Japanese Journal of Clinical Oncology Advance Access originally published online on May 15, 2006
Japanese Journal of Clinical Oncology 2006 36(5):269-273; doi:10.1093/jjco/hyl021
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© 2006 Foundation for Promotion of Cancer Research
Interstitial Shadow on Chest CT is Associated with the Onset of Interstitial Lung Disease Caused by Chemotherapeutic Drugs
Division of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan
For reprints and all correspondence: Seiji Niho, the Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwanoha 6-5-1, Kashiwa, Chiba 277-8577, Japan. E-mail: siniho{at}east.ncc.go.jp
Received October 10, 2005; accepted February 8, 2006
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Abstract |
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Objective: Pretreatment computerized tomography (CT) films of the chest was studied to clarify the influence of interstitial shadow on developing interstitial lung disease (ILD).
Methods: Eligible patients were those lung cancer patients who started to receive first-line chemotherapy between October 2001 and March 2004. Patients who received thoracic radiotherapy to the primary lesion, mediastinum, spinal or rib metastases were excluded. We reviewed pretreatment conventional CT and plain X-ray films of the chest. Ground-glass opacity, consolidation or reticular shadow without segmental distribution was defined as interstitial shadow, with this event being graded as mild, moderate or severe. If interstitial shadow was detected on CT films of the chest, but not via plain chest X-ray, it was graded as mild. Patients developing ILD were identified from medial records.
Results: A total of 502 patients were eligible. Mild, moderate and severe interstitial shadow was identified in 7, 8 and 5% of patients, respectively. A total of 188 patients (37%) received tyrosine kinase inhibitor (TKI) treatment, namely gefitinib or erlotinib. Twenty-six patients (5.2%) developed ILD either during or after chemotherapy. Multivariate analyses revealed that interstitial shadow on CT films of the chest and treatment history with TKI were associated with the onset of ILD.
Conclusions: It is recommended that patients with interstitial shadow on chest CT are excluded from future clinical trials until this issue is further clarified, as it is anticipated that use of chemotherapeutic agents frequently mediate onset of ILD in this context.
Key Words: interstitial lung disease • interstitial shadow • chemotherapy • lung cancer • CT
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Interstitial lung disease (ILD) is known to be an adverse event in cancer chemotherapy and radiotherapy. Recently, ILD has attracted considerable attention in Japan since the observation that gefitinib caused ILD (1). Gefitinib is a tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor and is active in patients with recurrent non-small cell lung cancer (NSCLC) after platinum-based chemotherapy (2,3). Gefitinib was first approved for the treatment of advanced NSCLC by the Japanese regulatory agencies on 5 July 2002. From August 2002 to April 2003,
28 000 patients with NSCLC were given gefitinib in Japan. However, 616 patients suffered from ILD and 246 patients died of ILD, according to a report from AstraZeneca. The West Japan Thoracic Oncology Group conducted a retrospective survey to clarify the risk factors related to ILD (4). Out of 1976 patients with NSCLC who received gefitinib across 84 institutions, 91 patients were suspected of having developed ILD. This group also analyzed the patients' background, together with computerized tomography (CT) films of the chest, before treatment and at the onset of ILD in this subcohort. Five experts in thoracic radiology in these extramural reviews diagnosed ILD in 64 patients. Multivariate analysis indicated that the predictive risk factors for the development of ILD were as follows: male, smoking and existence of idiopathic pulmonary fibrosis. However, this group did not review CT films of the chest in all 1976 patients. How much interstitial shadow on chest CT impacts ILD development remains unknown. ILD has a high associated risk of death, even if steroid therapy resolves ILD temporarily. Furthermore, ILD affects salvage chemotherapy. In cases where patients are at a high risk of developing ILD, anti-cancer drugs that tend to cause ILD should be avoided. Previous analysis often included only those cases developing ILD, but not all cases undergoing chemotherapy (4,5). The frequency of interstitial shadow in pretreatment CT films of the chest in patients with lung cancer remains unknown, and also how much interstitial shadow confers a risk toward ILD. To further clarify the influence of interstitial shadow on developing ILD, we retrospectively analyzed pretreatment CT films of the chest in consecutive lung cancer patients receiving chemotherapy.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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We retrospectively reviewed the medical records of lung cancer patients who began to receive first-line chemotherapy between October 2001 and March 2004 at the Division of Thoracic Oncology in the National Cancer Center Hospital East. Patients who received thoracic radiotherapy to the primary lesion, mediastinum, spinal or rib metastases were excluded. Plural pulmonologists (S.N., Y.H.K., K.Y., and K.G.) reviewed pretreatment conventional CT and plain X-ray films of the chest. Whether patients had developed ILD or not was blinded to the pulmonologists when they read the films. Conventional spiral CT films were used in our analysis, as high-resolution CT was not routinely conducted. Ground-glass opacity, consolidation or reticular shadow without segmental distribution was defined as interstitial shadow. Localized low attenuation area was defined as emphysema. The grading criteria for interstitial shadow was mild (<10% in bilateral lower lobes), moderate (10–30% in bilateral lower lobes) and severe (>30% in bilateral lower lobes) (Figs 1, 2, and 3). These breakpoints (10 and 30%) were chosen for convenience sake. Interstitial shadow detected on CT films of the chest, but not on plain X-ray, corresponded to mild interstitial shadow. The grading criteria for pulmonary emphysema were mild (<10% in bilateral lungs), moderate (10–30% in bilateral lungs) and severe (>30% in bilateral lungs).
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We identified patients developing ILD, utilizing medical records. ILD was diagnosed on the basis of standard or high-resolution CT findings of the chest (diffuse ground-glass opacity, reticular shadow or consolidation without segmental distribution), elevation of serum levels of lactate dehydrogenase (LDH) and/or KL-6, and lack of response to antibiotics. Bronchoalveolar lavage had not been performed to rule out infections. Most patients diagnosed as ILD were treated with corticosteroids. We compared patients who either had or had not developed ILD in terms of existence and severity of interstitial shadow, emphysema and/or pulmonary bullae on CT films of the chest, as well as patient characteristics including age, gender, smoking history and regimens of received chemotherapy. Comparisons between proportions were performed using a Fisher exact test or a Pearson chi-square test, as appropriate. Multivariate analyses were performed using the logistic regression procedure to determine the relationship between several factors and the onset of ILD.
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RESULTS |
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A total of 502 patients were eligible, with the relevant patient characteristics shown in Table 1. A total of 74% of patients were male and 84% of patients had NSCLC, while the remaining 16% had small cell lung cancer; 79% of the patients were smokers, while 21% never smoked. Platinum-based chemotherapy was performed on 384 patients (76%). A total of 188 patients (37%) received tyrosine kinase inhibitor (TKI) treatment, namely gefitinib or erlotinib. TKI therapy was administered as a first-line (n = 48), second-line (n = 68), third-line (n = 62), fourth-line (n = 9) or fifth-line (n = 1) regimen. Out of 48 patients treated with TKI as a first-line treatment 41 had been entered into a phase II trial of single agent treatment with gefitinib (6).
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Radiological findings on this patient cohort are listed in Table 2. Interstitial shadow was detected on chest X-ray and CT in 13 and 20% of patients, respectively. Mild, moderate or severe interstitial shadow was identified in 7, 8 or 5% of patients. Pulmonary emphysema was detected in 38% of patients. Mild, moderate or severe pulmonary emphysema was detected in 18, 10 or 10% of patients. Pulmonary bullae were detected in 20% of patients.
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Twenty-six patients (5.2%) developed ILD either during or after chemotherapy. The last regimen of chemotherapy received prior to the onset of ILD included platinum plus vinorelbine or gemcitabine (n = 4), platinum plus taxane (n = 4), other platinum-based chemotherapy (n = 2), vinorelbine plus gemcitabine (n = 2), docetaxel plus gemcitabine (n = 2), single agent treatment with taxane (n = 2) and TKI treatment (n = 10). Out of 26 patients who developed ILD, 14 had a history of taking TKI. Four patients developed ILD after first- or second-line chemotherapy with TKI followed by combination chemotherapy of cisplatin plus vinorelbine (n = 2) or single agent treatment with docetaxel (n = 2).
Univariate analyses demonstrated that male gender (P = 0.0361) and interstitial shadow on CT films of the chest (P = 0.0096) were significantly associated with the onset of ILD (Tables 1 and 3). Multivariate analyses showed interstitial shadow on CT films of the chest [odds ratio (OR): 3.20, 95% confidence interval (CI): 1.34–7.59] and treatment history with gefitinib or erlotinib (OR: 3.17, 95% CI: 1.36–7.36) were associated with the onset of ILD. Male gender was not a significant risk factor for development of ILD in multivariate analysis (OR: 4.33, 95% CI: 0.97–19.38) (Table 4). Univariate and multivariate analyses demonstrated that neither interstitial shadow on X-ray films nor the number of chemotherapy regimens was associated with the onset of ILD.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Pulmonary fibrosis or interstitial pneumonia is considered to be a risk factor for ILD caused by drugs (5). In line with the information for prescription, patients with obvious interstitial shadow on chest X-ray should avoid gemcitabine or irinotecan. Although patients with interstitial shadow on chest X-ray were excluded in previous clinical trials in Japan, unexpectedly frequent ILD has been reported, as in the case of combination chemotherapy with docetaxel and gemcitabine (7). Is interstitial shadow on chest X-ray an appropriate criterion to detect interstitial pneumonia or pulmonary fibrosis and avoid ILD? Generally, chest CT can detect interstitial shadow more clearly than chest X-ray. Specifically, high-resolution CT of the chest is essential in diagnosing interstitial pneumonia. However, it has not been determined exactly how much more interstitial shadow detected by CT reveals the onset of ILD. We analyzed CT films of consecutive lung cancer patients who underwent chemotherapy without thoracic radiation therapy. Retrospective review of medical records identified that 26 out of 502 patients developed ILD. We found that interstitial shadow on CT films was associated with onset of ILD, but that interstitial shadow on X-ray was not. We divided interstitial shadow into three classes: mild, moderate and severe. Interstitial shadow on X-ray means moderate to severe interstitial pneumonia. Eight out of 37 patients (22%) with mild interstitial shadow not detected on chest X-ray developed ILD. The reason for the high rate of ILD in patients with mild interstitial shadow is unknown. The criteria of no interstitial shadow on chest X-ray did not sufficiently reduce the risk of ILD. Treatment history with TKI, either gefitinib or erlotinib, was also associated with onset of ILD in multivariate analysis. Conversely, treatment with gemcitabine or irinotecan was not associated with onset of ILD.
Our retrospective analyses have several limitations. We avoided treatment with gemcitabine, irinotecan or TKI in the case of patients with moderate to severe interstitial shadow detectable on chest X-ray films. Some patients who were transferred to another hospital just after chemotherapy may have developed ILD, but detailed clinical courses after transfer were not available. Early death after chemotherapy due to disease progression might conceal the onset of ILD. Although these biases may exist, our analyses were made with an extensive cohort of patients, and therefore the results obtained are of significance.
The frequency of ILD in Japanese patients was reported to range between 3 and 15% in previous clinical trials (6–8). This rate appears to be higher than that observed in the rest of the world. Explanations include the possibility that ILD may be more prevalent among the Japanese or, alternatively, that a greater awareness of the disease could lead to more frequent diagnosis. Furthermore, there may be an increased genetic susceptibility to ILD specifically among the Japanese population (5).
Patients with interstitial shadow on chest X-ray have been excluded in previous clinical trials to avoid ILD caused by chemotherapeutic agents. However, this criterion alone is considered insufficient. It is recommended that patients with interstitial shadow on chest CT are excluded from future clinical trials until this issue is clarified, as it is anticipated that use of chemotherapeutic agents frequently mediate onset of ILD in this context. Therefore, physicians need to understand the associated risk of ILD in patients with interstitial shadow on chest CT and obtain informed consent from patients before administering chemotherapy in clinical practice.
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Acknowledgments |
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This work was supported by the Public Trust Haraguchi Memorial Cancer Research Fund.
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References |
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7 Takeda K, Negoro S, Tamura T, Nishiwaki Y, Kudoh S, Fukuda H, et al. Docetaxel versus docetaxel plus gemcitabine for second-line treatment of non-small cell lung cancer: results of a JCOG randomized trial (JCOG0104). J Clin Oncol 2004;22:625s.
8 Kunitoh H, Watanabe K, Onoshi T, Furuse K, Niitani H, Taguchi T. Phase II trial of docetaxel in previously untreated advanced non-small-cell lung cancer: a Japanese cooperative study. J Clin Oncol 1996;14:1649–55.
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