Impact of interstitial lung disease and simultaneous lung cancer on therapeutic possibilities and survival

Abstract

Background
Fibrosing interstitial lung diseases (ILDs) are associated with poor survival and an increased risk of developing lung cancer (LC). Patient and LC characteristics, therapeutic possibilities and survival in this rare patient population are not well established.

Methods
Fibrosing ILD patients treated at the Department of Pulmonology Semmelweis University were reviewed retrospectively between 2012–2018 (N = 160). All patients with concomitant LC (N = 23) underwent detailed pulmonary evaluation. Cancer characteristics including driver mutation data, as well as therapy and survival were analyzed.

Results
ILD‐LC patients (56% men, mean age 73 ± 6 years) had mild‐moderate lung functional impairment (forced vital capacity [FVC]: 80 ± 24%ref., forced expiratory volume in one second [FEV1]: 76 ± 27%ref.; transfer factor of the lung for carbon monoxide [TLCO]: 62 ± 25% reference). In 56% of cases histology confirmed adenocarcinoma followed by squamous cell carcinoma in 26%. Lobectomy could only be performed in one case; driver mutation was present in one patient. Chemotherapy was most commonly administered; however, 26% could only receive supportive palliative care. Four idiopathic pulmonary fibrosis patients received concomitant nintedanib to their LC treatment. Median survival of ILD‐LC patients was only 321 days.

Conclusions
Diagnosis and therapy of ILD‐LC is challenging and patients have a very limited survival. A significant proportion of patients could only receive palliative care indicating the need for better management strategies in this special patient population. The evaluation of the effect of cotreatment with antifibrotics needs further study.

Key points

• Interstitial lung diseases are often associated with lung cancer
• Diagnosis is challenging and therapy often limited due to underlying lung disease. Patients received platinum based chemotherapy or only supportive care.

Full text

ORIGINAL ARTICLE
Impact of interstitial lung disease and simultaneous lung
cancer on therapeutic possibilities and survival
Eniko Barczi
1
, Tamas Nagy
1
, Livia Starobinski
1
, Abigel Kolonics-Farkas
1
, Noemi Eszes
1
, Aniko Bohacs
1
,
Adam Domonkos Tarnoki
2
, David Laszlo Tarnoki
2
& Veronika Müller
1
1 Department of Pulmonology, Semmelweis University, Budapest, Hungary
2 Medical Imaging Centre, Semmelweis University, Budapest, Hungary
Keywords
Interstitial lung disease; lung cancer;
nintedanib; survival; therapy.
Correspondence
Enik}
o Bárczi, MD, Department of
Pulmonology, Semmelweis University Töm}
o
street 25-29, 1083, Budapest, Hungary.
Tel: +36 1 355 9733
Fax: +36 1 214 2498
E-mail: eniko.barczi@gmail.com
Received: 26 March 2020;
Accepted: 23 April 2020.
doi: 10.1111/1759-7714.13481
Thoracic Cancer 11 (2020) 1911–1917
Abstract
Background: Fibrosing interstitial lung diseases (ILDs) are associated with poor
survival and an increased risk of developing lung cancer (LC). Patient and LC
characteristics, therapeutic possibilities and survival in this rare patient popula-
tion are not well established.
Methods: Fibrosing ILD patients treated at the Department of Pulmonology
Semmelweis University were reviewed retrospectively between 2012–2018
(N= 160). All patients with concomitant LC (N= 23) underwent detailed pul-
monary evaluation. Cancer characteristics including driver mutation data, as well
as therapy and survival were analyzed.
Results: ILD-LC patients (56% men, mean age 73 6 years) had mild-moderate
lung functional impairment (forced vital capacity [FVC]: 80 24%ref., forced
expiratory volume in one second [FEV1]: 76 27%ref.; transfer factor of the
lung for carbon monoxide [TLCO]: 62 25% reference). In 56% of cases histol-
ogy confirmed adenocarcinoma followed by squamous cell carcinoma in 26%.
Lobectomy could only be performed in one case; driver mutation was present in
one patient. Chemotherapy was most commonly administered; however, 26%
could only receive supportive palliative care. Four idiopathic pulmonary fibrosis
patients received concomitant nintedanib to their LC treatment. Median survival
of ILD-LC patients was only 321 days.
Conclusions: Diagnosis and therapy of ILD-LC is challenging and patients have
a very limited survival. A significant proportion of patients could only receive
palliative care indicating the need for better management strategies in this special
patient population. The evaluation of the effect of cotreatment with antifibrotics
needs further study.
Key points:
•Interstitial lung diseases are often associated with lung cancer
•Diagnosis is challenging and therapy often limited due to underlying lung dis-
ease. Patients received platinum based chemotherapy or only supportive care.
Introduction
Interstitial lung diseases (ILDs) are often irreversible and pro-
gressive with poor prognosis.
1
Idiopathic pulmonary fibrosis
(IPF) is one of the most common ILD with the highest mor-
tality.
2
Actually available antifibrotic therapies are decreasing
lung function loss; however, there are no drugs available to
repair damaged lung tissue or reverse progression.
3, 4
Lung cancer (LC) is the leading cause of malignancy-
associated mortality in Hungary.
5
LC prevalence in patients
with IPF varies from 4% to 48%, making it the most seri-
ous comorbidity.
6
Pulmonary fibrosis is a proven risk fac-
tor for LC development, as relationship between fibrotic
areas and lung carcinogenesis, referred to as “scarcinoma”
is described.
7
Advanced age, male sex, smoking history and
Thoracic Cancer 11 (2020) 1911–1917 © 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd 1911
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the
original work is properly cited.
Thoracic Cancer ISSN 1759-7706

simultaneous emphysema are among the main risk factors
for lung carcinogenesis in IPF patients.
8
In ILDs, especially in advanced fibrosing lung disease,
histological verification is often challenging due to
impaired lung function, comorbidities and higher risk of
complications. Delay in diagnosis and less access to ade-
quate tissue samples contributes to limited treatment
options. Concomitant lung diseases (eg, chronic obstructive
lung disease, emphysema, ILDs, lung infections) are often
delaying or complicating diagnosis and/or treatment.
9
As LC is often associated with reduced survival and
ILDs are frequently progressive with shorter life expec-
tancy, our aim was to analyze LC patients in our Hungar-
ian ILD cohort. Therapeutic possibilities and outcome
were analyzed in both sexes.
Methods
Study population
ILD patients from the Department of Pulmonology
Semmelweis University were retrospectively reviewed dur-
ing the period of 1 November 2012 to 1 November 2018.
Systematic search revealed 160 patients with ILD diagnosis.
Out of these patients, 23 were diagnosed with simultaneous
LC. LCs were classified according to the World Health
Organization classification. Staging of LC has been
established by the actual TNM seventh and eighth editions
accordingly.
10, 11
ILD was always classified at the multidisciplinary team
discussion which included a pulmonologist, medical oncol-
ogist, radiologist and immunologist, based on American
Thoracic Society (ATS)/European Respiratory Society
(ERS)/Japanese Respiratory Society (JRS)/ Latin American
Thoracic Association (ALAT) official guidelines.
12, 13
ILD
consisted of IPF (N= 18), connective tissue disease (CTD)-
ILD (N= 3) and nonspecific interstitial pneumonia (NSIP)
(N= 2). All IPF patients were also enrolled into the
European MultiPartner IPF Registry (EMPIRE).
14, 15
Pulmonary evaluation
At baseline and every follow-up physical examination was
performed, and a detailed medical history was taken with
special emphasis on symptoms (dry/productive cough, spu-
tum, chest pain), respiratory infections and comorbidities.
Lung function measurements included functional vital
capacity (FVC), forced expiratory volume in 1 second
(FEV1), FEV1/FVC and total lung capacity (TLC) by
means of electric spirometer and plethysmography (PDD-
301/s, Piston, Budapest, Hungary) according to the Ameri-
can Thoracic Society and European Respiratory Society
guidelines.
16
The highest of three technically acceptable
maneuvers was used. Transfer factor of the lung for carbon
monoxide (TLCO) was measured with single breath CO
method (PDD-301/s, Piston, Budapest, Hungary) and coef-
ficient (KLCO) calculated. Lung function variables were
expressed as percentage of predicted values. Arterialized
capillary blood gases, pH and bicarbonate levels were ana-
lyzed at rest at room temperature (Cobas b 221, Roche,
Budapest, Hungary). Gender-age-physiology (GAP) score
was calculated for all ILD patients.
17
Lung cancer assessment
High resolution computed tomography (HRCT) examina-
tion was performed. LC cell type, epidermal growth factor
(EGFR), KRAS and if available programmed death
ligand-1 (PD-L1) data were collected, as well as Eastern
Cooperative Oncology Group Performance Status (ECOG
PS). Therapy modalities were summarized, and treatment
outcomes with special emphasis on survival.
Ethical statement
Written informed consent was obtained from all subjects
prior to their admission to the EMPIRE registry (TUKEB
69/2015). As this was a retrospective real-world analysis no
registration as a clinical trial was needed.
Statistical analysis
Statistical analysis was performed using Graph Pad soft-
ware (GraphPad Prism 5.0 Software, Inc., La Jolla, CA,
USA). Data are expressed as mean standard deviation.
Differences between groups for parametric data were eval-
uated with Student’st-test after testing for normality using
a Kolmogorov-Smirnov test, while chi-square test was
applied for analyzing categorical data. Examinations could
not be performed in all cases due to the health state of
patients, and the actual number of analyzed patients is
reported in the respective tables. Survival was estimated
using the Kaplan-Meier method and calculated from the
diagnosis of LC. A P-value <0.05 was defined as statistically
significant.
Results
From the 160 ILD patients analyzed 14% were identified
with concomitant LC. Patient characteristics are summa-
rized in Table 1. Patients were older age, and men were
significantly older than women. GAP score, and a widely
used mortality risk assessment tool for IPF, showed that
32% of the patients were in stage II, while 27% were in
stage III. Comparing the two genders the difference was
significant, more women being in GAP stage I. Majority of
1912 Thoracic Cancer 11 (2020) 1911–1917 © 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd
ILD and simultaneous lung cancer therapy E. Barczi et al.

patients had two or three comorbidities, the two most fre-
quent conditions were hypertension and type 2 diabetes.
Functional parameters are summarized in Table 2. Lung
function showed a mild restrictive ventilatory pattern,
without differences between genders in predicted values.
Blood gases showed higher pCO
2
in women as compared
to men, without differences in pO
2
.
Histology verified adenocarcinoma in 13 patients (56%)
being the most LC type in this cohort, while six patients
(26%) had squamous cell lung cancer. Small cell lung can-
cer (SCLC) was found only in two patients and in two
cases only non-small cell lung cancer (NSCLC) diagnosis
could be established (Table 3). Cause of death in the
majority of patients was progression of lung cancer (86%),
while advanced lung fibrosis was the cause in 14% of cases.
At the time of the LC diagnosis 14 patients (61%) had
locally advanced or metastatic stage (IIIB, IV) disease.
Early local stages (I, II, IIIA) were diagnosed in 39% of all
patients. Among patients diagnosed with adenocarcinoma,
mutational analysis was performed in 13 cases, one patient
showed EGFR mutation, four patients KRAS mutation,
while PD-L1 expression was confirmed in three samples.
More men had squamous cell lung cancer as compared to
women.
PS was mainly two (61%), and only 30% of patients were
fit enough (PS 0–1) for multiple treatment modalities.
LC was treated according to the histology type, TNM,
PS and treatment availability at the time of diagnosis. Each
case was discussed by the onco-team. Treatments are sum-
marized in Table 3. Lobectomy could only be performed in
one case. Chemotherapy was most commonly adminis-
tered; however, six patients (26%) could only receive best
supportive palliative care. Four IPF patients received
nintedanib in addition to their concomitant LC treatment.
Treatment outcomes are individually shown in Fig 1.
One patient with the longest survival, who was still alive in
2019, had a small tumor, underwent lobectomy and still
receives nintedanib.
Median survival was 321 days, lower as compared to the
most severe IPF (FVC < 60%; N= 22; average median sur-
vival 460 days) population as published previously.
18
Median survival among in our cohort for males was
Table 1 Patient characteristics
Parameters
All patients Women Men P-value
N=23 N=10 N= 13 (women vs. men)
Age (years) 73.8 6.2 70.40 6.15 76.54 5.04 0.02
Smoking: N (%)
Former smoker 19 (83) 7 (70) 12 (92) 0.28
Never smoker 4 (17) 3 (30) 1 (8) 0.16
BMI (kg/m2) 25.33 5.17 25.73 6.17 25.03 4.55 0.76
ECOG PS: N (%)
0–1 7 (30) 3 (30) 4 (31) 0.96
2 14 (61) 6 (60) 8 (61) 0.94
3–4 2 (9) 1 (10) 1 (8) 0.84
GAP: N (%)
Stage I 10 (43) 7 (70) 3 (23) 0.02
Stage II 7 (32) 3 (30) 4 (33) 0.99
Stage III 6 (27) 0 6 (50) 0.05
Comorbidities: N (%)
0 2 (9) 1 (10) 1 (8) 0.99
1 2 (9) 1 (10) 1 (8) 0.99
2 12 (52) 5 (50) 7 (53) 0.99
3 7 (30) 3 (30) 4 (31) 0.99
Symptoms: N (%)
Dyspnea 17 (74) 8 (80) 9 (69) 0.55
Cough and sputum 16 (70) 7 (70) 9 (69) 0.96
Chest pain 4 (17) 2 (20) 2 (15) 0.77
HRCT: N (%)
pUIP 15 (65) 6 (60) 9 (69) 0.64
UIP 8 (35) 4 (40) 4 (31) 0.64
ILD disease: N (%)
CTD-ILD or NSIP 5 (22) 3 (30) 2 (15) 0.39
IPF 18 (78) 7 (70) 11 (85) 0.39
BMI, body mass index; CTD, connective tissue disease; ECOG PS, Eastern Cooperative Oncology Group Performance Status; GAP,
gender-age-physiology; HRCT, high resolution CT; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; NSIP, nonspecific interstitial
pneumonia.
Thoracic Cancer 11 (2020) 1911–1917 © 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd 1913
E. Barczi et al. ILD and simultaneous lung cancer therapy

340 days, while in women 288 days. No difference between
sexes was noted in median survival (P= 0.643) (Fig 2).
Discussion
We confirmed 23 LC cases in ILD patients. In a previous
study, 2% of the non-IPF-ILD and 3% of IPF patients
developed simultaneous LC,
19
and this rate was higher in
our cohort (7% and 6%). The first studies of ILD associated
LC appeared in the last decades and several reviews discuss
the mechanism of LC development in ILDs.
20, 21
In our study, 15 patients were diagnosed with ILD first
and cancer developed after a median of 888 days (range
19–1557) which is in line with previous observations as LC
Table 2 Lung function and capillary blood gas values at baseline
Parameters
All patients Women Men P-value
N=23 N=10 N= 13 (women vs. men)
Lung function and diffusion test
FVC (L) 2.48 0.82 1.94 0.70 2.93 0.75 0.01
FVC (%) 80.80 24.00 78.70 28.20 82.60 20.90 0.71
FEV1 (L) 1.81 0.70 1.42 0.58 2.15 0.63 0.01
FEV1 (%) 75.50 26.70 70.90 32.60 79.30 21.40 0.47
FEV1/FVC 0.90 0.20 0.90 0.20 1.00 0.20 0.29
TLC (L) 4.09 1.36 3.90 1.70 4.34 0.80 0.51
TLC (%) 75.80 26.50 77.50 30.20 74.10 23.90 0.77
TLCO (mmol/min/kPa) 4.47 2.11 3.95 2.04 5.32 2.15 0.27
TLCO (%) 61.80 24.90 60.20 28.30 64.20 21.00 0.77
Capillary blood gas test
pH 7.42 0.03 7.40 0.03 7.43 0.02 0.05
pCO
2
(mmHg) 36.96 4.58 40.6 4.16 34.78 3.35 0.01
pO
2
(mmHg) 61.62 8.60 57.17 7.43 64.29 8.46 0.11
TLCO, transfer factor of the lung for carbon monoxide; FVC, forced vital capacity; FEV1, forced expiratory volume in 1.0 seconds; TLC, total lung
capacity
Table 3 Lung cancer histology, stage and mutation type, cancer treatment and cause of death
Parameters
All Women Men
P-valueN=23 N=10 N=13
Histology: N (%)
Adenocarcinoma 13 (56) 7 (70) 6 (46) 0.25
Squamous cell lung cancer 6 (26) 1 (10) 5 (39) 0.12
Small cell lung cancer (SCLC) 2 (9) 1 (10) 1 (8) 0.85
Other (non-small cell lung cancer [NSCLC]) 2 (9) 1 (10) 1 (8) 0.85
TNM: N (%)
Local (I, II, IIIA) 9 (39) 5 (50) 4 (31) 0.34
Locally advanced/metastatic (IIIB, IV) 14 (61) 5 (50) 9 (69) 0.34
Adenocarcinoma
Mutation type: N (%)
KRAS mutant 4 (31)
EGFR mutant 1 (7)
EGFR,KRAS wild-type 8 (62)
Treatment: N (%)
Lobectomy 1 (4)
Platinum doublet therapy +/−irradiation 12 (52)
Mono chemotherapy +/−irradiation or only irradiation 4 (17)
Best supportive care
Not receiving active oncotherapy 5 (22)
Refusing active oncotherapy 1 (4)
Cause of death: N (%)
Progressive lung fibrosis 3 (14)
Progression of lung cancer 18 (86)
1914 Thoracic Cancer 11 (2020) 1911–1917 © 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd
ILD and simultaneous lung cancer therapy E. Barczi et al.

is mostly diagnosed after ILD.
22
When a working diagnosis
of IPF is made, the patient should be closely monitored,
and clinical, radiological, and laboratory assessments
repeated as appropriate so that their diagnosis can be
reviewed at regular intervals (ideally based on further
rounds of MDD).
23, 24
In another eight cases, cancer and
ILD were diagnosed simultaneously.
LC is often diagnosed late in Hungary, leading to high
mortality,
5
and adenocarcinoma is the most frequent LC type.
Similarly, in our cohort, adenocarcinoma was the most fre-
quently diagnosed type of LC (56%), in contrast with other
studies which found squamous cell carcinoma more common
(41% vs. 26%),
19
or a similar distribution was revealed.
20
The
majority of our patients already had metastatic disease, also
in line with previous observations, as diagnosis is often late
and a significant proportion of the patients did not meet the
criteria to receive combined chemotherapy.
9
Activating mutations in the EGFR gene was detected
in only one case, and 62% of the patients showed
EGFR/KRAS wild phenotype while PD-L1 > 1% expres-
sion was found in three cases. In Hungary, KRAS test-
ing is routinely performed due to special
reimbursement issues. Previous data confirmed 32.1%
KRAS mutation lung adenocarcinoma in our country,
which is within the average (25%–35%) of other obser-
vations.
25, 26
In our ILD patients with lung adenocarci-
noma four patients (31%) were harboring the KRAS
mutation, three had UIP and one CTD-ILD. This is in
line with a previous study where less frequent EGFR
and more frequent KRAS mutations were observed in
UIP-positive cases.
27
Operability was rarely applied in our study, and only
one patient was suitable for lobectomy. Platinum doublet
therapy +/−irradiation was most frequently used (52%),
although radiotherapy was applied carefully because of the
possibility of radiation pneumonitis in severe ILD.
28
Recent
clinical trials assessing the effect of immunotherapy alone,
or in combination with chemotherapy, excluded patients
with ILDs as it might increase severe immune-related
pneumonitis.
29, 30
In a significant proportion of patients, PS did not allow
detailed examination and/or more effective oncotherapy
due to their underlying lung disease. High tumor burden
and poor PS often limit therapeutic possibilities. Five
patients received only best supportive care and one patient
refused all suggested therapies.
In four out of 11 patients with IPF, additional therapy
with nintedanib was used. Nintedanib is widely used for
the treatment of IPF as it is slows progression of functional
decline.
31
It is important to note that nintedanib has only
been available in Hungary for IPF treatment since 2015,
and is the main reason why only 36% of patients received
this drug. The efficacy of nintedanib in advanced NSCLC
in combination with chemotherapy has been reported in
P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 P12 P13 P14 P15 P16 P17 P18 P19 P20 P21 P22 P23
Gender
Smoking status
GAP stage
Nintedanib therapy for IPF
Lung cancer histology NA NA
Lung cancer stage
ECOG PS
Therapy
Underlying disease
Cause of death NA NA
P1-P23: number of individual patients; GAP: Gender Age Physiology; ECOG PS: Eastern Cooperative Oncology Group Performance Status, SCLC: small cell lung cancer
died at day 2015alive
1557 1516
1129
713
463 384 374 360 322 320 253 248 241 202 150 134 131 113 84 65 19
0
200
400
600
800
1000
1200
1400
1600
1800
2000
Survival days
Figure 1 Summary of patients, disease characteristics and therapies of individual patients. ( ) Female; ( ) Male; ( ) Former smoker; ( ) Never
smoker; ( ) GAP I; ( ) GAP II; ( ) GAP III; ( ) Nintedanib therapy; ( ) Adenocarcinoma; ( ) Squamous cell carcinoma; ( ) Small cell lung can-
cer; ( ) Early stage (I, II, IIIA); ( ) Locally advanced/metastatic (IIIB, IV); ( ) ECOG 0–1; ( ) ECOG 2; ( ) ECOG 2–3; ( ) IPF; ( ) CTD-ILD or NSIP;
() Lobectomy; ( ) Platinum doublet therapy +/- irradiation; ( ) Mono chemotherapy +/- irradiation or only irradiation; ( ) Not receiving/refusing
active oncotherapy; ( )Progressive lung fibrosis; ( ) Progression of lung cancer.
Thoracic Cancer 11 (2020) 1911–1917 © 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd 1915
E. Barczi et al. ILD and simultaneous lung cancer therapy

the LUME-Lung 1 and LUME-Lung 2 trials.
32
Nintedanib
may play a role in the treatment of IPF-associated lung
cancer as it can slow progression of both diseases individu-
ally;
31, 33, 34
however, no data on IPF and LC treatment are
available.
Pirfenidone, the other antifibrotic therapy used in the
treatment of IPF, has shown advantages for decreased LC
development rates.
35
In our cohort, none of our patients
received pirfenidone, as this drug was reimbursed later as
nintedanib by the Hungarian insurance system.
In conclusion, median survival was 321 days from the
diagnosis of LC (men: 340 days, women: 288 days) in ILD
patients. The prognosis of patients with ILD-LC is similar
to that for patients with advanced IPF only.
Therapeutic options are limited: operability was only
possible in one early stage tumor and 26% of the patients
were not fit enough for chemotherapy due to PS ≥2 and/or
underlying lung disease, or comorbidities. Interdisciplinary
evaluation of therapeutic options is mandatory for the final
decision in concomitant ILD-LC therapy. Further investi-
gations and larger patient group are needed to evaluate the
possible protective effect of antifibrotic drugs in ILD
patients for LC development.
Acknowledgments
Eniko Barczi is supported by “Development of scientific
workshops of medical, health sciences and pharmaceutical
educations”(EFOP-3.6.3-VEKOP-16-2017-00009).
This research did not receive any specific grant from
funding agencies in the public, commercial, or not-for-
profit sectors.
Disclosure
All authors declare that they have no conflict of interests.
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