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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


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


UITNODIGING








Paranimfen:


+31 6 29466025


+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


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

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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

http://prof.dr/


promotor: prof.dr. E.F. Smit

copromotoren: dr. M. Dahele

dr. K.J. Hartemink

http://prof.dr/


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

31

43

57

63

77

93

97

105109 113 117 121


CHAPTER 1

Introduction and outline of the thesis


8

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


1

9

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


10

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


1

11

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.


12

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

http://www.cijfersoverkanker.nl/selecties/Incidentie_long_en_luchtpijpkanker/img54d0ecb34ed7b.


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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


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

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


18

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.


2

19

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


20

CHAPTER 2

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


2

21

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


22

CHAPTER 2

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).


2

23

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.


24

CHAPTER 2

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


2

25

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


26

CHAPTER 2

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.


2

27

REFERENCES

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3. Kozower BD, Larner JM, Detterbeck FC, et al. 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

4. Bezjak A, Temin S, Franklin G, et al. Definitive and Adjuvant Radiotherapy in Locally Advanced Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Society for Radiation Oncology Evidence-Based Clinical Practice Guideline. J Clin Oncol 2015;33:2100-2105

5. 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


7. 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



10. Darling GE, Li F, Patsios D, et al. Neoadjuvant chemoradiation and surgery improves survival outcomes compared with definitive chemoradiation in the treatment of stage IIIA N2 non-small-cell lung cancer. Eur J Cardiothorac Surg 2015;48:684-690

11. Dickhoff C, Hartemink KJ, van de Ven PM, et al. Trimodality therapy for stage IIIA non-small cell lung cancer: Benchmarking multi-disciplinary team decision-making and function. Lung Cancer 2014;85:218-223





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16. 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


18. Weder W, Collaud S, Eberhardt WE, et al. Pneumonectomy is a valuable treatment option after neoadjuvant therapy for stage III non-small-cell lung cancer. J Thorac Cardiovasc Surg 2010;139:1424-1430

19. Forrest LF, Adams J, Wareham H, et al. Socioeconomic inequalities in lung cancer treatment: systematic review and meta-analysis. PLoS Med 2013;10:e1001376

20. Lüchtenborg M, Riaz SP, Coupland VH, et al. High procedure volume is strongly associated with improved survival after lung cancer surgery. J Clin Oncol 2013;31:3141-3146

21. Kim AW, Liptay MJ, Bonomi P, et al. Neoadjuvant chemoradiation for clinically advanced non-small cell lung cancer: an analysis of 233 patients. Ann Thorac Surg 2011;92:233-243

22. 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.

23. Asamura H, Chansky K, Crowley J, et al. on behalf of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee. The lASLC Lung Cancer Staging Project: Proposals for the Revision of the N Descriptors in the Forth coming Eighth Edition of the TNM Classification for Lung Cancer. J Thorac Oncol 2015;10:1675-1684

24. Jakobsen E, Green A, Oesterlind K, et al. Nationwide quality improvement in lung cancer care: the role of the Danish Lung Cancer Group and Registry. J Thorac Oncol 2013;8:1238-1247

25. 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

26. Douillard JY, Rosell R, De Lena M, et al, Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 2006;7:719-727

27. Douillard JY, Rosell R, De Lena M, et al. Impact of postoperative radiation therapy on survival in patients with complete resection and stage I, II, or IIIA non-small-cell lung cancer treated with adjuvant chemotherapy: the adjuvant Navelbine International Trialist Association (ANITA) Randomized Trial. Int J Radiat Oncol Biol Phys 2008;72:695-701

28. Lally BE, Zelterman D, Colasanto JM, et al. Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the surveillance, epidemiology, and end results database. J Clin Oncol 2006;24:2998-3006

29. Péchoux CL, Mercier O, Belemsagha D, et al. Role of adjuvant radiotherapy in completely resected non-small-cell lung cancer. EJC Suppl 2013;11:123-130

30. De Leyn P, Dooms C, Kuzdzal J. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer. Eur J Cardiothorac Surg 2014;45:787-798


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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


32

CHAPTER 3

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.


3

33

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.


34

CHAPTER 3

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).


3

35

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


36

CHAPTER 3

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.


3

37

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.


38

CHAPTER 3

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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39

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].


40

CHAPTER 3

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. 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


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


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


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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CHAPTER 4

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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45

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.


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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CHAPTER 4

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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47

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.


48

CHAPTER 4

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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49

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


50

CHAPTER 4

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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51

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


4

53

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].


54

CHAPTER 4

REFERENCES

1. Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thor Oncol 2007;2:706-714

2. Oncoline NSCLC: http://www.oncoline.nl/niet-kleincellig-longcarcinoom

3. Vansteenkiste J, De Ruysscher D, Eberhardt WE, et al; ESMO Guidelines Working Group. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24:vi89-vi98

4. 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

5. 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

6. Albain, KS, Swann RS, RuschVW, 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

7. Vos CG, Hartemink KJ, Blaauwgeers JL, et al. Trimodality for superior sulcus tumours: evolution and evaluation of a treatment protocol. Eur J Surg Oncol 2013;39:197-203

8. Rami-Porta R, Crowley JJ, Goldstraw P. The revised TNM staging system for lung cancer. Ann Thorac Cardiovasc Surg 2009;15:4–9

9. Shen KR, Meyers BF, Larner JM, Jones DR; American College of Chest Physicians. Special treatment issues in lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007;132:290S-305S

10. van Reij EJ, Dahele M, van de Ven PM, et al. Changes in non-surgical management of stage III NSCLC at a single institution between 2003-2010. Acta Oncol 2014;53:316-323

11. Senthi S, Senan S. Surgery for early-stage lung cancer: post-operative 30-day versus 90-day mortality and patient-centred care. Eur J Cancer 2014;50:675-677


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

http://www.oncoline.nl/niet-kleincellig-longcarcinoom


4

55

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

19. Li J, Dai CH, Chen P, Li XQ, Shi SB, Wu JR. Results of trimodality therapy in patients with stage IIIA (N2-bulky) and stage IIIB non-small-cell lung cancer. Clin Lung Cancer 2009;10:353-359

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

21. Lococo F, Cesario A, Margaritora S, et al. Induction therapy followed by surgery for T3-T4/N0 non-small cell lung cancer: long-term results. Ann Thorac Surg 2012;93:1633-1640

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

24. Ripley RT, Rusch VW. Role of induction therapy: surgical resection of non-small cell lung cancer after induction therapy. Thorac Surg Clin 2013;23:273-285

25. Shah AA, Berry MF, Tzao C, et al. Induction chemoradiation is not superior to induction chemotherapy alone in stage IIIA lung cancer. Ann Thorac Surg 2012;93:1807-1812

26. Hallqvist A, Bergman B, Nyman J. Health related quality of life in locally advanced NSCLC treated with high dose radiotherapy and concurrent chemotherapy or cetuximab--pooled results from two prospective clinical trials. Radiother Oncol 2012;104:39-44

27. Grutters JP, Joore MA, Wiegman EM, et al. Health-related quality of life in patients surviving non-small cell lung cancer. Thorax 2010;65:903-907

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


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


58

CHAPTER 5

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.


5

59

REFERENCES



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


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


PART II

New roles for surgery after chemoradiotherapy:

recurrent or persistent disease and complications


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


64

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.


6

65

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.


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


66

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).


6

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


68

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


6

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


70

CHAPTER 6

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


6

71

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


72

CHAPTER 6

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


6

73

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.


74

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


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


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


6

75


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


78

CHAPTER 7

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.


7

79

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.


80

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).


7

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


82

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


7

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


84

CHAPTER 7

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


7

85

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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CHAPTER 7

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


7

87

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.


7

89

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


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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CHAPTER 8

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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95

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


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


CHAPTER 9

Discussion and future perspectives


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CHAPTER 9

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


9

99

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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CHAPTER 9

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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101

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








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


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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List of publications

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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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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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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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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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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!

THE ROLE OF SURGERY

IN THE TREATMENT OF


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


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