Cancer Chemother Pharmacol DOI 10.1007/s00280-015-2816-6

ORIGINAL ARTICLE

Safety of topotecan monotherapy for relapsed small cell lung cancer patients with pre‑existing interstitial lung disease Yasunori Enomoto1,5 · Naoki Inui2,5 · Shiro Imokawa3 · Masato Karayama4,5 · Hirotsugu Hasegawa1 · Yuichi Ozawa1 · Takashi Matsui1 · Koshi Yokomura1 · Takafumi Suda5 

Received: 25 March 2015 / Accepted: 18 June 2015 © Springer-Verlag Berlin Heidelberg 2015

Abstract  Purpose  To investigate the safety of intravenous topotecan monotherapy for relapsed small cell lung cancer (SCLC) patients with pre-existing interstitial lung disease (ILD). Methods  A total of 77 patients who received topotecan for the treatment of relapsed SCLC between April 2007 and April 2014 were reviewed. Patients with pre-existing ILD were identified using the pretreatment chest computed tomography. The safety of intravenous topotecan for SCLC patients with ILD was retrospectively examined, particularly focusing on topotecan-induced acute exacerbation of ILD (AE-ILD). Results  Twenty-three patients were identified as having pre-existing ILD [median age 74 (range 55–85) years; 21 men]. At the first topotecan administration, two-thirds (65.2 %) had an Eastern Cooperative Oncology Group performance status 0 or 1. Topotecan was administered intravenously as second-line (n  = 11) or later chemotherapy (n = 12). The median number of treatment cycles was two

* Yasunori Enomoto [email protected]; enomotoy@hama‑med.ac.jp 1

Department of Respiratory Medicine, Respiratory Disease Center, Seirei Mikatahara General Hospital, 3453 Mikatahara‑cho, Kita‑ku, Hamamatsu 433‑8558, Japan

2

Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, Japan

3

Department of Respiratory Medicine, Iwata City Hospital, Iwata, Japan

4

Department of Clinical Oncology, Hamamatsu University School of Medicine, Hamamatsu, Japan

5

Second Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan







(range 1–7). The most common adverse events with grade 3 or 4 were neutropenia in 13 patients (56.5 %) and thrombocytopenia in 10 patients (43.5 %). Febrile neutropenia was observed in six patients (26.1 %) and resulted in one death. AE-ILD occurred in five patients (21.7 %; 95 % confidence interval 4.9–38.5 %) 5–18 days after the last administration of topotecan and was fatal in three cases. Conclusions  Intravenous topotecan monotherapy can be unsafe for relapsed SCLC patients with pre-existing ILD. Clinicians should be cautious regarding topotecan-induced AE-ILD as a lethal complication. Keywords  Topotecan · Nogitecan · Interstitial lung disease · Acute exacerbation

Introduction Small cell lung cancer (SCLC) has a tendency for early dissemination, and most patients have extensive and inoperable disease at the time of diagnosis. Although SCLC has the most aggressive clinical course than any other lung cancer, it responds considerably well to chemotherapy. Firstline platinum-based combination chemotherapy, in particular, has provided a survival benefit [1]. However, a majority of SCLC patients eventually experience disease progression after first-line chemotherapy and become candidates for the second-line treatment [2]. Topotecan, or nogitecan in Japan, is a specific inhibitor of topoisomerase I and is the only drug approved for second-line chemotherapy of SCLC by the US Food and Drug Administration. According to previous randomized phase II and III trials with intravenous topotecan monotherapy, the overall response rate and median survival time have been reported as 13.3–24.3 % and 5.4–8.4 months, respectively [3–10].

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Interstitial lung disease (ILD) is characterized by variable degrees of inflammation and fibrosis of the lung parenchyma [11]. There are many known causes of ILD, including smoking, environmental/occupational exposure, and drugs, as well as unknown causes (idiopathic). In patients with ILD, acute exacerbation of ILD (AE-ILD) by any known or unknown cause is one of the most lethal complications [12–14]. Because chemotherapeutic agents can be an identifiable cause of AE-ILD, it should be carefully determined whether the benefit of chemotherapy exceeds the risk of chemotherapy-induced AE-ILD in lung cancer patients with pre-existing ILD [15–17]. Compared with chemotherapy for non-SCLC, there are fewer established therapeutic agents for SCLC. In particular, agents for salvage chemotherapy or those that can be used for patients with ILD are insufficient. Although amrubicin and irinotecan are promising drugs for second-line chemotherapy [8–10, 18], they have considerable lung toxicity [19, 20] and are contraindicated for patients with interstitial pneumonia or lung fibrosis in Japan. Topotecan is a candidate for the salvage chemotherapy regimen in SCLC patients with ILD. However, it remains unclear whether it can be used safely in such patients. In the present study, we aimed to evaluate the safety of intravenous topotecan for relapsed SCLC patients with pre-existing ILD. We focused on the occurrence of topotecan-induced AE-ILD because of its potential lethality.

Methods The study protocol was approved by the review board of each participating institution (Seirei Mikatahara General Hospital, Iwata City Hospital, and Hamamatsu University School of Medicine). We reviewed the medical records of 77 consecutive patients who received intravenous topotecan monotherapy for the treatment of relapsed SCLC at each institution between April 2007 and April 2014. At least two pulmonologists who had no knowledge of the patients’ information evaluated the results of the computed tomography (CT) performed within 4 weeks before the first topotecan administration and identified patients with preexisting ILD. The diagnostic criteria for ILD in the present study were the existence of chronic and bilateral reticular abnormality or ground-glass attenuation on pretreatment CT. The images were assessed for the following findings: reticulation, traction bronchiectasis, ground-glass attenuation, consolidation, honeycombing, micronodules, and emphysematous change. Each CT finding was recorded as present or absent. In addition, the extent of the normal lung area after the exclusion of lesions caused by ILD, emphysema, and cancer was evaluated. Using the recent guideline

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Cancer Chemother Pharmacol

for idiopathic pulmonary fibrosis (IPF) [21], ILD patterns on CT were classified into three groups: usual interstitial pneumonia (UIP) pattern (subpleural and basal-predominant reticular abnormality with honeycombing), possible UIP pattern (subpleural and basal-predominant reticular abnormality without apparent honeycombing), and inconsistent with UIP pattern. Patients with pulmonary infection, embolism, congestion, or carcinomatous lymphangitis were excluded using biochemical and microbiological tests, echocardiography, and subsequent clinical course. Patients with post-radiation fibrotic change were also excluded. Topotecan-induced AE-ILD was diagnosed using the following criteria [13]: (a) deterioration or development of dyspnea; (b) CT findings indicating newly developed bilateral ground-glass attenuations with/without non-segmental consolidation superimposed on pre-existing interstitial shadows; and (c) less than 4 weeks between the last administration of topotecan and the onset of AE-ILD. Similar to the baseline assessment, cases with infection, congestion, pulmonary embolism, and carcinomatous lymphangitis were excluded. Other drug toxicities were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Data are described as number (percentage) or median (range). Mann–Whitney’s U test and Fisher’s exact test were used for group comparison. Values of p 

Safety of topotecan monotherapy for relapsed small cell lung cancer patients with pre-existing interstitial lung disease.

To investigate the safety of intravenous topotecan monotherapy for relapsed small cell lung cancer (SCLC) patients with pre-existing interstitial lung...
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