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ANTICANCER RESEARCH 35: 4259-4264 (2015)

Efficacy and Safety of Combined , , and Bevacizumab for Patients with Advanced Non-squamous Non-small Cell Lung with Pre-existing Interstitial Lung Disease: A Retrospective Multi-institutional Study

YASUNORI ENOMOTO1,4, HIROTSUGU KENMOTSU2, NAOHIRO WATANABE3, TOMOHISA BABA1, HARUYASU MURAKAMI2, KIYOTAKA YOH3, TAKASHI OGURA1, TOSHIAKI TAKAHASHI2, KOICHI GOTO3 and TERUFUMI KATO1

1Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama City, Kanagawa, Japan; 2Division of Thoracic Oncology, Shizuoka Cancer Center, Sunto-gun, Shizuoka, Japan; 3Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan; 4Second Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan

Abstract. Aim: To investigate the efficacy and safety of inflammation or fibrosis and is a risk factor for development carboplatin, paclitaxel, and bevacizumab (CPB) combination of (1, 2). for lung cancer chemotherapy in patients with non-squamous non-small cell occasionally exacerbates pre-existing ILD and this can be lung cancer (NSCLC) with pre-existing interstitial lung fatal (3). Although treatment for lung cancer with ILD has disease (ILD). Patients and Methods: Twenty-five patients been investigated, optimal regimens showing favorable with non-squamous NSCLC with ILD who underwent CPB efficacy and safety, particularly with low risk of between March 2007 and July 2013 were analyzed chemotherapy-induced acute exacerbation of ILD (AE-ILD), for treatment profiles. Results: The median age was 67 have not been yet established. Several studies evaluated the (range=53-79) years and 96% were men. The triplet efficacy and safety of carboplatin and paclitaxel (CP) doublet chemotherapy was repeated for a median of four cycles. The chemotherapy in patients with non-small cell lung cancer objective response rate was 72% (18/25), the median (NSCLC) with ILD (4-10). Minegishi et al. investigated 100 progression-free survival time was 7.2 months, and the patients with NSCLC and ILD and reported that CP therapy median overall survival time was 8.5 months. The most was associated with markedly lower AE-ILD incidence than frequent adverse event of grade 3 or more was neutropenia other regimens (4). CP therapy is currently considered as a (72%, 18/25). Chemotherapy-induced acute exacerbation of relatively suitable regimen for treatment of this population, ILD occurred in 12% of patients. Conclusion: CPB therapy particularly in Japan. may be an effective and feasible regimen even for patients Bevacizumab, a recombinant, humanized monoclonal with ILD, although clinicians should be concerned regarding antibody against vascular endothelial (VEGF), neutropenia and acute exacerbation of ILD. inhibits tumor and subsequent tumor growth and metastasis (11). A phase III, randomized controlled trial Interstitial lung disease (ILD) is a heterogeneous group of by the Eastern Cooperative Oncology Group (ECOG) non-neoplastic disorders resulting from lung parenchymal compared the efficacy and safety of therapy with CP and bevacizumab (CPB) with CP therapy in patients with advanced non-squamous NSCLC (ECOG 4599 trial) (12). This pivotal trial demonstrated a marked improvement in Correspondence to: Yasunori Enomoto, MD, 1-20-1 Handayama, objective response rate (ORR), median progression-free Higashi-ku, Hamamatsu City, Shizuoka 431-3192, Japan. Tel: +81 survival (PFS), and overall survival (OS) in the CPB group 534352111, Fax: +81 534352153, e-mail: yasuyasuyasu29@ compared to the CP group (ORR=35% vs. 15%; PFS=6.2 yahoo.co.jp; [email protected] months vs. 4.5 months; OS=12.3 months vs. 10.3 months). Key Words: Bevacizumab, interstitial lung disease, non-small cell Additionally, similar tendencies were re-confirmed in the lung cancer, acute exacerbation. JO19907 trial in Japan (ORR=61% vs. 31%; PFS=6.9 vs. 5.9

0250-7005/2015 $2.00+.40 4259 ANTICANCER RESEARCH 35: 4259-4264 (2015) months; OS=22.8 vs. 23.4 months) (13). According to the Table I. Baseline characteristics of patients treated with combined results of these trials, CPB therapy is a standard regimen for carboplatin, paclitaxel, and bevacizumab therapy. advanced non-squamous NSCLC. However, the eligibility or Patients (n=25) exclusion criteria of the protocols did not mention patients with pre-existing ILD; it is unclear whether CPB therapy is Median age (range), years 67 (53-79) preferable for this population. Herein, we aimed to Gender, male/female, n 24/1 retrospectively evaluate the efficacy and safety of CPB ECOG performance status, 0-1/2-3, n 22/3 therapy in patients with NSCLC with ILD. Smoking history, current or former/never 25/0 Median smoking pack-years (range) 46 (15-98) Clinical stage, IIIA/IIIB/ӀV/recurrence, n 1/3/16/5 Patients and Methods Adenocarcinoma/other*, n 21/4 CT pattern§, UIP/possible/inconsistent‡, n 13/8/4 This retrospective study was approved by the Institutional Review Emphysema, yes/no, n 22/3 Boards of the Kanagawa Cardiovascular and Respiratory Center, National Cancer Center Hospital East, and Shizuoka Cancer Center ECOG: Eastern Cooperative Oncology Group; UIP: usual interstitial (approval numbers: 26-18, 2014-391, and T26-35-26-1-2, respectively). pneumonia. *Non-small cell lung cancer (n=2), pleomorphic carcinoma § We reviewed medical records of 208 consecutive patients who (n=1), and large cell neuroendocrine carcinoma (n=1); definition underwent CPB therapy as a first-line treatment regimen for advanced according to the 2011 guideline for idiopathic pulmonary fibrosis (14); ‡because of extensive ground-glass attenuation (n=3) and (clinical stage III or IV or recurrence after surgical resection) non- peribronchovascular distribution (n=1). squamous NSCLC at each Institution between March 2007 and July 2013. Carboplatin at a dose of area under the concentration–time curve of 6 mg/ml×min, paclitaxel at a dose of 200 mg/m2, and bevacizumab at a dose of 15 mg/kg were administered to all patients on day 1 every three weeks. Three pulmonologists (Y. E., N. W., and H. K.) evaluated smokers. The UIP pattern on baseline CT was the most conventional or high-resolution computed tomography (CT) within 4 weeks before CPB therapy and identified 25 patients with pre-existing common (52%, 13/25). An emphysematous change was ILD. The diagnostic criteria for ILD were presence of chronic and detected in 88% of patients. There were no patients with brain bilateral reticular abnormality or ground-glass attenuation on metastases at baseline. Two patients were confirmed as having pretreatment CT. According to the recent guideline for idiopathic pathological ILD and both the patients displayed UIP. Only pulmonary fibrosis (IPF) (14), we classified CT scans into three groups: one patient received systemic corticosteroid administration for usual interstitial pneumonia (UIP) pattern (subpleural and basal the pre-existing ILD (20 mg/day prednisolone). Long-term predominant reticular abnormality with honeycombing and no findings oxygen therapy was administered to another patient. The of atypical features of IPF), possible UIP pattern (subpleural and basal predominant reticular abnormality without apparent honeycombing), others had not undergone any treatment for their ILDs. and pattern inconsistent with UIP. Chemotherapy-induced AE-ILD was diagnosed on the basis of the CT findings of bilateral ground-glass Efficacy. The CPB triplet chemotherapy was repeated for a attenuation with/without focal consolidation superimposed on pre- median of four (range=1-6) cycles, and thereafter, 60% existing interstitial shadows. Cases with apparent pulmonary infection, (15/25) of patients received a median of four (range=1-30) congestion, and carcinomatous lymphangiomatosis were excluded. To cycles of bevacizumab maintenance chemotherapy. diagnose AE-ILD associated with chemotherapy, the duration between Treatment responses were recorded as follows: PR: n=18; the last chemotherapy administration and AE-ILD onset was defined as 4 weeks or less. Objective tumor response was assessed as complete SD: n=3; PD: n=1; NE: n=3. The ORR was 72% [95% response, partial response (PR), stable disease (SD), progressive disease confidence interval (CI)=54-90%], the median PFS with (PD), or not evaluable (NE) according to the Response Evaluation first-line chemotherapy was 7.2 months (95% CI=3.6-10.8 Criteria in Solid Tumors version 1.1 (15). Toxicities were graded using months), and the median OS was 8.5 months (95% CI=6.1- the Common Terminology Criteria for Adverse Events version 4.0 (16). 10.8 months). The median follow-up time was 28.0 months. PFS was defined as days from the first CPB administration to the The Kaplan–Meier survival curves for PFS and OS are confirmation of PD or death. OS was defined as days from the first shown in Figures 1 and 2, respectively. The unadjusted 1- administration to death or censoring. Patients were censored if alive on July 31, 2014. The Kaplan–Meier survival method was used to estimate year survival probability was calculated as 40%. median survival. Safety. Safety profiles are summarized in Table II. Grade 3 or Results more neutropenia (72%, 18/25) was most frequently observed as a severe adverse event. Febrile neutropenia was also Patients’ characteristics. The patients’ characteristics are listed observed in 20% of patients (5/25), and one patient died from in Table I. At first CPB administration, median age was 67 this event. Additionally, another patient died after lung (range=53-79) years, 18 patients (72%) were aged ≥65 years. infection during a period of severe neutropenia. The majority of patients were men and had an ECOG Chemotherapy-induced AE-ILD was observed in 12% of performance status 0-1. All patients were current or former patients (3/25, 95% CI=0-25%; males, aged 53-75 years). Two

4260 Enomoto et al: Combination of Carboplatin, Paclitaxel and Bevacizumab for Non-squamous NSCLC with ILD

Figure 1. Progression-free survival curve for 25 patients with non- Figure 2. Overall survival curve for 25 patients with non-squamous non- squamous non-small cell lung cancer with pre-existing interstitial lung small cell lung cancer with pre-existing interstitial lung disease. disease.

of them underwent the event during the first cycle of CPB Table II. Adverse events with grade 3 or more experienced by patients triplet chemotherapy. One patient developed AE-ILD during treated with combined carboplatin, paclitaxel, and bevacizumab therapy. the first cycle of bevacizumab maintenance chemotherapy Patients (n=25) after four cycles of triplet chemotherapy. The pre-treatment CT scans showed the UIP pattern in two patients and pattern Grade 3 Grade 4 Grade 5 inconsistent with UIP (n=1). Although the three patients were treated with intravenous/oral corticosteroid therapy, one patient Neutropenia 4 14 - died. The patient who had the pattern inconsistent with UIP Febrile neutropenia 3 1 1 Pneumonitis (AE-ILD) 2 0 1 on pre-treatment CT died from respiratory failure 14 days after Lung infection 0 0 1 AE-ILD onset. The other grade 3 non-hematological toxicities Thromboembolic event were pulmonary embolism (n=1), fatigue (n=1), (pulmonary embolism) 1 0 0 (n=1), and constipation (n=1). Three patients stopped the Fatigue 1 0 0 triplet chemotherapy because of peripheral sensory Hypertension 1 0 0 Constipation 1 0 0 neuropathy, although the severity was less than grade 3. After CPB therapy, 13 patients received subsequent AE-ILD: Acute exacerbation of interstitial lung disease. such as pemetrexed and S-1 monotherapy. Two patients developed AE-ILD induced by second-line pemetrexed monotherapy. Among the 25 patients in the entire cohort, there were 22 deaths during the follow-up. The causes were lung cancer (n=18), neutropenia-related Several previous studies analyzed CP with/without infection (n=2), AE-ILD during CPB therapy (n=1), and AE- bevacizumab therapy for patients with NSCLC and ILD (5, 7, ILD during pemetrexed therapy (n=1). 9, 10, 17). A data summary, including ours, is provided in Table III. Although directly comparing the results of these Discussion small studies is difficult, our efficacy profile (ORR of 72%; median PFS of 7.2 months) would be relatively favorable. This study included 25 patients with advanced non-squamous Conversely, chemotherapy-induced AE-ILD by CPB therapy NSCLC with pre-existing ILD who underwent CPB therapy for was observed in 12% of our patients (95% CI=0-25%). AE- first-line treatment. The ORR was 72% (18/25; 95% CI=54- ILD incidence on CP therapy was reported to be 0-26.7% 90%) and the median PFS was 7.2 months (95% CI=3.6-10.8 (Table III), which was comparable to our results. This months). The most frequent severe adverse event was comparability suggests at least that the addition of bevacizumab neutropenia (72%. 18/25), and 12% (3/25) of patients developed to CP therapy may not raise AE-ILD risk. , a chemotherapy-induced AE-ILD during this treatment. inhibitor that targets VEGF receptor, platelet-

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Table III. Comparison of previous studies for the combination chemotherapy of carboplatin plus paclitaxel with/without bevacizumab for patients with non-small cell lung cancer with pre-existing interstitial lung disease.

Author (ref.) N Paclitaxel ORR (%) mPFS (m) AE-ILD (%)

Carboplatin+paclitaxel Shukuya et al. (5) 15 Weekly 33 2.5 26.7 Watanabe et al. (9) 16 Weekly 56 NA NA Shimizu et al. (17) 11 Weekly 27 4.4 0.0 Minegishi et al. (7) 16 Tri-weekly 61 5.3 5.6 Kenmotsu et al. (10) 63 Tri-weekly 35 NA 7.9

Carboplatin+paclitaxel+bevacizumab Shimizu et al. (17) 10 Weekly 40 5.3 10.0 Our study 25 Tri-weekly 72 7.2 12.0

ORR: Objective response rate; mPFS: median progression-free survival; AE-ILD: acute exacerbation of interstitial lung disease; NA: not available.

derived , and first-line CPB therapy might degrade such factors and lead receptor, is suggested to reduce acute exacerbation incidences to treatment termination in these patients. In addition, the in patients with IPF (18). VEGF is a target of bevacizumab and efficacy of second- or subsequent-line chemotherapies might nintedanib, and VEGF inhibition may have favorable effects on not be effective, or chemotherapy options may be limited lung cancer and pre-existing ILD. because of AE-ILD risks. In fact, two patients in our study Two reports have evaluated CPB therapy for advanced non- developed AE-ILD induced by second-line pemetrexed squamous NSCLC patients with pre-existing ILD (17, 19). monotherapy. It would be challenging to determine whether Shimizu et al. retrospectively compared 10 patients treated the benefit of chemotherapy exceeded AE-ILD risks in this with CPB therapy against 11 patients treated with CP therapy population. (17). The ORR and median PFS were reported as 40% vs. There are several important limitations to this study. Firstly, 27%; 5.3 months vs. 4.4 months, respectively. Although these this was a retrospective study with a small number of patients. differences were not statistically significant, their results Secondly, we could not fully exclude the possibility of other suggested that CPB therapy increased efficacy even in diseases with ILD- or AE-ILD-like findings, such as patients with ILD. Suzuki et al. reported on four patients who carcinomatous lymphangiomatosis and infectious diseases. Few underwent CPB therapy (19). Interestingly, one patient in patients underwent bronchoalveolar lavage or lung biopsy, their study received 10 cycles of bevacizumab maintenance although these invasive procedures are difficult to apply to chemotherapy, and achieved long PFS of 487 days. In our every patient with advanced lung cancer in clinical settings. cohort, bevacizumab maintenance chemotherapy was In conclusion, our data suggest that CPB therapy for first- administered to 60% (15/25) of patients, and four received 10 line treatment of non-squamous NSCLC has a relatively or more cycles without severe complications. Bevacizumab favorable efficacy and feasibility even in patients with ILD, maintenance may be feasible for patients with ILD; the although the risk of fatal complications, including severe significance of this should be evaluated in future studies. neutropenia and AE-ILD, should be fully monitored. Several adverse events other than AE-ILD were observed in our cohort. The most common one with grade 3 or more References was neutropenia, which occurred in as many as 72% (18/25) of patients. Unfortunately, two patients died from 1 Hubbard R, Venn A, Lewis S and Britton J: Lung cancer and neutropenia-related infection (febrile neutropenia and lung cryptogenic fibrosing alveolitis. A population-based cohort study. infection). As demonstrated in the ECOG 4599 trial (12), the Am J Respir Crit Care Med 161: 5-8, 2000. addition of bevacizumab to CP therapy could increase the 2 Park J, Kim DS, Shim TS, Lim CM, Koh Y, Lee SD, Kim WS, frequency of severe neutropenia. We should be careful with Kim WD, Lee JS and Song KS: Lung cancer in patients with neutropenia as well as AE-ILD when using this regimen. idiopathic pulmonary fibrosis. Eur Respir J 17: 1216-1219, 2001. The median OS was very close to the median PFS in this 3 Kudoh S, Kato H, Nishiwaki Y, Fukuoka M, Nakata K, Ichinose Y, Tsuboi M, Yokota S, Nakagawa K, Suga M; Japan Thoracic study and may have been influenced by several factors. Radiology Group, Jiang H, Itoh Y, Armour A, Watkins C, Second-line chemotherapy was administered to only 52% Higenbottam T and Nyberg F: Interstitial lung disease in Japanese (13/25) of our patients. Although changes in performance patients with lung cancer: a cohort and nested case–control study. status and quality of life were not evaluated in this study, the Am J Respir Crit Care Med 177: 1348-1357, 2008.

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