Summary of the Japanese Respiratory Society statement for the treatment of lung cancer with comorbid interstitial pneumonia

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Summary of the Japanese Respiratory Society statement for the treatment of lung cancer with comorbid interstitial pneumonia Takashi Ogura a, Nagio Takigawa b, Keisuke Tomii c, Kazuma Kishi d, Yoshikazu Inoue e, Eiki Ichihara f, Sakae Homma g, Kazuhisa Takahashi h, Hiroaki Akamatsu i, Satoshi Ikeda a, Naohiko Inase j, Tae Iwasawa k, Yuichiro Ohe l, Hiromitsu Ohta m, Hiroshi Onishi n, Isamu Okamoto o, Kazumasa Ogawa d, Kazuo Kasahara p, Hiroki Karata q, Takumi Kishimoto r, Yuka Kitamura q, Akihiko Gemma s, Hirotsugu Kenmotsu t, Hiroyuki Sakashita j, Susumu Sakamoto g, Katsutoshi Sekine u, Yuichi Takiguchi v, Yuji Tada w, Shinichi Toyooka x, Yuko Nakayama y, Yasuhiko Nishioka z, Koichi Hagiwara aa, Masaki Hanibuchi ab, Junya Fukuoka q, Yuji Minegishi s, Toyoshi Yanagihara o, Nobuyuki Yamamoto i, Hiromasa Yamamoto x, Mina Gaga ac, Kwun M. Fong ad, Charles A. Powell ae, Katsuyuki Kiura f,*, on behalf of DLD/TO Assemblies of JRS a

Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Japan Department of General Internal Medicine 4, Kawasaki Medical School, Japan c Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Japan d Department of Respiratory Medicine, Respiratory Center, Toranomon Hospital, Japan e Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, Japan f Department of Allergy and Respiratory Medicine, Okayama University Hospital, Japan g Department of Respiratory Medicine, Toho University Omori Medical Center, Japan h Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Japan i Third Department of Internal Medicine, Wakayama Medical University, Japan j Department of Respiratory Medicine, Tokyo Medical and Dental University, Japan k Department of Radiology, Kanagawa Cardiovascular and Respiratory Center, Japan l Department of Thoracic Oncology, National Cancer Center Hospital, Japan m Department of Pulmonary Medicine, Jichi Medical University Saitama Medical Center, Japan n Department of Radiology, University of Yamanashi, Japan o Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Japan p Department of Respiratory Medicine, Cellular Transplantation Biology, Kanazawa University Graduate School of Medicine, Japan q Department of Pathology, Nagasaki University Hospital, Japan r Department of Research, Research and Training Center for Asbestos-Related Diseases, Japan s Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Japan t Division of Thoracic Oncology, Shizuoka Cancer Center, Japan u Department of Internal Medicine, Saitama Municipal Hospital, Japan v Department of Medical Oncology, Chiba University Hospital, Japan b

* Corresponding author. https://doi.org/10.1016/j.resinv.2019.06.001 2212-5345/© 2019 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved. Please cite this article as: Ogura T et al., Summary of the Japanese Respiratory Society statement for the treatment of lung cancer with comorbid interstitial pneumonia, Respiratory Investigation, https://doi.org/10.1016/j.resinv.2019.06.001

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Department of Respirology, Graduate School of Medicine, Chiba University, Japan Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan y Department of Radiation Oncology, National Cancer Center Hospital, Japan z Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Science, Tokushima University, Japan aa Department of Pulmonary Medicine, Department of Internal Medicine Jichi Medical University, Japan ab Department of Internal Medicine, Shikoku Central Hospital, Japan ac Respiratory Medicine Dept and Asthma Center, Athens Chest Hospital "Sotiria", Greece ad Department of Thoracic Medicine, The Prince Charles Hospital, School of Medicine, The University of Queensland, Australia ae Department of Medicine, Icahn School of Medicine at Mount Sinai, USA x

article info

abstract

Article history:

Dramatic progress in targeted therapy and immunotherapy has been changing clinical

Received 13 December 2018

practices in lung cancer. With the accumulation of clinical practice, it has become clear

Received in revised form

that pre-existing interstitial pneumonia (IP) could be a risk factor for drug-induced lung

23 May 2019

injury, which has enhanced awareness regarding the difficulty in treating lung cancer with

Accepted 3 June 2019

comorbid IP. Unfortunately, there is only low-grade evidence in the field of lung cancer

Available online xxx

with comorbid IP, because almost all clinical trials exclude such patients. There have been very few specialized clinical trials for patients with lung cancer and underlying IPs thus far. Therefore, it is necessary to treat such cases empirically or to give up on the treatment itself. Considering these circumstances, establishing how to treat lung cancer with comorbid IP is an urgent issue. This paper is a summary of the official statement reported by the Diffuse Lung Disease/Thoracic Oncology Assembly and the Japanese Respiratory Society (JRS) in 2017, which attempts to approach lung cancer with comorbid IP systematically. © 2019 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

Contents 1. 2.

3. 4.

5.

6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chapter I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Classification of IP and lung cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Clinical, pathological, and imaging-based classification of IP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. Pathological classification of lung cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chapter II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Molecular biology of IP and lung cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chapter III . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Clinical profile of lung cancer with comorbid IP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2. Ethnic differences in drug-induced pneumonia associated with anti-cancer agents . . . . . . . . . . . . . . . . . . . Chapter IV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Diagnosis of lung cancer with comorbid IP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.1. Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.2. Imaging diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chapter V . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Therapy for lung cancer with comorbid IP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.1. Treatment for lung cancer with comorbid IP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.2. Diagnosis of AE of IP and associated predictive factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.3. Treatment for acute exacerbation of IP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.4. Effect of anti-cancer chemotherapy on comorbid IP, with countermeasures . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.5. Effect of molecular-targeted drugs on IP, with countermeasures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.6. Effect of immune checkpoint inhibitors on IP, with countermeasures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.7. Effect of radiotherapy on IP, with countermeasures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00

Please cite this article as: Ogura T et al., Summary of the Japanese Respiratory Society statement for the treatment of lung cancer with comorbid interstitial pneumonia, Respiratory Investigation, https://doi.org/10.1016/j.resinv.2019.06.001

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7.

3

Chapter VI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Combined pulmonary fibrosis and emphysema (CPFE) and lung cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 7.1.1. CPFE and lung cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 7.1.2. Surgical treatment of lung cancer with comorbid CPFE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 7.1.3. Chemotherapy in lung cancer with comorbid CPFE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 III . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Clinical profile of lung cancer with comorbid IP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Ethnic differences in drug-induced pneumonia associated with anti-cancer agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 IV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Imaging diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 V . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 1. Treatment for lung cancer with comorbid IP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2. Diagnosis of acute exacerbation of interstitial pneumonia and associated predictive factors . . . . . . . . . . . . . . . . . . . 00 3. Treatment for acute exacerbation of interstitial pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4. Effect of chemotherapy on interstitial pneumonia and countermeasures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Selection of chemotherapy for NSCLC with comorbid IP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Selection of chemotherapy for small-cell lung cancer with comorbid IP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Effect of each anti-cancer drug on comorbid IP, with countermeasures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5. Effect of molecular-targeted drugs on IP and countermeasures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Selection of molecular-targeted drugs for driver oncogene-positive lung cancer with comorbid interstitial pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Effect of small-molecule compounds on interstitial pneumonia and countermeasures . . . . . . . . . . . . . . . . . . . . . . . 00 Effect of monoclonal antibodies on IP and countermeasures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 6. Effect of immune checkpoint inhibitors on IP, with countermeasures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 7. Effect of radiotherapy on IP, with countermeasures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Radiation pneumonitis associated with chemoradiotherapy (particularly in cases with comorbid IP) . . . . . . . . . . 00 Radiation pneumonitis after stereotactic radiotherapy (particularly in cases with comorbid IP)―including basic knowledge of radiation pneumonitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 VI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

7.1.

1. Introduction Recently, there have been remarkable advances in lung cancer treatment, especially drug therapy, including molecular target treatment and immunotherapy. Evaluations in clinical trials are indispensable for new therapeutic development. However, almost all lung cancer clinical trials exclude patients with comorbid interstitial pneumonia (IP) from their registration. For this reason, lung cancer with comorbid IP has been completely left behind, and there is little evidence for its therapy. With little evidence available for assessment, patients with lung cancer and comorbid IP must make the ultimate choice to treat or not to treat the disease. This paper is a summary of the official statement reported by the Diffuse Lung Disease/Thoracic Oncology Assembly and the JRS in 2017. The statement was made by expert board members, listed as the authors of this paper, and went

through the peer-review process by 18 reviewers, with one or two reviewers reviewing per section. The board members always included “interstitial pneumonia,” “pulmonary fibrosis,” and “interstitial lung disease (ILD)” as search words when they searched for related articles. The purpose of the statement is to shed light on any missing pieces of evidence for lung cancer, and to understand how to treat this disease with comorbid IP. Given that most clinical trials exclude not only idiopathic pulmonary fibrosis (IPF), but also other interstitial lung diseases, we defined “IP” in this paper as interstitial lung disease including, idiopathic IPs (IIPs) and secondary IPs, such as drug-induced IP, radiation pneumonitis, and pneumoconiosis. By carrying out this work, we hope to lead the creation of treatment guidelines for lung cancer with comorbid IP in the future. This paper includes newly published information [1].

Please cite this article as: Ogura T et al., Summary of the Japanese Respiratory Society statement for the treatment of lung cancer with comorbid interstitial pneumonia, Respiratory Investigation, https://doi.org/10.1016/j.resinv.2019.06.001

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2. Chapter I 2.1. Classification of IP and lung cancer 2.1.1. Clinical, pathological, and imaging-based classification of IP ▪ The classification of IP has been primarily based on pathological diagnosis. In 2002, an international multidisciplinary classification of IIPs was issued by the American Thoracic Society/European Respiratory Society (ATS/ERS). In 2013, a revision of the multidisciplinary classification was published, and has become the current international classification [1]. The JRS adopts this classification [2]. ▪ IIPs are classified into the following types: IPF, idiopathic non-specific interstitial pneumonia (INSIP), interstitial lung disease accompanied by respiratory bronchiolitis (RB-ILD), desquamative interstitial pneumonia (DIP), cryptogenicorganizing pneumonia (COP), acute interstitial pneumonia (AIP), idiopathic lymphoid interstitial pneumonia (LIP), idiopathic pleuroparenchymal fibroelastosis (PPFE), and unclassifiable IIPs [1]. A clinical classification system based on pathological patterns has also been proposed. Typical IPF can be diagnosed from the findings of highresolution computed tomography (HRCT) and clinical findings. ▪ The radiological and pathological patterns used in the classification of IIPs are also used for the classification of secondary IPs. ▪ In many cases of lung cancer with comorbid IP, it is not possible to perform a surgical lung biopsy; as a result, many cases are categorized as “unclassifiable IIPs” [1]. There are many reports of classification being based on the presence or absence of honeycomb lung in HRCT.

2.1.2. Pathological classification of lung cancer ▪ The pathological classification of lung cancer has undergone major changes in recent years. First, the International Association for the Study of Lung Cancer (IASLC) proposed a new classification of lung adenocarcinoma in 2011 [3], and then in 2015, the World Health Organization (WHO) amended the classification [4]. In response, the 8th edition of the General Rules on the Clinical and Pathological Handling of Lung Cancer was issued in January 2017.

3. Chapter II 3.1. Molecular biology of IP and lung cancer ▪ Risk factors common to both IP and lung cancer include smoking, environmental or occupational exposure to harmful substances, bacterial or viral infection, and chronic tissue damage [1,2]. ▪ Molecular mechanisms common to the development of both IP and lung cancer include genetic and epigenetic

mutations, micro-RNA expression abnormalities, inhibition of apoptosis associated with the activation of intracellular signal transduction, and the weakening of cellular interaction [1e12]. ▪ To find treatments for lung cancer with comorbid IP, it will be essential to further elucidate the molecular mechanisms involved in the onset, progression, and development toward an intractable status of IP and lung cancer, as well as to investigate control methods that target the relevant molecules.

4. Chapter III 4.1. Clinical profile of lung cancer with comorbid IP 4.1.1. Epidemiology ▪ There have only been a few reports on the frequency of lung cancer with comorbid IIPs, other than IPF. ▪ The frequency varies between reports, but lung cancer has a high rate of IPF comorbidity, reaching between 2.0e16.7% at the time of IPF diagnosis [1e7], and a cumulative rate of 2.7e31.3% [1e16]. Although the rates from some autopsy reports are 17.0e48.2% [17e21], the rate of comorbidity with IPF is generally considered to be approximately 10e20%. ▪ Comorbidity of lung cancer in IPF is high, even after the adjustment of associated risk factors for lung cancer, including old age, male sex, and a history of smoking [12,15]. ▪ Lung cancer with comorbid IP often develops as squamous cell carcinoma at a peripheral honeycomb lesion of the lower lobe [4,22,23], though the reports are inconsistent [3e5,7,14,24]. ▪ Comorbidity with IPF has a poor prognosis in conjunction with lung cancer [25e29]. Similarly, comorbidity with lung cancer has a poor prognosis in IPF [7]. ▪ The rate of comorbid lung cancer is also high in the following conditions: hypersensitivity pneumonitis [30,31], pneumoconiosis [32,33], and asbestosis [33], but in the case of collagen vascular disease-interstitial lung disease (CVDILD), the rate is likely to vary depending on the underlying condition [34e40]. Combined pulmonary fibrosis and emphysema (CPFE) also has a high rate of comorbidity with lung cancer [41,42].

4.1.1.1. Frequency of comorbid lung cancer in IIPs (Table 1). IPF is known to have a high rate of comorbidity with lung cancer. However, there are very few reports on the frequency of comorbid lung cancer and IIPs, other than IPF. Kreuter et al. reported that 42 (15.8%) out of 265 IPF patients, 6 (4.2%) out of 142 INSIP patients, and 4 (5.6%) out of 71 COP patients had comorbidity with lung cancer [6]. There are also very few reports regarding other IIPs, and the present section focuses mainly on IPF. Frequency of comorbid lung cancer in IPF significantly differs from that in the reported cohorts, because the comorbidity rate increases over time, and depends largely on the duration of the follow-up period of the IPF. Other relevant

Please cite this article as: Ogura T et al., Summary of the Japanese Respiratory Society statement for the treatment of lung cancer with comorbid interstitial pneumonia, Respiratory Investigation, https://doi.org/10.1016/j.resinv.2019.06.001

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Table 1 e Frequency of lung cancer comorbidity in patients with IPF (CFA, UIP) Reporter

Year published Country No. of IPF cases No. of lung cancer cases Frequency (%) Relative risk Reference

Comorbidity rate at autopsy Kawai 1987 Japan 47 Matsushita 1995 Japan 83 Hironaka 1999 Japan 70 Qunn 2002 Japan 72 Araki 2003 Japan 86 (65 yrsþ) Comorbidity rate at death (from the death certificate) Wells 1996 US Harris 1998 UK 1951 Harris 2010 UK 488 Cumulative comorbidity rate Turner-Warwick 1980 UK 205 1990 Japan 38 Kinoshitaa Ohtsuka 1991 Japan 45 Nagai 1992 Japan 99 Takeuchia 1996 Japan 102 Lee 1996 S. Korea 244 1997 Japan 434 Oguraa Hubbard 2000 UK 890 Ozawa 2009 Japan 103 Park 2001 S. Korea 281 Le 2007 UK 1064 Lee 2012 S. Korea 1685 Xu 2012 China 104 Kreuter 2014 Germany 265 Hyldgaard 2014 Denmark 121 Tomassetti 2015 Italy 181

8 40 32 31 15

17.0 48.2 45.7 43.1 17.4

[17] [18] [19] [20] [21]

109 46

4.81 5.6 9.4

[43] [44] [45]

20 (4) 13 8 31 23 (17) 32 118 (33) 39 21 63 29 114 (89) 24 (17) 42 (15) 7 23(7)

9.8 (2.0) 7.9 17.8 31.3 22.5 (16.7) 13.1 27.2 (7.6) 4.4 20.4 22.4 2.7 6.8 (5.3) 23.1 (16.3) 15.8(5.6) 5.8 12.7 (3.9)

14.1

7.31

4.96

[1] [8] [9] [10] [2] [11] [3] [12] [13] [14] [15] [4] [5] [6] [16] [7]

( ) ¼ cases with comorbidity at the time of diagnosis. IPF, idiopathic pulmonary fibrosis; CFA, cryptogenic fibrosing alveolitis; UIP; usual interstitial pneumonia. a idiopathic interstitial pneumonias.

factors include, accuracy of IPF diagnosis and patient characteristics included in each cohort.

4.1.1.2. Clinical characteristics of IIPs with comorbid lung cancer 4.1.1.2.1. Background factors, histology, and tumor site. Generally, lung cancer lesions develop more frequently in the fibrotic site or in the lower lobe (Table 2). Mizushima et al. carried out a review of the clinical characteristics of IPF with comorbid lung cancer that were reported in Japan between 1980 and 1994 [22]. Of the 154 patients, 131 had a single primary lung cancer, 20 had double primary lung cancer, and 3 had triple primary lung cancer. Males, smokers, squamous cell carcinomas, and lower lobe lesions were more common among patients with IPF and comorbid lung cancer. the cancerous lesions were frequently seen at a peripheral site. Multiple primary types of cancer were frequently seen in autopsy cases and often developed as small-cell carcinomas [18,20]. There are many other reports with similar findings (Table 2), and it is generally thought that lung cancers develop frequently at fibrotic sites in the lower lobe. Conversely, in a South Korean report by Park et al. lung cancer lesions were more frequently found in the upper lobe (52%) than in the lower lobe (43%) [14]. They also reported that only 23 cancers (37%) developed inside the fibrotic area. The reason for the discrepancy with the paper by Park et al. is uncertain, but they discuss in the paper that a possible reason might be the misdiagnosis of IPF. Not all the patients in their study were

histologically diagnosed using surgical biopsy. Tomassetti et al. compared 23 cases of IPF with comorbid lung cancer with 158 cases without lung cancer. There was a higher incidence of IPF with comorbid lung cancer in smokers (91.3% vs. 71.6%), those with CPFE (52% vs. 32%), and when the cancer lesion was in the upper lobe of the lung and peripheral dominant [7]. The lung cancer lesions predominantly developed in the fibrotic area (73%). Lee et al. compared lung cancer that developed at IPF-associated areas with those that developed at other sites [4]. Of the 114 IPF patients, 43 had lung cancer lesions at IPFnon-associated areas, and 23 had lung cancer lesions in their upper lobe. Seventy-three patients had lung cancer lesions at IPF-associated areas, 13 of which had lesions in their upper lobes. Kishi et al. undertook an analysis of the HRCT profile of IPF with comorbid lung cancer. Seventeen of the 30 patients developed lung cancer in association with honeycomb lesions. While, the remaining 13 developed lung cancer at sites distant from the honeycomb lesions, 12 in the upper lobe and one in the lower lobe of the lung [24]. However, these tumors were adjacent to reticular shadows suggestive of fibrosis. The above findings indicate that lung cancer lesions also occur in the upper lobe and at non-fibrotic sites. It is thus difficult to conclude from the epidemiological data whether both IP and lung cancer are present due to a common cause, or whether squamous metaplasia or other features at fibrotic sites are the origins of these tumors. 4.1.1.2.2. Prognosis. In the Hokkaido Study, a large-scale observational study in which 553 IPF patients, diagnosed

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Reporter

Turner-Warwick Mizushima（single cancer)a Mizushima (multiple cancers)a Takeuchi Lee Ogura Hironaka Park Qunn Aubry Ozawa Harris Lee Xu Song Lee Kreuter Tomassetti Khan

Year Country No. of published subjects 1980 1995 1995 1996 1996 1997 1999 2001 2002 2002 2009 2010 2012 2012 2014 2014 2014 2015 2015

UK Japan Japan Japan S.Korea Japan Japan S.Korea Japan US Japan UK S.Korea China S.Korea S.Korea Germany Italy Ireland

20 131 23 22 32 118 32 63 31 24 21 46 114 24 43 70 265 23 34

Male (%)

Ave. age (yrs)

Smoking history (%)

Histology Sq/Ad/Sm (%)

85.0 90.8 95.7 90.9 96.9 91.5 96.9 96.9 96.8 87.5 95.2 87.0 94.7 91.7 95.3 94.3 92.8 82.6 62.9

62.1

89.5 96.1 100.0

60/13/0 42/34/14 33/29/33 36/27/18 56/22/19 39/47/23 33/20/30 35/30/19 32/29/29 67/29/0 38/29/19

64.4 70.5 66 67.3 63.7 66.8 69.4 72.3 65.5 68.4b 68.5 64.7 68 70 66.9 71.1

86.4 96.9 89.0 85.0 91.7 77.8 95.7 85.8 87.5 79.0 94.3 92.8 91.3 100.0

33/36/25/33/17 42/40/5 40/30/12 36/31/19 39/35/13 41/38/12

Lesion site Lesion site Lesion site Reference peripheral (%) fibrotic (%) upper /middle/lower lobe (%) 90.6 97.8 90.9 65.6 71.6 90.0 63.4 84.0

43/3/58 27/3/67 36/9/55 22/6/66 40/7/53 36.5 75.0

77.1 79.2

68.9 70.8 70.0

66.7 91.3 82.4

72.7 85.3

51/3/47 36/7/54 29/8/42

35/4/59 23/2/77 40/4/55 60/7/31 61/0/39 38/3/59

IPF, idiopathic pulmonary fibrosis; CFA, cryptogenic fibrosing alveolitis; UIP; usual interstitial pneumonia; Sq, squamous cell carcinoma; Ad, adenocarcinoma; Sm, small cell carcinoma. a Integrated analysis of 17 reports in Japan from 1980 to 1994. b At the time of death.

[1] [22] [22] [2] [11] [3] [19] [14] [20] [23] [13] [45] [4] [5] [49] [28] [6] [7] [47]

respiratory investigation xxx (xxxx) xxx

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Table 2 e Clinical characteristics of lung cancer with comorbid IPF (CFA, UIP)

respiratory investigation xxx (xxxx) xxx

between 2003 and 2007 were observed until September 2011, lung cancer was the third-leading cause of death, accounting for 11% of mortality [46]. Tomassetti et al. investigated whether comorbid lung cancer had an impact on IPF prognosis and found that patients had a median survival period of 38.7 months, which was significantly shorter than the 63.9 months for patients with IPF alone [7]. The hazard ratio in the comorbidity group, adjusted for patients history, was 7.0 times that of the IPF-only group. The cause of death was respiratory failure in 43%, lung cancer progression in 13%, and complications from lung cancer treatment in 17%. Conversely, to study the impact of comorbid IPF on lung cancer prognosis, Saito et al. compared post-surgical survival of stage IA non-small cell lung cancer (NSCLC) patients with and without comorbid IPF. The 5-year survival of the 28 patients with comorbid IPF was 54.2%, significantly lower than that of the 322 patients without comorbid IPF (88.3%). IPFcomorbidity was identified as a poor prognostic factor in a multivariate analysis [25]. Similarly, in an analysis by Watanabe et al., the 5-year survival rate in Stage I lung cancer with comorbid IPF was 61.6%, whereas it was 83.0% in the noncomorbidity group [26]. Meanwhile, Goto et al. reported, in an analysis of post-surgical cases, that IPF may be a poor prognostic factor at pathological stages I/II, but not at pathological stages III/IV [27]. Lee et al. studied 33 lung cancer patients with comorbid IPF and reported that comorbid IPF is a poor prognostic factor in surgical cases irrespective of age, sex, histology, or disease stage. The 5-year survival rate was 38%, significantly less than the 73% in the non-IPF control group [28]. Omori et al. reported on post-surgical lung cancer cases with comorbid IIPs, 46 with usual interstitial pneumonia (UIP) and 57 without UIP and found that the 5-year survival rates was 22.1% and 53.2%, respectively. While rates of IIPrelated death from respiratory failure were 26.1% and 7.0%, respectively. Indicating that comorbidity with IPF had an even worse post-surgical prognostic factor than that of other IIPs [29]. Khan et al. analyzed 34 cases with comorbid IPF among 637 lung cancer patients, and their prognosis was poor, irrespective of stage or received therapy [47]. Aubry et al. also analyzed 24 cases with comorbid IPF among 554 lung cancer patients [23]. The median survival period was 2.3 years following IPF diagnosis and 1.6 years following lung cancer diagnosis.

4.1.1.3. Frequency of comorbid lung cancer in secondary IP, CPFE and associated clinical characteristics 4.1.1.3.1. CVD-ILD. In lung cancer comorbid with CVD-ILD, it has been suggested that the involvement of fibrotic lesions that arise during the course of rheumatoid arthritis (RA), or systemic sclerosis (SSc) contribute to the disease. However, CVD itself and its therapy has also been pointed to as a possible underlying factor for lung cancer. It has also been suggested that the treatment for collagen disease has a carcinogenic effect. Ohno et al. undertook a clinical investigation of CVD-ILD cases with comorbid lung cancer [34]. Of 73 CVD-ILD patients, 9 (5 RA, 2 SSc, and 2 polymyositis/dermatomyositis; PM/DM) had lung cancer lesions. Of these, 5 were adenocarcinoma and 2 were squamous cell carcinoma. In contrast to lung cancer lesions in IPF, there was no lower lobe

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predominance among lung cancer lesions in collagen lung disease. 4.1.1.3.1.1. Rheumatoid arthritis (RA). Takayanagi et al. reported that 14 (19.4%) of 72 RA/IIP patients had comorbid lung cancer, including 7 with a simultaneous diagnosis [35]. This finding suggests that RA/UIP could be a risk factor for the development of lung cancer. In an investigation of lung cancer risk in RA/IIP patients, the risk of developing lung cancer was significantly higher in those who smoked (odds ratio of 14.93) or had a history of smoking 20 pack-years or more (odds ratio of 21.27). In a cohort study by Bernatsky et al. of 23,810 RA patients, comorbid lung cancer was found in 960, and this group (16.6%) had a higher rate of comorbid IP than the nonlung cancer group (5.7%) [36]. The adjusted hazard ratio (HR) for the presence or absence of IP, to estimate the effect RAcomorbidity alone has on the development of lung cancer, was 2.87. 4.1.1.3.1.2. Systemic sclerosis (SSc). In a study evaluating the risk of lung cancer in SSc, Hashimoto et al. reviewed 405 patients with this disease. They found 27 patients with malignant disease, including 10 lung cancer patients, all of whom had comorbid IP [37]. Five patients, all female, had adenocarcinoma. Upon death the 4 for who had an autopsy performed, cancer was found in the IP region. Among the females, the standardized incidence ratio, estimated the effect of SSccomorbidity on lung cancer, to be 6.48. Kang et al. found that, out of 112 SSc patients at a South Korean facility, 4 had lung cancer (NSCLC), and all of whom were females, 2 of whom had comorbid IP and were non-smokers [38]. Meanwhile, the relationship between SSc and lung cancer was studied by Pontifex et al., who found that smoking was a risk factor for lung cancer (risk ratio 7.04 times), but for pulmonary fibrosis, it represented no additional risk [39]. Katzen et al. released a report on 17 SSc patients who developed lung cancer [40]. A total of 82% of them were female, and 65% were smokers. Twelve patients showed scleroderma associated lung involvement, among which 10 had adenocarcinoma, one had squamous cell carcinoma, and one had large-cell neuroendocrine carcinoma (LCNEC). 4.1.1.3.2. Chronic hypersensitivity pneumonitis (CHP). Kuramochi et al. reported that comorbid lung cancer in chronic hypersensitivity pneumonitis (CHP) patients, displays similar characteristics to lung cancer comorbid with IPF, such as dominant squamous cell carcinoma at a peripheral lung location [30]. Of 104 patients, 11 (10.6%) were found to have a total of 15 comorbid lung cancer lesions. Four had multiple cancers. A smoking history was present in all cases, and squamous cell carcinoma was the most frequently found cancer at 53%, all from a peripheral origin. Four patients were diagnosed with squamous cell carcinoma during the followup period for CHP. Seven lesions (47%) were in contact with honeycomb lung, while 4 (27%) were in a bullous region and 4 (27%) in normal lungs. Ogata et al. studied 161 CHP patients, and comorbid lung cancer developed in 18 cases (11.2%) [31]. They also compared CHP in those with emphysema and without emphysema. The emphysema group developed lung cancer at a significantly higher rate (24.5%) compared to the non-emphysema group (4.6%). In the CHP with emphysema group, adenocarcinoma was found in 41.7% and squamous cell cancer was found in 33.3% of the patients.

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respiratory investigation xxx (xxxx) xxx

4.1.1.3.3. Pneumoconiosis/asbestosis. Katabami et al. reported that, out of 563 pneumoconiosis patients, excluding cases of asbestosis, 55 (10%) had comorbid diffuse IP [32]. Incidence of lung cancer was higher among patients with comorbid diffuse IP than among those without it, at 29 (53%) and 78 (15%), respectively. In the group with comorbid diffuse IP, peripheral squamous cell carcinoma was frequent, and in 74% the cancer developed in the IP region. It has been reported elsewhere that the risk ratio of comorbid lung cancer is also high in asbestosis and silicosis [33].

DAD pattern drug-induced pneumonia. A phase III study, CheckMate017, which determined the efficacy of nivolumab for advanced squamous cell lung cancer, showed that 6 of 131 patients had drug-induced pneumonia [6]. CheckMate057, which determined the efficacy of nivolumab for nonsquamous cell lung cancer, showed that 10 of 287 patients had drug-induced pneumonia [7]. It remains unclear whether ICI-induced pneumonia develops more frequently in Japanese people.

4.1.1.3.4. Combined pulmonary fibrosis and emphysema (CPFE). Kitaguchi et al. reported that 22 of 47 CPFE patients

4.1.2.2. Highly frequent pathological DAD in Japanese patients.

had comorbid lung cancer (46.8%), including 12 cases of squamous cell carcinoma and 7 of adenocarcinoma (31.8%). Sugino et al. reported that 46 of 108 IPF cases also had comorbid emphysema and that 62 had IPF alone. A higher rate of lung cancer comorbidity was seen in the former group, at 23 cases (50.0%) versus 9 cases (14.5%) [41]. Meanwhile, Kwak et al. undertook a retrospective study of lung cancer comorbidity, in which there were 48 patients with CPFE, 48 with IPF, and 96 with pulmonary emphysema [42]. In the CPFE group, lung cancer developed in 25 patients, but the associated risk was not different between the CPFE and IPF groups. For more detail information, please see Chapter VI. CPFE and lung cancer.

4.1.2. Ethnic differences in drug-induced pneumonia associated with anti-cancer agents ▪ The Japanese population often shows diffuse alveolar damage (DAD),a type of drug-induced pneumonia in reaction to gefitinib and similar drugs [1]. ▪ It is postulated that the Japanese have a genetic predisposition to DAD. ▪ Currently, a number of studies are in progress to determine the genetic predisposition to DAD of the Japanese population. The candidate genes include human immunodeficiency virus type I enhancer binding protein 3 (HIVEP3), nonmetastatic cell 7 (NME7), and mucin 4 (MUC4).

Drug-induced pneumonitis with a DAD pattern has pathological similarities with acute exacerbation (AE) of IIPs, acute progressive IP in clinically amyopathic dermatomyositis (CADM) and acute respiratory distress syndrome (ARDS) [8]. An epidemiologic IPF cohort study among Japanese patients revealed that in 40%, the cause of death was AE. While in America, 18% of the IPF patients died of AE, suggesting that Japanese IPF patients die more frequently from AE.

5. Chapter IV 5.1. Diagnosis of lung cancer with comorbid IP 5.1.1. Biomarkers ▪ As the molecular profiles of lung cancer and IP have many similarities, it seems possible that there are common factors in their onset [1e4]. ▪ The molecular profile of lung cancer with comorbid IP has not been sufficiently elucidated, but as research progresses, biomarkers may be discovered that can be used for early diagnosis of lung cancer with comorbid IP. ▪ In lung cancer comorbid with IP, if changes in cell-free DNA and microRNA in the blood were to be identified, they could act as biomarkers for early diagnosis. In particular, microRNA in the blood is a promising candidate, as it is known for having a stable presence in the human plasma [5].

4.1.2.1. Highly frequent drug-induced pneumonia in Japanese patients. Drug-induced pneumonias frequently develop, especially in Japanese patients compared to those from other countries [1e3]. On the basis of clinicopathological findings, they are classified into several types: non-cardiogenic pulmonary edema (NCPE), hypersensitivity pneumonia (HP), acute eosinophilic pneumonia (AEP), DAD, non-specific interstitial pneumonia (NSIP), organizing pneumonia (OP), etc [3]. Among them, DAD is reported to be frequently fatal in Japanese patients [4]. Kudo et al. reported that gefitinibinduced pneumonia was 13 times more frequent in Japanese people (3.98%, AstraZeneca Case-control study) than in Americans (0.3%, FDA approval letter) [5]. Recently, immune check point inhibitors (ICIs), such as nivolumab have been applied in clinical settings, but it has been reported that ICI also causes drug-induced pneumonia. Pneumonia induced by ICIs often respond to steroid therapy, and appears to be caused by a different mechanism from the

5.1.2. Imaging diagnosis ▪ During the imaging diagnosis of IP, images should be interpreted bearing in mind that comorbid lung cancer is frequently present. ▪ The comparative interpretation of images is very important. It would be safer to suspect lung cancer, when newly solid nodules appear during the clinical course, at the border between IP and normal lungs [1e3]. ▪ As there are limitations to diagnosis based on computed tomography (CT) alone, an overall diagnosis based on the combined use of positron emission tomography (PET) and magnetic resonance imaging (MRI) should be considered [4e6]. ▪ Imaging diagnosis is not only important to diagnose the presence and disease stage of lung cancer, it also plays an

Please cite this article as: Ogura T et al., Summary of the Japanese Respiratory Society statement for the treatment of lung cancer with comorbid interstitial pneumonia, Respiratory Investigation, https://doi.org/10.1016/j.resinv.2019.06.001

respiratory investigation xxx (xxxx) xxx

important role in identifying the pattern and the degree of severity of interstitial pneumonia.

6. Chapter V 6.1. Therapy for lung cancer with comorbid IP 6.1.1. Treatment for lung cancer with comorbid IP It is unclear whether chemotherapy prolongs the survival of advanced lung cancer patients with comorbid IP, compared to the best supportive care. In the treatment of lung cancer with comorbid IP, the risk of fatal AE must be considered. Use of anti-cancer agents must take into account the risk versus the benefit. Therefore, it is necessary to carefully assess both lung cancer and IP. It is also necessary to respect the patient’s wishes in the treatment selection. The Japanese Guideline for the Treatment of Idiopathic Pulmonary Fibrosis 2017 was published by the Japanese Respiratory Society and the Ministry of Health, Labour and Welfare, via the Study Group on Diffuse Pulmonary Disorders, Scientific Research, and Research on Intractable Diseases [1]. This guideline lays out clinical questions for the chronic stable phase and also for AE of IPF and lung cancer comorbidity. One of the clinical questions is: “Is chemotherapy recommended for lung cancer patients with comorbid IPF or other IPs?” The corresponding answer is: “We suggest that lung cancer patients with comorbid IPF or other IPs should be treated with chemotherapy, but that this therapy may not be a reasonable option in a minority of patients (weak recommendation, quality of evidence very low).” Clinical trials for lung cancer often exclude patients with IP, and no large-scale phase III studies have been carried out in patients with advanced lung cancer comorbid with IP. However, as noted in the present chapter, there are several relevant research reports, albeit with relatively small numbers of cases. Moreover, chemotherapy is widely applied in actual medical practice for lung cancer with comorbid IP, which is the basis for the above statement. The anti-cancer agents selected for use in lung cancer with comorbid IP should be agents that have a low incidence of IP as a side effect. Table 3 presents the descriptions, relating to IP, contained in the Japanese package inserts of anti-cancer agents used in lung cancer. Firstly, irinotecan is contraindicated in patients with IP or pulmonary fibrosis. Next, gemcitabine and amrubicin are contraindicated in patients with IP or pulmonary fibrosis advanced enough that is clearly identifiable from plain chest X-ray images and is accompanied by clinical symptoms. It should be noted that, apart from platinum preparations and drugs containing anti-vascular endothelial growth factor (VEGF) antibodies, careful administration is recommended for many anti-cancer agents, and a warning relating to IP is included in the case of treatments with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI), anaplastic lymphoma kinase (ALK)-TKI, and in particular, anti-programmed cell death protein 1 (PD-1) antibodies. Among the drugs with the highest frequency of associated IP are, gefitinib, with 1% to less than 10%, nivolumab with 5.1%, and amrubicin with 0.1% to less than 5%, but these are chiefly

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frequencies under clinical trial conditions and not the frequencies when administered to patients with pre-existing IP. As chemotherapeutic agents are used in a variety of cancers, including lung cancer, physicians administering these agents need to have a thorough familiarity with anti-cancer drugs and IP. One of the issues to be addressed going forward, is the identification of risk factors for AE, during the treatment of lung cancer patients with comorbid IP. There are already reports that point to a UIP pattern on HRCT [2], and reduced values for vital capacity [3], but analysis covering a larger number of cases is needed to improve treatment results. In addition, anti-cancer drugs for lung cancer with comorbid IP are often studied as a first-line treatment, but there are few reports on second-line treatments or later, and the further accumulation of case evidence is therefore eagerly awaited. Lastly, ICIs have appeared as anti-cancer agents, but since their safety and efficacy in lung cancer with comorbid IP is unclear, relevant reports are needed going forward.

6.1.2. Diagnosis of AE of IP and associated predictive factors ▪ For the diagnosis of AE of IPF, it was previously necessary to rule out cardiac failure, infectious disease, drug-induced pneumonitis, etc [1]. Now, however, a new approach has been proposed whereby these conditions are diagnosed collectively as AE of IPF, which are classified into either idiopathic AE, which has no trigger factors or triggered AE [2]. ▪ In the new approach, AE of comorbid IP caused by anticancer therapy, including drugs, radiation, and surgery is classified as triggered AE. ▪ AE of IP occurs yearly in 5% to 15% of patients [3]. Associated predictive factors include a reduced forced vital capacity (FVC), plasma saturation (PaO2), and 6-minute walking distance at baseline. Comorbid pulmonary hypertension, past history of AE, and an elevated Krebs von den Lungen-6 (KL-6) value are also seen [4e10]. Predictive factors for triggered AE after surgery include, the extent of pulmonary resection, reduced pre-surgical vital capacity (VC) and diffusing capacity (DLCO), and UIP-pattern [11,12]. ▪ High levels of serum KL-6 are a risk factor for AE among patients with IPF [10]. Presently, there are no other blood biomarkers which actually predict AE-IPF.

6.1.3. Treatment for acute exacerbation of IP ▪ Effective pharmacological treatment for AE-IPF is limited. The ATS/ERS/JRS/Latin American Thoracic Association (ALAT) guideline for IPF gives a weak recommendation to administer corticosteroids (CS) for the treatment of AE-IPF, although the evidence level for this is very low [1]. Pulsed doses of intravenous CS is commonly used in our clinical practice [2]. ▪ In recent years, polymyxin B-immobilized fiber columndirect hemoperfusion (PMX-DHP)1 and anti-coagulation treatments such as recombinant thrombomodulin1 and

1

Not approved for the treatment of AE of IP in Japan

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Class Platinum preparations

Plantalkaloids

Generic name

Item

Cisplatin Carboplatin Nedaplatin Paclitaxel Paclitaxel (albms in-bound) Docetaxel Vinorelbine

Precautions (significant adverse reactions) Precautions (significant adverse reactions) Precautions (significant adverse reactions) Precautions (careful administration/serious side effects/other precautions) Precautions (careful administration/serious side effects) Precautions (careful administration/serious side effects/other precautions) Precautions (careful administration/serious side effects/other precautions/significant adverse reactions/use in the elderly) Warming/contraindication (patents with interstitial pneumonia or pulmonary fibrosis)/ precautions (important precautions/ significant adverse reactions) Precautions significant adverse reactions) Warning/contraindicationa/precautions (careful administration/important precautions/sideeffects) Warning/precautions (careful administration/important precautions/significant adverse reactions Precautions (significant adverse reactions) Precautions (careful administration/important precautions/significant adverse reactions)

Irinotecan

Antim etabolites

Etoposide Gemcitabine

Anticancer antibiotics

Pemetrexed Tegafur/uracil Tegafur/gim eracil/oterac il potessium Amrubicin

EGFR-TKI

Gefitinib Erlotinib Afatinib Osimertinib

ALK-TKI

Crizotinib Alectinib Ceritinib

Anti-PD-1 antibodies Anti-VEGF antibodies Anti-VEGFR-2 antibodies a

Nivolumab Pemrolizumab Bevacizumab Ramucirumab

Warning/contraindicationa/precautions (careful administration/important precautions/significant adverse reactions) Warning/Precautions (careful administration/important Precautions/significant adverse reactions/ other Precautions Warning/Precautions (careful administration/important Precautions/significant adverse reactions/ other Precautions Warning/Precautions (careful administration/important Precautions/significant adverse reactions) Warning/Precautions regarding dosage and administration /Precautions (careful administration/ important Precautions/significant adverse reactions) Warning/Precautions regarding dosage and administration /Precautions (careful administration/ important Precautions/significant adverse reactions) Warning/Precautions (careful administration/important Precautions/significant adverse reactions) Warning/Precautions regarding dosage and administration /Precautions (careful administration/ important Precautions/significant adverse reactions) Warning/Precautions (careful administration/important Precautions/significant adverse reactions) Warning/Precautions (careful administration/important Precautions/significant adverse reactions) Precautions (significant adverse reactions) Precautions (significant adverse reactions)

Frequency Less than 0.1% 0.1% Less than 0.1% 0.5% 0.8% 0.6% 1.4% 0.9% Less than 0.1% 1.0% 3.6% Less than 0.1% 0.3% 0.1 to less than 5% 1 to less than 10% 4.4% 3.1% 2.7% 1.7% 1.7% 1.4% 5.1% 3.1% 0.4% 0.4-1.7%

Contraindication: patients with interstitial pneumonia or pulmonary fibrosis clearly identifiable on plan chest X-ray images and additionally accompanied by clinical symptoms.

respiratory investigation xxx (xxxx) xxx

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Table 3 e Presents the descriptions relating to interstitial pneumonia (interstitial lung d disease) contained in the package inserts of anticancer agents used in lung cancer.

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respiratory investigation xxx (xxxx) xxx

neutrophil elastase inhibitors1 have been used, but no evidence-based therapy has been established [3e9]. ▪ There have been a few small-scale studies showing the efficacy of recombinant thrombomodulin,1 and multicenter double-blind randomized trials have been undertaken [5e7]. ▪ Because the prognosis of AE of IPF with comorbid lung cancer is poor, the indication for tracheal intubation should be assessed carefully. Non-invasive positive pressure ventilation (NPPV) and high-flow nasal cannula (HFNC), have been frequently used in recent years.

▪

▪

▪

6.1.4. Effect of anti-cancer chemotherapy on comorbid IP, with countermeasures 6.1.4.1. Selection of chemotherapy for NSCLC with comorbid IP ▪ Based on the experience of EGFR-TKI, the pulmonary toxicity of anti-cancer agents has required a call for vigilance. High-quality data on molecular-targeted drugs has been reported, regarding the relationship of pulmonary toxicity to ethnic differences and clinical backgrounds [1]. In cytotoxic anti-cancer drugs, the information regarding pulmonary toxicity in lung cancer patients with comorbid IP is scarce [2e5]. ▪ The most effective way to find the difference in pulmonary toxicity among drugs is to check the reports of large-scale clinical trials. However, many of the large-scale clinical trials are performed outside of Japan, which exclude patients with comorbid IP, and contain little data on pulmonary toxicity among Japanese patients. In any case, patients with comorbid IP are usually excluded from clinical trials to begin with. ▪ Molecular-targeted drugs and ICI are poorly suited for lung cancer patients with comorbid IP [6e7]. At present, clinicians must decide the therapeutic indications and the regimen based on their own experience. The establishment of a guideline is needed.

6.1.4.2. Selection of chemotherapy for Small-cell lung cancer (SCLC) with comorbid IP ▪ The proportion of patients with IP and comorbid lung cancer and the proportion of SCLC in lung cancer with

▪

comorbid IP are similar to that in lung cancer without IP [1e3]. In SCLC, chemotherapy has significant benefits. SCLC patients with comorbid IP are more likely to receive chemotherapy notwithstanding the risk of AE [4e8]. The options for first-line chemotherapy in SCLC are limited compared to NSCLC, but a consensus has been reached to make the standard treatment, a platinum preparation with concomitant etoposide therapy, and the standard treatment for cases with comorbid IP [9e12]. It is expected that second-line chemotherapy also improves prognosis of recurrent SCLC with comorbid IP [13e14]. However, the risk of AE may be greater than in first-line chemotherapy. It is hoped that future research results will contribute to the appropriate selection of cases and second-line regimens [15]. Chemoradiation therapy is not recommended for limiteddisease (LD)-SCLC with comorbid IP at present, because thoracic radiotherapy carries a high risk of AE of IP [16,17]. It is unknown whether radiotherapy could be possible if patients are selected appropriately.

6.1.4.3. Effect of each anti-cancer drug on comorbid IP, with countermeasures ▪ There is no drug with adequately established safety for the treatment of lung cancer with comorbid IP. ▪ Irinotecan is contraindicated for patients with comorbid IP or pulmonary fibrosis in Japan. Amrubicin and gemcitabine are contraindicated for patients with symptomatic comorbid IP or fibrosis, that is identifiable by plain chest X-ray.

6.1.4.3.1. Platinum preparation. A platinum-containing regimen is one of the first-line chemotherapies for SCLC and for EGFR mutation-negative and ALK mutation-negative NSCLC. Platinum preparations used in lung cancer treatment are cisplatin, carboplatin, and nedaplatin. Little data regarding adverse effects of platinum preparation monotherapy is available, platinum preparation is frequently used in combination therapy and it is difficult to exclude the influence of the concomitant drugs used in combination therapy on the frequency of IP. In Table 4, studies of platinumcontaining regimens for NSCLC with comorbid IP are

Table 4 e Study of combination chemotherapy including platinum preparation for NSCLC with comorbid IP Author Minegishi [5] Sekine [6] Shukuya [20] Kinoshita [48] Okuda [27] Watanabe [26] Shimizu [19] Shimizu [19] Enomoto [49] Kenmotsu [18]

Regimen

N

Study design

CBDCA þ weekly PTX CBDCA þ S1 CBDCA (weekly or monthly) þ weekly PTX Any Platinum þ VNR CDDP þ VNR CBDCA þ PTX CBDCA þ PTX þ Bv CBDCA þ PTX þ Bv Any

18 21 15 22 19 67 11 10 25 104

Prospective Prospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective

AE (%) 1 2 4 3 3 7 0 1 3 9

(5.6%) (10%) (27%) (14%) (16%) (10.4%) (0%) (10%) (12%) (9%)

Median OS 10.6 m 9.7 m 7.0 m 5.4 m 7.4 m 7.4 m 9.7 m 16.1 m 8.5 m 9.9 m

AE, acute exacerbation of IP; OS, overall survival; CBDCA, carboplatin; PTX, paclitaxel; VNR, vinorelbine; Bv, bevacizumab.

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shown. In a prospective clinical trial for 18 NSCLC patients with comorbid IIPs, carboplatin þ weekly paclitaxel was as effective for patients without IP (response rate, 61%; median survival period, 10.6 months) [1]. AE of IP was observed in one case (5.6%). Another prospective clinical trial for 21 lung cancer patients with comorbid IP, carboplatin þ S1 was also effective (response rate, 33%; overall survival period, 10.4 months). A non-lethal AE of IP was observed in 2 cases (10%) [2]. 6.1.4.3.1.1. Cisplatin. The Japanese package insert of cisplatin [Randa®(revised version of August 2014)] states that IP is one of the serious side effects, which occur in less than 0.1%. Studies at the time of approval and in 8,787 subjects post-marketing show that lung damage was observed in 0.5% (data from interviews). Domestic phase III clinical trials have shown that the frequency of IP as an adverse effect of platinum-containing regimes among the Japanese population is 1-5% [3e5]. 6.1.4.3.1.2. Carboplatin. The package inserts of Carboplatin® and Paraplatin® (revised version as of April 2016) state that IP is one of the serious side effects, which occur in 0.1%. Domestic phase III clinical trials showed that the frequency of IP as an adverse effect of carboplatin þ paclitaxel was 0e1% [3,6]. 6.1.4.3.1.3. Nedapaltin. The Japanese package insert of nedaplatin [Aqupla®(revised version of June 2009)] does not state any data about IP as an adverse effect. However, in a domestic phase III clinical trial, the frequency of IP as an adverse effect of nedaplatin þ docetaxel was reported to be 6 in 177 subjects (3%), including one grade 5 case [5].

6.1.4.3.2. Plant-derived agents.

6.1.4.3.2.1. Irinotecan.

The Japanese package insert of irinotecan [Campto®(revised version of March 2015)] states that IP is one of the serious side effects, which occur in 0.9%, based on a post-marketing surveillance program (15,385 cases). Irinotecan is contraindicated for patients with comorbid IP or pulmonary fibrosis. In a domestic prospective clinical trial of irinotecan monotherapy, the frequency of IP was 4e18% [7e10]. As the package insert states it is contraindicated, there is almost no data on the safety of irinotecan in patients with preexisting IP. 6.1.4.3.2.2. Topotecan (nogitecan). Regarding nogitecan, the Japanese package insert [Hicamtin®(revised version as of November 2015)] does not state any data regarding IP as an adverse effect. In a domestic phase III clinical trial for recurrent SCLC, IP was observed in 2% of the nogitecan monotherapy group [11]. In a retrospective analysis of 23 SCLC patients with comorbid IP, the AE of IP was observed in 5 cases (21.7%), including 3 lethal cases [12]. 6.1.4.3.2.3. Etoposide. The Japanese package insert of etoposide [Vepesid® (revised version as of May 2016)] states that IP is one of the serious side effects, which occur in less than 0.1%. Studies at the time of approval and after a post-marketing surveillance program of 4,586 subjects found IP at a rate of 0.02% (from interviews). There is a report on a prospective clinical study to evaluate the safety of a carboplatin þ etoposide regime in small-cell lung cancer patients with comorbid idiopathic IPs. AE was observed in 1 of 17 enrolled patients (5.9%), the response rate was 88.2%, and the median survival period was 8.7 months [13].

Meanwhile, in a retrospective analysis of 52 SCLC patients with comorbid IP, exacerbation of IP was observed in 1 subject (2%) under a regime of carboplatin þ etoposide [14]. 6.1.4.3.2.4. Paclitaxel. The Japanese package insert of paclitaxel [Taxol®(revised version of April 2016)] states that IP is one of the serious side effects, which occur in 0.5%. It is controversial whether a weekly paclitaxel schedule may increase adverse events in IP compared to a standard 3-week schedule [15]. A post-marketing surveillance program found that the incidence rate of serious IP and other forms of lung damage was 0.27% (5 of 1,862 subjects) in cases with the approved washout period of at least 3 weeks, but was 1.41% (12 of 852 subjects) in cases with a washout period of less than 3 weeks (from interviews). In a domestic phase II clinical trial of a weekly paclitaxel monotherapy regime for recurrent SCLC, pulmonary toxicity was observed in 14% [16]. In a retrospective analysis of a carboplatin þ paclitaxel regime for lung cancer with comorbid IP, exacerbation of IP was reported at a rate of 0e27% [17e20]. 6.1.4.3.2.5. Docetaxel. The Japanese package insert of docetaxel [Taxotere®(revised version as of December 2014)] state that IP is one of the serious side effects, which occurred in 0.6% in the post-marketing surveillance program of 3,281 subjects. In a domestic phase III clinical trial for advanced NSCLC, IP was observed in 2.9e5.3% [21e23]. In a retrospective study of 392 NSCLC patients, docetaxelassociated IP occurred in 25.9% with comorbid ILD. They found that pre-existing interstitial change or emphysema were risk factors for docetaxel-associated IP [24]. In a retrospective study of 35 NSCLC patients with comorbid IP who received docetaxel monotherapy as secondline treatment, exacerbation of IP was observed in 14.3% [25]. In another retrospective study of 27 NSCLC patients with comorbid IP who received docetaxel monotherapy as secondline treatment, AE was reported in 26% [18]. 6.1.4.3.2.6. Vinorelbine. The Japanese package insert of vinorelbine [Navelbine®(revised version as of February 2015)] states that in the post-marketing surveillance of 3,250 patients, drug-induced pneumonia developed in 1.4%. In a retrospective study of 67 NSCLC patients with comorbid IP who received cisplatin þ vinorelbine combination therapy, exacerbation of IP was observed in 10.4% [26]. In another retrospective study of 35 NSCLC patients with comorbid IP who received a platinum preparation and vinorelbine, exacerbation of IP was observed in 15.8% [27].

6.1.4.3.3. Anti-tumor antibiotics.

6.1.4.3.3.1. Amrubicin.

In a development-stage phase II trial conducted in Japan in 61 NSCLC patients, 3 patients developed IP during amrubicin monotherapy and 2 of them died as a result. All 3 patients had pre-existing IP [28]. In response to this finding, amrubicin is now contraindicated as a general principle for patients with comorbid symptomatic IP that is clearly identifiable from a plain chest X-ray. In two domestic phase II study for SCLC, the frequency of IP associated with amrubicin was 3.0-3.5% [29,30]. In a retrospective study in 100 SCLC patients receiving amrubicin as a monotherapy, new onset of IP was observed in 3 (3.4%) out of 88 patients who had no pre-existing IP and exacerbation of IP was observed in 4 (33.3%) out of 12 patients who had pre-existing IP [31].

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6.1.4.3.4. Anti-metabolites.

6.1.4.3.4.1. Gemcitabine.

The safety of gemcitabine was evaluated among 481 patients who participated in domestic clinical trials [32e36]. AE was observed in 3 (30%) out of 10 patients who had pre-existing IP, and 2 cases of these were fatal. Based on this finding, the administration of gemcitabine is contraindicated for patients with pre-existing symptomatic IP which is clearly identifiable from chest X-ray images. In epidemiological research using a Japanese Diagnosis Procedure Combination (DPC) database, IP developed in 428 (1.7%) out of 25,924 cases who received gemcitabine chemotherapy in the period from 2010 to 2013 (pancreatic cancer, 9,070 cases; urothelial cancer, 5,578 cases; biliary tract cancer, 4,803 cases; lung cancer, 4,388 cases; ovarian cancer, 1,339 cases; breast cancer, 746 cases). The cumulative rates of IP at 3, 6, and 12 months after the initiation of gemcitabine were 1.1% (95% confidence interval (CI) 1.0e1.2%), 1.5% (95% CI 1.4e1.7%), and 1.9% (95% CI 1.7e2.1%), respectively [37]. The greatest risk factors for the development of IP associated with gemcitabine were age of 81 years or above (HR 2.61, 95% CI 1.69e4.02) and lung cancer (HR 2.81, 95% CI 2.16e3.65), followed by a history of heavy smoking, chemotherapy prior to gemcitabine, and distant metastasis [37]. The combination with bleomycin, docetaxel, and paclitaxel is also a risk factor for serious lung damage, and combinations with these drugs should be avoided [37e43]. In a retrospective study of lung cancer in patients with comorbid IP, exacerbation of IP was observed in 4 (24%) out of 17 subjects that received gemcitabine. A UIP-pattern was observed in 3 out of 4 of these cases [44]. 6.1.4.3.4.2. S1. In a retrospective study of lung cancer with comorbid IP, exacerbation of IP was observed in 3 (21%) out of 14 patients treated with S1 [44]. Additionally, in a phase II study of the safety and efficacy of carboplatin and S1 combination therapy in 21 patients with untreated advanced NSCLC with comorbid IP, AE was observed during this first-line treatment at a rate of 10% (2/21) [6]. 6.1.4.3.4.3. Pemetrexed. In a domestic phase II study of pemetrexed monotherapy for 225 NSCLC patients, IP occurred in 8 (3.6%) [45]. In a post-marketing all-case registry study of pemetrexed þ cisplatin, IP was observed in 0.9% out of 903 patients [46,46a]. In a retrospective study of pemetrexed monotherapy for NSCLC patients with comorbid IIPs, exacerbation of IP was observed in 3 (12%) out of 25 patients [47].

6.1.5. Effect of molecular-targeted drugs on IP, with countermeasures 6.1.5.1. Selection of molecular-targeted drugs for driver oncogene-positive lung cancer with comorbid IP ▪ The identification of driver oncogenes in lung cancer is being drastically promoted, along with the development of specific molecular-targeted drugs. ▪ Gefitinib is a pioneer molecular-targeted drug, however, following Japanese approval in 2002, fatal cases of gefitinibassociated IP started to appear one after another, and became a problem in Japan [1,2].

▪ Pre-existing IP has been identified as a risk factor associated with gefitinib; the use of molecular-targeted drugs in lung cancer with comorbid IP must be carried out with extreme caution [1]. ▪ Re-administration of molecular-targeted drugs for patients, who have a history of drug-induced IP associated with the same molecular-targeted drugs, must be decided on an individual basis by evaluating the risks and benefits, and only carried out after giving an adequate explanation and obtaining patient consent [3e11].

6.1.5.2. Effect of small-molecule compounds on IP, with countermeasures ▪ A consensus has been established on the diagnosis and treatment of drug-induced IP [5]. However, IP manifests as a wide range of pathologies, and many unclear points remain, such as its onset mechanism and ethnic differences in its frequency. ▪ Even in the case of lung cancer with target molecules that would normally benefit from the administration of molecular-targeted drugs, a fair number of issues remain to be resolved. Such as, the appropriateness of administration in cases where very mild pre-existing IP is present, should administration be repeated when there is an actual therapeutic benefit but non-severe IP has developed, and the optimal treatment in the event of drug-induced IP developing.

6.1.5.3. Effect of countermeasures

monoclonal

antibodies

on

IP,

with

▪ There are currently two antibodies used for advanced lung cancer: bevacizumab and ramucirumab. Both manifest their action through the inhibition of angiogenesis [1,2]. ▪ The relationship between these angiogenesis inhibitors and IP has not been studied in detail. Judging by the content reported thus far, there appears to be no evidence that these angiogenesis inhibitors increase the risk of IP associated with cytotoxic anti-cancer agents and moleculartargeted drugs. ▪ On the other hand, there is little evidence relating to the safety of the administration of angiogenesis inhibitors in lung cancer with comorbid IP or lung cancer with comorbid radiation pneumonitis [3e5]. In the future, necitumumab may be used in clinical practice, but as it is an anti-EGFR antibody, there are concerns that it may induce IP [6,7]. This is an issue that must be addressed going forward.

6.1.6. Effect of immune checkpoint inhibitors on IP, with countermeasures ▪ ICIs have shown remarkable efficacy in patients with lung cancer, but at the same time, they cause drug-induced IP in some patients [1e4].

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▪ There are still very few articles about ICI-induced IP, and many questions remain, including those about its pathogenesis, and risk factors [5]. ▪ At present, we have no answers to these questions, whether we should administer ICIs to lung cancer patients with comorbid IP or radiation pneumonitis. It is also not known whether we should re-administer ICIs to patients who have a history of ICI-induced IP. ▪ In a prospective trial of nivolumab for 6 NSCLC patients with comorbid mild IIPs, none of the patients experienced exacerbation of IIPs in the 12 weeks after the initiation of nivolumab treatment and 3 out of the 6 patients achieved a partial response [6]. Prospective, large-scale studies with long-term observation will be necessary.

6.1.7. Effect of radiotherapy on IP, with countermeasures 6.1.7.1. Radiation pneumonitis associated with chemoradiotherapy (particularly in cases with comorbid IP) ▪ Radiotherapy causes side effects including, radiation esophagitis, dermatitis which usually occurs during thoracic irradiation and radiation pneumonitis which usually arises after thoracic radiation [1,2]. As it can be fatal, radiation pneumonitis is one of the most severe side effects of radiation therapy. ▪ When planning radiotherapy, a range of dose restrictions is applied as a predictive factor to avoid the occurrence of serious side effects [3,4]. In chemoradiotherapy for locally advanced lung cancer, the radiation field often needs to be large, including the mediastinal hilum. Moreover, chemoradiation can induce side effects more strongly than radiation alone [1e3]. ▪ There are almost no reports on chemoradiotherapy for lung cancer patients with comorbid IP. At present, indication of chemoradiotherapy for lung cancer with comorbid IP in routine clinical practice must be considered carefully.

6.1.7.2. Radiation pneumonitis after stereotactic radiotherapy (particularly in cases with comorbid IP) ▪ Radiation pneumonitis is the most-problematic adverse event of stereotactic radiotherapy. ▪ Stereotactic radiotherapy is frequently used for early-stage small lung cancer and lung oligometastasis to irradiate them with pinpoint accuracy [1,2]. However, in lung cancer with comorbid IP, stereotactic radiotherapy frequently induces serious radiation pneumonitis [3,4]. ▪ There are no prospective studies showing the incidence of serious radiation pneumonitis after stereotactic radiotherapy. In retrospective studies, the incidence of severe radiation pneumonitis after stereotactic radiotherapy was significantly higher among patients with lung cancer and comorbid IP than lung cancer alone. Grade 3 or higher radiation pneumonitis occurred in 10-20%, and grade 5 (fatal) disease occurred in 5-6% of patients with lung cancer and comorbid IP after stereotactic radiotherapy [2,5e7]. It

should be remembered that rigorous prospective research will likely result in a still-higher incidence of stereotactic radiation-induced exacerbation of comorbid IP. ▪ Stereotactic radiotherapy for lung cancer with comorbid IP is not necessarily contraindicated, but it is important to reduce the exposure of normal lung tissue to irradiation, and to take precautions following treatment.

7. Chapter VI 7.1. Combined pulmonary fibrosis and emphysema (CPFE) and lung cancer ▪ CPFE is a clinical syndrome characterized by CT findings of emphysema in the upper lung field and of fibrosis in the lower lung field [1e6]. ▪ CPFE has a high rate of lung cancer comorbidity, with squamous cell cancer being the most-frequent histological type [7e9]. ▪ There are very few reports on the treatment of lung cancer with comorbid CPFE. ▪ The incidence of AE of comorbid CPFE after surgery is reported to be 2.0e7.4% [7,10], thus no higher than in lung cancer with comorbid IP [11]. ▪ There are almost no reports which have focused on chemotherapy for lung cancer with comorbid CPFE. Therefore, currently, clinicians assess the use of chemotherapy for lung cancer with comorbid CPFE, using the criteria of treatment with chemotherapy for lung cancer with comorbid IP. ▪ There have been no reports on the safety and efficacy of radiotherapy for lung cancer with comorbid CPFE.

7.1.1. CPFE and lung cancer The combined term of “pulmonary fibrosis and emphysema” (CPFE) was first used in 2005 by Cottin et al. in a summary report on 61 cases with CT findings of emphysema in the upper lung field and fibrosis in the lower lung field [1]. Currently, CPFE is not recognized as an officially defined clinical radiological or pathological disease entity. However, because of its specific clinical character (high prevalence of lung cancer, pulmonary hypertension, etc.), “CPFE" has been discussed and introduced as a specific syndrome or a concept of a combined status of IP (connective tissue diseases and IIP) and emphysema. We understand the controversies, but we discuss “CPFE” separately in this section. CPFE has been reported to occur in 8.0e49.2% of patients diagnosed with IPF, although the rate differs according to the definition of CPFE [2e4]. The characteristics of CPFE is as follows. Nearly all the patients with CPFE are heavy smokers and male. Although most patients with CPFE show only a mild reduction in the FEV1/FVC ratio and VC, they do show a severely reduced diffusion capacity and marked hypoxia on exertion [1e3,12]. Furthermore, it is reported that 47-55% of patients with CPFE have further complications with pulmonary hypertension, which is one of the poor prognostic factors

Please cite this article as: Ogura T et al., Summary of the Japanese Respiratory Society statement for the treatment of lung cancer with comorbid interstitial pneumonia, Respiratory Investigation, https://doi.org/10.1016/j.resinv.2019.06.001

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of CPFE [1,2,4,13]. The average prognosis for CPFE was reported to be 2.1 years to 8.5 years, but when complicated with pulmonary hypertension, the survival rate decreased to 1-year in 60% of patients [3]. The incidence of lung cancer is 5-30% among patients with IP [14e17], and 6-17% among those with chronic obstructive pulmonary disease (COPD), respectively [18,19]. Among patients with CPFE, the incidence of lung cancer is 42-51% [3,7,13,20]. Moreover, out of those patients that have lung cancer accompanied with CPFE, a relatively high proportion also have squamous cell cancer [7e9,12,13,20,21]. CPFE can thus be viewed as a syndrome that is strongly influenced by smoking and that has a high frequency of comorbid lung cancer and pulmonary hypertension.

lung cancer patients with comorbid IIPs, 39 received chemotherapy and the frequencies of AE during the first- and secondline chemotherapy treatment was 5.1% and 12.8%, respectively. There was no significant difference between the two groups regarding the rate of AE, and overall survival after firstline chemotherapy. The most frequently used regimes were carboplatin þ paclitaxel (55.4%) and a platinum preparation þ etoposide (33.7%), which have been confirmed to be tolerable in lung cancer with comorbid IP [23]. In general, chemotherapy for NSCLC with comorbid IP is reported to be associated with the development of AE of IP at a rate of around 5.6e32% [20e23], and the frequency of AE in the CPFE group in this report (9.1%) appears to be within the permissible range.

7.1.2. Surgical treatment of lung cancer with comorbid CPFE

Conflict of interest

A large-scale, joint, multi-center, retrospective cohort study, conducted in Japan found that surgical treatment in 1,763 lung cancer patients with comorbid IP, was followed by AE in approximately 9.3% of all cases, among which the mortality rate was 43.9% [10]. There have been several retrospective studies of surgical treatment for lung cancer with comorbid CPFE. Mizogami et al. reported that the 1- and 2-year survival rate after surgery for 27 cases of lung cancer with comorbid CPFE were 96.2% and 76.5%, respectively [7]. Post-surgical AE occurred in 2 cases (7.4%), one of them was fatal. Fukui et al [8]. undertook a retrospective study of 1,507 patients whom had lung cancer surgery and found that, compared to the idiopathic IP group (84) and the pulmonary emphysema group (197), the CPFE group (137) had a poorer prognosis (90-day mortality rates of 0%, 3.0%, and 7.3%, respectively). The rate of post-surgical AE in the CPFE group was 5.1%. Mimae et al. reported that the 90-day mortality rate and 3-year survival rate after surgery for 265 lung cancer patients with comorbid CPFE were 6.0% and 58.4%, respectively. Post-surgical AE occurred in 2.0% [9]. Similarly, in a study by Kumagai et al [11]. looking at surgery in 365 lung cancer patients with comorbid CPFE, the post-surgical prognosis and period until recurrence, were significantly poorer than in cases without comorbid CPFE. In those reports, the prognosis after pulmonary resection was worse among NSCLC patients with CPFE than those with IP alone, although the incidence of AE after surgery was not significantly higher among patients with CPFE compared to IP alone [10]. However, these reports are on retrospective studies, analyzing heterogeneous data with different judgements of surgical indication and different types of surgery, which could be potentially bias. It should also be noted that the forms of IP accompanying CPFE were not limited to IPF.

7.1.3. Chemotherapy in lung cancer with comorbid CPFE There are only a few reports that focus on chemotherapy for lung cancer with comorbid CPFE. As far as we searched, there was just one retrospective study [22]. In this paper, Minegish et al. compared the frequency of AE between lung cancer patients with comorbid CPFE and those with comorbid IIPs. In the group of 88 lung cancer patients with comorbid CPFE, 44 patients received chemotherapy and the frequency of AE during the first- and second-line chemotherapy treatment was 9.1% and 13.6%, respectively. On the other hand, in the group of 63

JRS statement for the treatment of lung cancer with comorbid interstitial pneumonia This form is blank, since this statement has been approved by the Board of Directors of the JRS and submitted by the Editorial Office on behalf of the corresponding author.

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interstitial fibrosis-type pneumoconiosis. Am J Respir Crit Care Med 2000;162:295e300. Hillerdal G, Henderson DW. Asbestos, asbestosis, pleural plaques and lung cancer. Scand J Work Environ Health 1997;23:93e103. Ohno S, Oshikawa K, Kitamura S, et al. Clinico-pathological analysis of interstitial pneumonia associated with collagen vascular disease in patients with lung cancer. Nihon Kyobu Shikkan Gakkai Zasshi 1997;35:1324e9 [Article in Japanese]. Takayanagi N, Tokunaga D, Tsuchiya Y, et al. Lung cancer associated with rheumatoid arthritis and usual interstitial pneumonia. Nihon Kokyuki Gakkai Zasshi 2008;46:438e42 [Article in Japanese]. Bernatsky S, Clarke A, Suissa S. Lung cancer after exposure to disease modifying anti-rheumatic drugs. Lung Cancer 2008;59:266e9. Hashimoto A, Arinuma Y, Nagai T, et al. Incidence and the risk factor of malignancy in Japanese patients with systemic sclerosis. Intern Med 2012;51:1683e8. Kang KY, Yim HW, Kim IJ, et al. Incidence of cancer among patients with systemic sclerosis in Korea: results from a single centre. Scand J Rheumatol 2009;38:299e303. Pontifex EK, Hill CL, Roberts-Thomson P. Risk factors for lung cancer in patients with scleroderma: a nested case-control study. Ann Rheum Dis 2007;66:551e3. Katzen JB, Raparia K, Agrawal R, et al. Early stage lung cancer detection in systemic sclerosis does not portend survival benefit: a cross sectional study. PLoS One 2015;10:e0117829. Sugino K, Ishida F, Kikuchi N, et al. Comparison of clinical characteristics and prognostic factors of combined pulmonary fibrosis and emphysema versus idiopathic pulmonary fibrosis alone. Respirology 2014;19:239e45. Kwak N, Park CM, Lee J, et al. Lung cancer risk among patients with combined pulmonary fibrosis and emphysema. Respir Med 2014;108:524e30. Wells C, Mannino DM. Pulmonary fibrosis and lung cancer in the United States: analysis of the multiple cause of death mortality data, 1979 through 1991. South Med J 1996;89:505e10. Harris JM, Cullinan P, McDonald JC. Does cryptogenic fibrosing alveolitis carry an increased risk of death from lung cancer? J Epidemiol Community Health 1998;52:602e3. Harris JM, Johnston ID, Rudd R, et al. Cryptogenic fibrosing alveolitis and lung cancer: the BTS study. Thorax 2010;65:70e6. Natsuizaka M, Chiba H, Kuronuma K, et al. Epidemiologic survey of Japanese patients with idiopathic pulmonary fibrosis and investigation of ethnic differences. Am J Respir Crit Care Med 2014;190:773e9. Khan KA, Kennedy MP, Moore E, et al. Radiological characteristics, histological features and clinical outcomes of lung cancer patients with coexistent idiopathic pulmonary fibrosis. Lung 2015;193:71e7. Song DH, Choi IH, Ha SY, et al. Extrapulmonary lymphangioleiomyoma: clinicopathological analysis of 4 cases. Korean J Pathol 2014;48:188e92.

Ethnic differences in drug-induced pneumonia associated with anti-cancer agents [1] Inoue A, Saijo Y, Maemondo M, et al. Severe acute interstitial pneumonia and gefitinib. Lancet 2003;361:137e9. [2] McCurry J. Japan deaths spark concerns over arthritis drug. Lancet 2004;363:461.

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[3] Kubo K, Azuma A, Kanazawa M, et al. Consensus statement for the diagnosis and treatment of drug-induced lung injuries. Respir Investig 2013;51:260e77. [4] Azuma A, Hagiwara K, Kudoh S. Basis of acute exacerbation of idiopathic pulmonary fibrosis in Japanese patients. Am J Respir Crit Care Med 2008;177:1397e8. [5] Azuma A, Kudoh S. High prevalence of drug-induced pneumonia in Japan. JMAJ: Japan Medical Association Journal 2007;50:405e11. [6] Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015;373:123e35. [7] Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015;373:1627e39. [8] Matsuki Y, Yamashita H, Takahashi Y, et al. Diffuse alveolar damage in patients with dermatomyositis: a six-case series. Mod Rheumatol 2012;22:243e8.

Chapter IV Biomarkers [1] Antoniou KM, Tomassetti S, Tsitoura E, Vancheri C. Idiopathic pulmonary fibrosis and lung cancer: a clinical and pathogenesis update. Curr Opin Pulm Med 2015;21:626e33. [2] Vancheri C. Common pathways in idiopathic pulmonary fibrosis and cancer. Eur Respir Rev 2013;22:265e72. [3] Wang Y, Kuan PJ, Xing C, et al. Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. Am J Hum Genet 2009;84:52e9. [4] Nathan N, Giraud V, Picard C, et al. Germline SFTPA1 mutation in familial idiopathic interstitial pneumonia and lung cancer. Hum Mol Genet 2016;25:1457e67. [5] Makarova JA, Shkurnikov MU, Wicklein D, et al. Intracellular and extracellular microRNA: An update on localization and biological role. Prog Histochem Cytochem 2016;51:33e49.

Imaging diagnosis [1] Sakai S, Ono M, Nishio T, et al. Lung cancer associated with diffuse pulmonary fibrosis: CT-pathologic correlation. J Thorac Imaging 2003;18:67e71. [2] Yoshida R, Arakawa H, Kaji Y. Lung cancer in chronic interstitial pneumonia: early manifestation from serial CT observations. AJR Am J Roentgenol 2012;199:85e90. [3] Oh SY, Kim MY, Kim JE, et al. Evolving early lung cancers detected during follow-up of idiopathic interstitial pneumonia: serial CT features. AJR Am J Roentgenol 2015;204:1190e6. [4] Ohno Y, Koyama H, Yoshikawa T, et al. N stage disease in patients with NSCLC: efficacy of quantitative and qualitative assessment with STIR turbo spin-echo imaging, diffusionweighted MR imaging, and fluorodeoxyglucose PET/CT. Radiology 2011;261:605e15. [5] Ohno Y, Koyama H, Yoshikawa T, et al. Diffusion-weighted MR imaging using FASE sequence for 3T MR system: Preliminary comparison of capability for N-stage assessment by means of diffusion-weighted MR imaging using EPI sequence, STIR FASE imaging and FDG PET/CT for NSCLC patients. Eur J Radiol 2015;84:2321e31. [6] De Wever W, Stroobants S, Coolen J, Verschakelen JA. Integrated PET/CT in the staging of NSCLC: technical aspects and clinical integration. Eur Respir J 2009;33:201e12.

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Chapter V 1. Treatment for lung cancer with comorbid IP [1] Homma S, Bando M, Sakamot S, et al. Japanese guidlene for the treatment of idiopathic pulmonary fibrosis. Respiratory Investigation 2018. [2] Kenmotsu H, Naito T, Kimura M, et al. The risk of cytotoxic chemotherapy-related exacerbation of interstitial lung disease with lung cancer. J Thorac Oncol 2011;6:1242e6. [3] Enomoto Y, Inui N, Kato T, et al. Low forced vital capacity predicts cytotoxic chemotherapy-associated AE of interstitial lung disease in patients with lung cancer. Lung Cancer 2016;96:63e7.

[4]

[5]

[6]

[7]

2. Diagnosis of acute exacerbation of interstitial pneumonia and associated predictive factors [1] Collard HR, Moore BB, Flaherty KR, et al. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2007;176:636e43. [2] Collard HR, Ryerson CJ, Corte TJ, et al. AE of idiopathic pulmonary fibrosis: an international working group report. Am J Respir Crit Care Med 2016;194:265e75. [3] Ryerson CJ, Cottin V, Brown KK, Collard HR. Acute exacerbation of idiopathic pulmonary fibrosis: shifting the paradigm. Eur Respir J 2015;46:512e20. [4] Homma S, Sugino K, Sakamoto S. The usefulness of a disease severity staging classification system for IPF in Japan: 20 years of experience from empirical evidence to randomized control trial enrollment. Respir Investig 2015;53:7e12. [5] Kondoh Y, Taniguchi H, Katsuta T, et al. Risk factors of acute exacerbation of idiopathic pulmonary fibrosis. Sarcoidosis Vasc Diffuse Lung Dis 2010;27:103e10. [6] Collard HR, Yow E, Richeldi L, et al. Suspected acute exacerbation of idiopathic pulmonary fibrosis as an outcome measure in clinical trials. Respir Res 2013;14:73. [7] Bhatti H, Girdhar A, Usman F, et al. Approach to acute exacerbation of idiopathic pulmonary fibrosis. Ann Thorac Med 2013;8:71e7. [8] Judge EP, Fabre A, Adamali HI, Egan JJ. Acute exacerbations and pulmonary hypertension in advanced idiopathic pulmonary fibrosis. Eur Respir J 2012;40:93e100. [9] Johannson KA, Vittinghoff E, Lee K, et al. Acute exacerbation of idiopathic pulmonary fibrosis associated with air pollution exposure. Eur Respir J 2014;43:1124e31. [10] Ohshimo S, Ishikawa N, Horimasu Y, et al. Baseline KL-6 predicts increased risk for acute exacerbation of idiopathic pulmonary fibrosis. Respir Med 2014;108:1031e9. [11] Yano T, Koga T, Ninomiya S, et al. A review of Japanese literatures concerning surgery for lung cancer with idiopathic interstitial pneumonia. Kyobu Geka 2002;55:131e3. discussion 133-134. [12] Sato T, Teramukai S, Kondo H, et al. Impact and predictors of acute exacerbation of interstitial lung diseases after pulmonary resection for lung cancer. J Thorac Cardiovasc Surg 2014;147:1604e11. e3.

3. Treatment for acute exacerbation of interstitial pneumonia [1] ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement idiopathic pulmonary fibrosis: evidence -based guidelines for diagnosis and management. Am J Respir crit Care Med 2011;183:788e824. [2] Homma S, Bando M, Sakamot S, et al. Japanese guidlene for the treatment of idiopathic pulmonary fibrosis. Respir Investig 2018;56(4):268e91. [3] Enomoto N, Mikamo M, Oyama Y, et al. Treatment of acute exacerbation of idiopathic pulmonary fibrosis with direct

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hemoperfusion using a polymyxin B-immobilized fiber column improves survival. BMC Pulm Med 2015;15:15. Abe S, Azuma A, Mukae H, et al. Polymyxin B-immobilized fiber column (PMX) treatment for idiopathic pulmonary fibrosis with acute exacerbation: a multicenter retrospective analysis. Intern Med 2012;51:1487e91. Isshiki T, Sakamoto S, Kinoshita A, et al. Recombinant human soluble thrombomodulin treatment for acute exacerbation of idiopathic pulmonary fibrosis: a retrospective study. Respiration 2015;89:201e7. Kataoka K, Taniguchi H, Kondoh Y, et al. Recombinant human thrombomodulin in acute exacerbation of idiopathic pulmonary fibrosis. Chest 2015;148:436e43. Tsushima K, Yamaguchi K, Kono Y, et al. Thrombomodulin for acute exacerbations of idiopathic pulmonary fibrosis: a proof of concept study. Pulm Pharmacol Ther 2014;29:233e40. Ishii Y, Kitamura S, Kira S, et al. A Phase II Clinical Study of a Neutrophil Elastase lnhibitor;ONO-50460 Na on Acute Exacerbation in IIP Patients. J. Clin. Therap. Med. 1998;14:397e420 [Article in Japanese]. Ishii Y, Kitamura S, Ando M, et al. A Phase III Clinical Study of a Neutrophil Elastase lnhibitor;ONO-50460 Na on Acute Exacerbation in IIP Patients. J. Clin. Therap. Med. 1998;14:421e46 [Article in Japanese].

4. Effect of chemotherapy on interstitial pneumonia and countermeasures Selection of chemotherapy for NSCLC with comorbid IP [1] Kudoh S, Kato H, Nishiwaki Y, et al. Interstitial lung disease in Japanese patients with lung cancer: a cohort and nested case-control study. Am J Respir Crit Care Med 2008;177:1348e57. [2] Lee T, Park JY, Lee HY, et al. Lung cancer in patients with idiopathic pulmonary fibrosis: clinical characteristics and impact on survival. Respir Med 2014;108:1549e55. [3] Isobe K, Hata Y, Sugino K, et al. Clinical Characteristics of Acute Exacerbation of Interstitial Pneumonia Associated with Lung Cancer After Anti-cancer Treatment. Jpn J Lung Cancer 2007;47:849e54 [Article in Japanese]. [4] Kondoh Y, Nishiyama O, Ichikawa M, et al. issues concerning treatment of lung cancer patients with interstitial pneumonia. Jpn J Lung Cancer 2008;48:732e6 [Article in Japanese]. [5] Minegishi Y, Takenaka K, Mizutani H, et al. Exacerbation of idiopathic interstitial pneumonias associated with lung cancer therapy. Intern Med 2009;48:665e72. [6] Minegishi Y, Sudoh J, Kuribayasi H, et al. The safety and efficacy of weekly paclitaxel in combination with carboplatin for advanced NSCLC with idiopathic interstitial pneumonias. Lung Cancer 2011;71:70e4. [7] Sekine A, Satoh H, Baba T, et al. Safety and efficacy of S-1 in combination with carboplatin in NSCLC patients with interstitial lung disease: a pilot study. Cancer Chemother Pharmacol 2016;77:1245e52.

Selection of chemotherapy for small-cell lung cancer with comorbid IP [1] Usui K, Tanai C, Tanaka Y, et al. The prevalence of pulmonary fibrosis combined with emphysema in patients with lung cancer. Respirology 2011;16:326e31. [2] Minegishi Y, Kokuho N, Miura Y, et al. Clinical features, anticancer treatments and outcomes of lung patients with combined pulmonary fibrosis and emphysema. Lung cancer 2014;85:258e63. [3] Isobe K, Hata Y, Sakamoto S, et al. Clinical characteristics of acute respiratory deterioration in pulmonary fibrosis

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Effect of each anti-cancer drug on comorbid IP, with countermeasures [1] Minegishi Y, Sudoh J, Kuribayasi H, et al. The safety and efficacy of weekly paclitaxel in combination with carboplatin for advanced NSCLC with idiopathic interstitial pneumonias. Lung Cancer 2011;71:70e4. [2] Sekine A, Satoh H, Baba T, et al. Safety and efficacy of S-1 in combination with carboplatin in NSCLC patients with interstitial lung disease: a pilot study. Cancer Chemother Pharmacol 2016;77:1245e52. [3] Ohe Y, Ohashi Y, Kubota K, et al. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced NSCLC: Four-Arm Cooperative Study in Japan. Ann Oncol 2007;18:317e23.

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5. Effect of molecular-targeted drugs on IP and countermeasures Selection of molecular-targeted drugs for driver oncogenepositive lung cancer with comorbid interstitial pneumonia [1] Ando M, Okamoto I, Yamamoto N, et al. Predictive factors for interstitial lung disease, antitumor response, and survival in NSCLC patients treated with gefitinib. J Clin Oncol 2006;24:2549e56. [2] Kudoh S, Kato H, Nishiwaki Y, et al. Interstitial lung disease in Japanese patients with lung cancer: a cohort and nested case-control study. Am J Respir Crit Care Med 2008;177:1348e57. [3] Takamochi K, Suzuki K, Bashar AH, et al. Readministration of gefitinib in a responder after treatment discontinuation due to gefinitib-related interstitial lung disease: a case report. J Med Case Rep 2007;1:138.

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[4] Xue X, Xue Q, Liu Y, et al. Gefitinib in combination with prednisolone to avoid interstitial lung disease during NSCLC treatment: a case report. Oncol Lett 2013;5:1599e600. [5] Zhang X, Li H, Zhu M, et al. Re-administration of gefitinib following diffuse interstitial lung disease in a patient with advanced lung adenocarcinoma: a case report and review of the literature. Oncol Lett 2015;9:2419e21. [6] Hotta K, Kiura K, Takigawa N, et al. Comparison of the incidence and pattern of interstitial lung disease during erlotinib and gefitinib treatment in Japanese Patients with NSCLC: the Okayama Lung Cancer Study Group experience. J Thorac Oncol 2010;5:179e84. [7] Chang SC, Chang CY, Chen CY, et al. Successful erlotinib rechallenge after gefitinib-induced acute interstitial pneumonia. J Thorac Oncol 2010;5:1105e6. [8] Takeda M, Okamoto I, Makimura C, et al. Successful treatment with erlotinib after gefitinib-induced severe interstitial lung disease. J Thorac Oncol 2010;5:1103e4. [9] Fukui T, Otani S, Hataishi R, et al. Successful rechallenge with erlotinib in a patient with EGFR-mutant lung adenocarcinoma who developed gefitinib-related interstitial lung disease. Cancer Chemother Pharmacol 2010;65:803e6. [10] Tian Q, Chen LA. Erlotinib achieved partial response in a NSCLC patient with gefitinib-induced interstitial lung disease. Case Rep Oncol 2011;4:464e6. [11] Arakawa N, Tsujita A, Saito N, et al. Successful erlotinib rechallenge after both gefitinib- and erlotinib-induced interstitial lung diseases. Respirol Case Rep 2013;1:17e9.

Effect of small-molecule compounds on interstitial pneumonia and countermeasures [5] Kubo K, Azuma A, Kanazawa M, et al. Consensus statement for the diagnosis and treatment of drug-induced lung injuries. Respir Investig 2013;51:260e77.

Effect of monoclonal antibodies on IP and countermeasures [1] Bevacizumab proves active in wide range of cancers. Oncology (Williston Park) 2004;18(1158):1199. [2] Spratlin J. Ramucirumab (IMC-1121B): Monoclonal antibody inhibition of vascular endothelial growth factor receptor-2. Curr Oncol Rep 2011;13:97e102. [3] Shimizu R, Fujimoto D, Kato R, et al. The safety and efficacy of paclitaxel and carboplatin with or without bevacizumab for treating patients with advanced nonsquamous NSCLC with interstitial lung disease. Cancer Chemother Pharmacol 2014;74:1159e66. [4] Suzuki H, Hirashima T, Kobayashi M, et al. Carboplatin plus paclitaxel in combination with bevacizumab for the treatment of adenocarcinoma with interstitial lung diseases. Mol Clin Oncol 2013;1:480e2. [5] Enomoto Y, Kenmotsu H, Watanabe N, et al. Efficacy and Safety of Combined Carboplatin, Paclitaxel, and Bevacizumab for Patients with Advanced Non-squamous NSCLC with Preexisting Interstitial Lung Disease: a retrospective multiinstitutional study. Anticancer Res 2015;35:4259e63. [6] Paz-Ares L, Mezger J, Ciuleanu TE, et al. Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous NSCLC (INSPIRE): an open-label, randomised, controlled phase 3 study. Lancet Oncol 2015;16:328e37. [7] Thatcher N, Hirsch FR, Luft AV, et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous NSCLC (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol 2015;16:763e74.

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6. Effect of immune checkpoint inhibitors on IP, with countermeasures [1] Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443e54. [2] Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell NSCLC. N Engl J Med 2015;373:123e35. [3] Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous NSCLC. N Engl J Med 2015;373:1627e39. [4] Nishino M, Tirumani SH, Ramaiya NH, Hodi FS. Cancer immunotherapy and immune-related response assessment: the role of radiologists in the new arena of cancer treatment. Eur J Radiol 2015;84:1259e68. [5] Nishino M, Ramaiya NH, Awad MM, et al. PD-1 inhibitorrelated pneumonitis in advanced cancer patients: radiographic patterns and clinical course. Clin Cancer Res 2016;22:6051e60. [6] Fujimoto D, Morimoto T, Ito J, et al. A pilot trial of nivolumab treatment for advanced NSCLC patients with mild idiopathic interstitial pneumonia. Lung Cancer 2017;111:1e5.

7. Effect of radiotherapy on IP, with countermeasures Radiation pneumonitis associated with chemoradiotherapy (particularly in cases with comorbid IP) [1] Segawa Y, Kiura K, Takigawa N, et al. Phase III trial comparing docetaxel and cisplatin combination chemotherapy with mitomycin, vindesine, and cisplatin combination chemotherapy with concurrent thoracic radiotherapy in locally advanced NSCLC: OLCSG 0007. J Clin Oncol 2010;28:3299e306. [2] Yamamoto N, Nakagawa K, Nishimura Y, et al. Phase III study comparing second- and third-generation regimens with concurrent thoracic radiotherapy in patients with unresectable stage III NSCLC: West Japan Thoracic Oncology Group WJTOG0105. J Clin Oncol 2010;28:3739e45. [3] Graham MV, Purdy JA, Emami B, et al. Clinical dosevolume histogram analysis for pneumonitis after 3D treatment for NSCLC (NSCLC). Int J Radiat Oncol Biol Phys 1999;45:323e9. [4] Tsujino K, Hirota S, Endo M, et al. Predictive value of dosevolume histogram parameters for predicting radiation pneumonitis after concurrent chemoradiation for lung cancer. Int J Radiat Oncol Biol Phys 2003;55:110e5.

Radiation pneumonitis after stereotactic radiotherapy (particularly in cases with comorbid IP)―including basic knowledge of radiation pneumonitis [1] Borst GR, Ishikawa M, Nijkamp J, et al. Radiation pneumonitis in patients treated for malignant pulmonary lesions with hypofractionated radiation therapy. Radiother Oncol 2009;91:307e13. [2] Onishi H, ShioyamaY, Matsumoto Y, et al. Japanese multiinstitutional study of stereotactic body radiotherapy for more than 2000 patients with stage I NSCLC. Int J Radiat Oncol Biol Phys 2013;87:S9. [3] Bahig H, Filion E, Vu T, et al. Excellent cancer outcomes following patient-adapted robotic lung sbrt but a case for caution in idiopathic pulmonary fibrosis. Technol Cancer Res Treat 2015;14:667e76. [4] Yamaguchi S, Ohguri T, Ide S, et al. Stereotactic body radiotherapy for lung tumors in patients with subclinical interstitial lung disease: The potential risk of extensive radiation pneumonitis. Lung Cancer 2013;82:260e5.

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[5] Onishi H, ShioyamaY, Matsumoto Y, et al. Japanese multiinstitutional study of stereotactic body radiation therapy for 678 medically operable patients with stage i NSCLC. Int J Radiat Oncol Biol Phys 2015;93:S102. [6] Ueki N, Matsuo Y, Togashi Y, et al. Impact of pretreatment interstitial lung disease on radiation pneumonitis and survival after stereotactic body radiation therapy for lung cancer. J Thorac Oncol 2015;10:116e25. [7] Yoshitake T, Shioyama Y, Asai K, et al. Impact of interstitial changes on radiation pneumonitis after stereotactic body radiation therapy for lung cancer. Anticancer Res 2015;35:4909e13.

Chapter VI [1] Cottin V, Nunes H, Brillet PY, et al. Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity. Eur Respir J 2005;26:586e93. [2] Mejia M, Carrillo G, Rojas-Serrano J, et al. Idiopathic pulmonary fibrosis and emphysema: decreased survival associated with severe pulmonary arterial hypertension. Chest 2009;136:10e5. [3] Jankowich MD, Rounds SI. Combined pulmonary fibrosis and emphysema syndrome: a review. Chest 2012;141:222e31. [4] Sugino K, Ishida F, Kikuchi N, et al. Comparison of clinical characteristics and prognostic factors of combined pulmonary fibrosis and emphysema versus idiopathic pulmonary fibrosis alone. Respirology 2014;19:239e45. [5] Kitaguchi Y, Fujimoto K, Hanaoka M, et al. Clinical characteristics of combined pulmonary fibrosis and emphysema. Respirology 2010;15:265e71. [6] Usui K, Tanai C, Tanaka Y, et al. The prevalence of pulmonary fibrosis combined with emphysema in patients with lung cancer. Respirology 2011;16:326e31. [7] Mizokami Y, Masunaga A, Kojima K, et al. Possible indication for surgical resection of lung cancer associated with combined pulmonary fibrosis and emphysema (CPFE). Nihon Kokyuki Gakkai Zasshi 2015;4:343e51 [Article in Japanese]. [8] Fukui M, Suzuki K, Matsunaga T, et al. Outcomes of lung cancer resection for patients with combined pulmonary fibrosis and emphysema. Surg Today 2016;46:341e7. [9] Mimae T, Suzuki K, Tsuboi M, et al. Surgical Outcomes of Lung Cancer in Patients with Combined Pulmonary Fibrosis and Emphysema. Ann Surg Oncol 2015;22(Suppl 3):1371e9.

[10] Sato T, Teramukai S, Kondo H, et al. Impact and predictors of acute exacerbation of interstitial lung diseases after pulmonary resection for lung cancer. J Thorac Cardiovasc Surg 2014;147:1604e11. e1603. [11] Kumagai S, Marumo S, Yamanashi K, et al. Prognostic significance of combined pulmonary fibrosis and emphysema in patients with resected NSCLC: a retrospective cohort study. Eur J Cardiothorac Surg 2014;46:e113e9. [12] Kwak N, Park CM, Lee J, et al. Lung cancer risk among patients with combined pulmonary fibrosis and emphysema. Respir Med 2014;108:524e30. [13] Ito T, Sugino K, Sakamoto S, et al. Clinicopathological characteristics of patients with combined pulmonary fibrosis and emphysema. Nihon Kokyuki Gakkai Zasshi 2012;1:182e9 [Article in Japanese]. [14] Turner-Warwick M, et al. Cryptogenic fibrosing alveolitis and lung cancer. Thorax 1980;35:496e9. [15] Ozawa Y, et al. Cumulative incidence of and predictive factor for lung cancer in IPF. Respirology 2009;14:723e8. [16] American Thoracic Society/European Respiratory Society international multidisciplinary consensus classification of the idiopathic interstitial pneumonia. Am J Respir Crit Care Med 2002;165:277e304. [17] Hubbard R, et al. Lung cancer and cryptogenic fibrosing alveolitis, A population-based cohort study. Am J Respir Crit Care Med 2000;161:5e8. [18] Smith MC, et al. Epidemiology and clinical impact of major comorbidities in patients with COPD. Int J Chron Obstruct Pulmon Dis 2014. [19] Miyazaki M, et al. Analysis of comorbid factors that increase the COPD assessment test score. Respir Res 2014;15:13. [20] Kitaguchi Y, Fujimoto K, Hanaoka M, et al. Clinical characteristics of combined pulmonary fibrosis and emphysema. Respirology 2010;15:265e71. [21] Girard N, Marchand-Adam S, Naccache JM, et al. Lung cancer in combined pulmonary fibrosis and emphysema: a series of 47 Western patients. J Thorac Oncol 2014;9:1162e70. [22] Minegishi Y, Kokuho N, Miura Y, et al. Clinical features, anticancer treatments and outcomes of lung cancer patients with combined pulmonary fibrosis and emphysema. Lung Cancer 2014;85:258e63. [23] Minegishi Y, Sudoh J, Kuribayasi H, et al. The safety and efficacy of weekly paclitaxel in combination with carboplatin for advanced NSCLC with idiopathic interstitial pneumonias. Lung Cancer 2011;71:70e744.

Please cite this article as: Ogura T et al., Summary of the Japanese Respiratory Society statement for the treatment of lung cancer with comorbid interstitial pneumonia, Respiratory Investigation, https://doi.org/10.1016/j.resinv.2019.06.001