poyck, C. Dickhoff, D.J. Gouma, W.L.E.M. Hesp. Outcome of 232 morbidly obese patients treated with laparoscopic adjustable gastric banding between 1995-2003. Dig Surg 2010;13:397-402
19. C. Dickhoff, F. Polat, P.P.C. Poyck, A.M. Oosterbaan, W.L.E.M. Hesp. Acute abdominal symptoms in patients with a gastric band. Ned Tijdschr Geneeskd 2010;154:A1504
20. C. Dickhoff, F. Polat, O.E.H. Elgersma, P.R. Schutte. Mediastinaal teratoom als oorzaak van persisterende hoestklachten. Ned Tijdschr Heelk 2009;3:106-108
21. C. Dickhoff, M.M. Campo, P.J.A. Ophof, A.F.C. Makkus, K.G. Tan, P.W. Plaisier. Urachus fistula: a rare first presentation of diverticulitis. Case Rep Gastroenterol 2008;2:287-290
22. C. Dickhoff, R.J. Leguit, J.F.M. Slors, W.L. Vervenne, W.A. Bemelman. Giant rectal gastrointestinal stromal tumors: a report of two cases. Case Rep Gastroenterol 2008;2:54-59
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CHAPTER 10
Summary
Samenvatting
List of publications
Curriculum Vitae
Dankwoord
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CURRICULUM VITAE
The life of Christian Dickhoff, a.k.a. Chris Dickhoff, began on May 17, 1976, which was a beautiful
and hot Monday. He grew up in a little town called Asten, Noord-Brabant (NL), and after
finishing secondary school ‘’College Asten-Someren’’, he was unfortunate to be excluded from
the medicine study in the Netherlands. To spend his time, he worked as a bricklayer for a year.
Then again, he was unlucky in the Numerus Fixus, so he decided to move to Belgium, where he
did his theoretical years of the medicine study at the Katholieke Universiteit Leuven. After this
adventure abroad, he completed the interns ‘Cum Laude’ at the Erasmus University Rotterdam
in 2003, and subsequently started residency (ANIOS) at the Department of Cardiothoracic
Surgery at the VU Medical Center (Drs. M.A.J.M. Huybregts). Shortly hereafter, he continued as
a resident at the Department of Surgery at the Academic Medical Center (Prof. dr. D.J. Gouma).
In 2005, the commission of Regio II expressed its believe in the potential of Chris Dickhoff
becoming a surgeon by accepting him as a surgical trainee. First stop was the Albert Schweitzer
Hospital in Dordrecht (4 years) under the inspiring supervision of Dr. R.J. Oostenbroek and
Dr. P.W. Plaisier. Here, pulmonary and endocrine surgery got his interest and after one year in
the Academic Medical Hospital (Prof. dr. O.R.C. Busch) he had permission to do his last year
of surgical training in Tergooi Ziekenhuizen Hilversum (Dr. J.P. Eerenberg) for an endocrine and
pulmonary differentiation. After finishing his residency in 2011, he started as a CHIVO thoracic
surgery at the VU Medical Center. Inspired by his supervisor, Dr. M.A. Paul, and not in the least by
the staff, Dr. J.W.A. Oosterhuis and Dr. K.J. Hartemink, he became a certified pulmonary surgeon
by July, 2012, and started research resulting in this thesis. Currently, he works with great joy as
a thoracic and endocrine surgeon at the VU Medical Center, Amsterdam, participating in both
the Department of Surgery (Prof. dr. H.J. Bonjer.) and the Department of Cardiothoracic Surgery
(Dr. A.B. Vonk).
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DANKWOORD
Aan allen die hebben bijgedragen aan dit proefschrift ben ik veel dank verschuldigd.
Uiteraard zijn er mensen zonder wie dit niet was gelukt. Allereerst de grondleggers van het idee
om ondergetekende te doen promoveren. Uiteindelijk begint het met vertrouwen. Daarvoor wil
ik Koen Hartemink en Max Dahele, mijn beide copromotoren extra bedanken. Zij hebben me
erg geholpen bij het initiëren, uitvoeren, finetunen, en completeren van dit onderzoek. Koen,
je hebt me nog enthousiaster gemaakt voor de longchirurgie dan ik al was, en bewonder je
omgang en onvoorwaardelijke inzet voor je patiënten. Hoewel jonger, een groot voorbeeld!
Max, bewonderenswaardig hoe aanstekelijk je enthousiasme is voor het vak, patiëntenzorg
en wetenschap. Ik ben jaloers op de manier waarop jij artikelen kan schrijven. I really much
appreciate your attitude that everything is ‘’technisch heel goed mogelijk’’, without ever lose
sight of the patient. Jouw input is van zeer groot belang geweest voor de kwaliteit van dit
proefschrift. Hoop nog lang met je te kunnen samenwerken!
Zonder promotor geen promotie, en dat is ook nu het geval. Beste Egbert, voor een brein
zoals dat van jou, moet het begeleiden van een chirurg niet altijd even makkelijk geweest zijn…
Heel veel dank!
De leden van de leescommissie; professor Bonjer, professor Groen, professor deLeyn,
professor de Ruyscher, professor Baas en dr. Spoelstra; wat een rijtje Kennis! Een uitermate
goede afspiegeling van de multidisciplinaire aanpak van het niet-kleincellig longcarcinoom! Ik
wil jullie allen enorm bedanken voor jullie inzet en beoordelen van dit proefschrift!
Alle co-auteurs; dank voor alle correcties, ideeën, aanmerkingen, opmerkingen etc.. wat
heeft geleid tot dit proefschrift. Prof. Senan, jou wil ik hier in het bijzonder noemen!
Collega’s van de afdeling Heelkunde en Cardio-thoracale Chirurgie; Dank voor jullie inzet en
betrokkenheid. Rick, Petr, Reinier en David: age before beauty!
Paranimfen Petr en Reinier; hopelijk opereren we samen nog lang en gelukkig….
Olle en Gilles, mooie gassies, en Lies, my princess; aan jullie heb ik het in ieder geval niet te
danken! Maar, wij blijven altijd bij elkaar!
En Ils….. wij ook, hou van je!
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CHAPTER 10
Summary
Samenvatting
List of publications
Curriculum Vitae
Dankwoord
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DANKWOORD
Dankzij de bijdrage en inzet van vele mensen is dit proefschrift tot stand gekomen. Enkelen wil
ik hieronder in het bijzonder bedanken.
Koen Hartemink en Max Dahele, de grondleggers van het idee om ondergetekende te doen
promoveren, mijn beide copromotoren. Jullie hebben me geholpen bij het initiëren, uitvoeren,
finetunen, en completeren van dit onderzoek. Veel dank voor het vertrouwen. Koen, je hebt me
nog enthousiaster gemaakt voor de longchirurgie dan ik al was. Ik bewonder je omgang met, en
onvoorwaardelijke inzet voor, je patiënten. Hoewel jonger dan ik, een groot voorbeeld!
Max, jouw enthousiasme voor patiëntenzorg en wetenschap is aanstekelijk. Ik ben jaloers op de
manier waarop jij artikelen kan schrijven. I really much appreciate your attitude that everything
is ‘’technisch heel goed mogelijk’’, without ever losing sight of the patient. Jouw input is van zeer
groot belang geweest voor de kwaliteit van dit proefschrift. Ik hoop nog lang met je te kunnen
samenwerken.
Mijn promotor Egbert Smit. Beste Egbert, voor een brein zoals dat van jou moet het begeleiden
van een chirurg niet altijd even makkelijk geweest zijn… Heel veel dank!
De leden van de leescommissie; prof. Bonjer, prof. Groen, prof. de Leyn, prof. de Ruysscher,
prof. Baas en dr. Spoelstra; wat een rijtje kennis en kunde! Een uitermate goede afspiegeling
van de multidisciplinaire aanpak van het niet-kleincellig longcarcinoom. Ik wil jullie allen enorm
bedanken voor jullie inzet en het beoordelen van dit proefschrift.
Alle co-auteurs; dank voor alle correcties, ideeën, aanmerkingen, opmerkingen etc… Prof. Senan,
jou wil ik hier in het bijzonder noemen.
Collega’s van de afdeling Heelkunde en Cardiothoracale Chirurgie; dank voor jullie inzet en
betrokkenheid. Rick, Petr, Reinier en David: age before beauty!
Paranimfen Petr en Reinier; …en we opereren samen nog lang en gelukkig….
Mijn best buds uit Asten: Stijn en Michel, ik ga snel weer broodjes worst maken voor jullie op
een zeilboot.
The boys-from-Bamse: Sies, Ivar, James, Ruben, Koen, Duncan, Sander, Russell, Ragnar, Paul,
Nick, Mark W, Harrie, Mark C, Maarten, Reinoud: mooie tijden…
Alex, my brother, say peace to Biggie and 2Pac!
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Gerard, Rita, Nicole, Wouter, Mieke, Bauke, Anouk, Matthijs, Raul (my PhD-brother-in-law!) dank
voor alles, maar vooral de gezelligheid.
Riet; vooral dank voor wat je allemaal voor pa hebt gedaan.
Mijn zussen Cathelijne, Barbara en Myra: respect!
Pa en ma, ik ben nog iedere dag trots op jullie.
Olle, Lies en Gilles; wij blijven altijd bij elkaar,
Ilse, wij ook!
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THE ROLE OF SURGERY
IN THE TREATMENT OF
LOCALLY ADVANCED NON-SMALL CELL
LUNG CANCER
Christian Dickhoff
THE RO
LE OF SU
RGERY IN
THE TREATM
ENT O
F LOCA
LLY AD
VAN
CED N
ON
-SMA
LL CELL LUN
G CA
NCER Christian Dickhoff
UITNODIGING
voor het bijwonen van deopenbare verdediging
van het proefschrift
The role of surgery in the treatment of locally advanced
non-small cell lung cancer
doorChristian Dickhoff
op vrijdag 8 december 2017om 11.45 uur
In de aula van de Vrije UniversiteitDe Boelelaan 1105 te Amsterdam
Paranimfen:
Petr [email protected]
+31 6 29466025
Reinier [email protected]
+31 6 24253208