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Address for correspondence: Hirotsugu Kenmotsu, MD, Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan
It is unknown what type of interstitial lung disease (ILD) has high risk for chemotherapy-related exacerbation of ILD. We investigated the risk of exacerbation of ILD for patients with lung cancer with ILD.
Methods
One hundred nine patients with lung cancer with ILD treated with cytotoxic chemotherapy at Shizuoka Cancer Center between August 2002 and April 2010 were retrospectively reviewed.
Results
On pretreatment computed tomography (CT) of the chest, 69 patients (63%) were identified with usual interstitial pneumonia (UIP) pattern, and 40 patients (37%) had non-UIP pattern. Patients with UIP pattern developed cytotoxic chemotherapy-related exacerbation of ILD more frequently than those with non-UIP pattern (30 versus 8%, p = 0.005). The incidence of grade 5 pulmonary toxicities was 9% in patients with UIP pattern, compared with 3% in those with non-UIP pattern. Multivariate analyses demonstrated that age (<70 years) and CT pattern (UIP) were significant independent risk factors for cytotoxic chemotherapy-related exacerbation of ILD. In small cell lung cancer, overall survival (OS) from the start of first-line chemotherapy was significantly shorter in UIP pattern than non-UIP pattern (median OS: 9 versus 16 months, p = 0.0475), whereas there was no significant difference in patients with non-small cell lung cancer (median OS: 12 versus 9 months, p = 0.2529).
Conclusions
Our results indicated that the incidence of exacerbation of ILD was significantly higher in patients with lung cancer with UIP pattern on CT findings than in those with non-UIP pattern. Therefore, great care is required when administering cytotoxic chemotherapy agents for patients with lung cancer with UIP pattern.
Interstitial lung disease (ILD) is called diffuse parenchymal lung disease and is a diverse group of pulmonary disorders classified together because of similar clinical, radiological, physiological, or pathological features.
A prospective large cohort study for gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has shown that preexisting ILD is not only a strong risk factor for gefitinib-related ILD but also a strong risk factor for cytotoxic chemotherapy-related ILD.
Cytotoxic chemotherapy agents, such as gemcitabine, docetaxel, and amrubicin, have been reported to develop severe ILD associated with cytotoxic chemotherapy.
Chemotherapy-related ILD is not common but is a potentially fatal complication of treatment for lung cancer.
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial pneumonia of unknown cause limited to the lungs and associated with poor prognosis.
European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias
This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001.
The American Thoracic Society (ATS) and European Respiratory Society (ERS) have defined IPF as clinical conditions characterized by progressive dyspnea and chronic cough, restrictive lung disease, and the histopathologic pattern of usual interstitial pneumonia (UIP).
European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias
This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001.
In clinical practice, patients with lung cancer with ILD have been carefully treated with cytotoxic chemotherapy. Nevertheless, it is unknown what kind of chemotherapeutic agents are optimal for patients with lung cancer with ILD. In addition, it is also unknown what type of ILD has high risk for exacerbation of ILD.
To assess the risk of cytotoxic chemotherapy-related ILD, we retrospectively analyzed pretreatment computed tomography (CT) and investigated the clinical course of patients with lung cancer with ILD.
METHODS
The medical records of patients with lung cancer with ILD treated with cytotoxic chemotherapy at the Shizuoka Cancer Center between August 2002 and April 2010 were retrospectively reviewed. In this study, pretreatment CT of the chest was evaluated by one radiologist (M.E.) and two pulmonologists (H.K. and T.N.), who had no knowledge of the patient's outcome. The chest CT examinations were performed using multidetector-row CT machine at the end of suspended inspiration. CT images were reconstructed to 5-mm slice thickness, and thin section chest CT with 1 mm reconstruction thickness was also performed for evaluating primary tumor and ILD. ILD was diagnosed when the criteria of ground-glass opacity, consolidation, or reticular shadow in both lung fields were met. On the basis of CT characteristics, we classified the patients with ILD into two groups: UIP pattern and non-UIP pattern. Diagnosis of UIP pattern was based on CT features as defined by the International Consensus Statement of the ATS and ERS, showing subpleural distribution, honeycombing, traction bronchiectasis, and architectural distortion (Figure 1A).
European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias
This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001.
Chemotherapy-related exacerbation of ILD was diagnosed on the basis of CT findings (bilateral ground-glass abnormality with or without focal consolidation, superimposed on pretreatment interstitial shadow) (Figure 1B).
Patients with apparent pulmonary infection, pulmonary embolism, or heart failure were excluded. Chemotherapy-related exacerbation of ILD was evaluated based on pneumonitis/pulmonary infiltrates by National Cancer Institute Common Terminology Criteria version 3.0—grade 3: symptomatic, interfering with activities of daily living, and oxygen indicated; grade 4: life-threatening; and grade 5: death. The patients who developed exacerbation of ILD within 1 year after thoracic radiotherapy and who received epidermal growth factor receptor tyrosine kinase inhibitor in the clinical course were excluded from chemotherapy-related exacerbation of ILD. To assess the incidence of exacerbation of ILD by treatment regimen, the duration between last administration of cytotoxic chemotherapy and the onset of exacerbation of ILD was defined as 4 weeks or less.
Univariate and multivariate analyses were performed to identify risk factors for the exacerbation of ILD associated with cytotoxic chemotherapy. All categorical variables were analyzed by the χ2 test or Fisher's exact test, as appropriate. Multivariate analyses were performed using a logistic regression procedure to assess the relationship between various factors and exacerbation of ILD. Clinical evaluation of overall survival (OS) after the start of first-line chemotherapy was conducted by the Kaplan-Meier method to assess the time to death. The log-rank test was used to compare cumulative survival in each group. All p values were reported as two-sided, and values less than 0.05 were considered statistically significant. This study was approved by the institutional review board.
RESULTS
Patient Characteristics
One hundred nine patients were diagnosed with lung cancer with ILD and treated with cytotoxic chemotherapy. The characteristics of the patients are shown in Table 1. The median age was 69 years (range: 54–84 years), and almost all patients were smokers and men with good performance status. Histologically, adenocarcinoma, squamous cell carcinoma, and small cell lung cancer (SCLC) were observed in 33, 30, and 30%, respectively. Others included large cell carcinoma and undifferentiated non-small cell cancer. Stages III and IV were observed in 40 and 53%, respectively, and recurrence after surgical resection occurred in 7%. In SCLC, limited and extensive diseases were observed in 33 and 67%, respectively. On the basis of pretreatment CT of the chest, 69 patients (63%) were identified with UIP pattern, and 40 patients (37%) had non-UIP pattern. Although there were some imbalances between the two groups in terms of stage IV (p = 0.044), there were no significant differences in patient characteristics between both groups.
Incidence of Cytotoxic Chemotherapy-Related Exacerbation of ILD
Of the 109 patients with ILD, 24 (22%) developed cytotoxic chemotherapy-related exacerbation of ILD. In particular, patients with UIP pattern developed cytotoxic chemotherapy-related exacerbation of ILD more frequently than those with non-UIP pattern (30 versus 8%, p = 0.005; Table 2). In addition, the incidence of grade 3 or worse pneumonitis/pulmonary infiltrates was significantly higher in patients with UIP pattern than in patients with non-UIP pattern (29 versus 5%, p = 0.003). Almost all of the patients who developed grade 3 or worse pulmonary toxicities received corticosteroid therapy. Nevertheless, 9% of the patients with UIP pattern died because of exacerbation of ILD, whereas 3% of those with non-UIP pattern died.
TABLE 2Incidence of Cytotoxic Chemotherapy-Related Exacerbation of ILD
The median time from last administration of cytotoxic chemotherapy to the diagnosis of the exacerbation of ILD was 17 days (range: 0–25 days). The incidence rate of exacerbation of ILD is shown in Table 3 for each agent; docetaxel (28%) or etoposide (24%) frequently led to exacerbation of ILD for patients with UIP pattern. On the other hand, the incidence of exacerbation of ILD was relatively low for vinorelbine or paclitaxel. Cisplatin or carboplatin was mainly administered with another agent, and it was difficult to assess the risk for ILD. In patients with SCLC, 63% of exacerbation of ILD occurred during the first-line chemotherapy, whereas in patients with non-small cell lung cancer (NSCLC) the corresponding proportion was 31%. In addition, only one patient received further chemotherapy after exacerbation of ILD.
TABLE 3Cytotoxic Chemotherapy Agents Considered to Cause the Exacerbation of ILD
The Risk of Cytotoxic Chemotherapy-Related Exacerbation of ILD
The results of the univariate analysis of risk factors for cytotoxic chemotherapy-related exacerbation of ILD are shown in Table 4. UIP pattern on CT was significantly associated with the exacerbation of ILD (p = 0.005). Multivariate analyses were performed using three variables (age, performance status, and CT pattern), and the results demonstrated that age (<70 years) (odds ratio [OR]: 2.75, 95% confidence interval: 1.03–7.93) and CT pattern (UIP) (OR: 6.98, 95% confidence interval: 2.04–33.79) were significant independent risk factors (Table 5).
TABLE 4Univariate Analysis of Risk Factors Associated with Cytotoxic Chemotherapy-Related Exacerbation of ILD
In this analysis, the median follow-up duration was 10.3 months. In SCLC, OS from the start of first-line chemotherapy was significantly shorter in patients with UIP pattern than those with non-UIP pattern (median OS: 9 versus 16 months, p = 0.048), whereas there was no significant difference in patients with NSCLC (median OS: 11 versus 9 months, p = 0.334).
DISCUSSION
In patients with IPF, the incidence of lung cancer is reported to be higher than in patients without IPF,
There are some reports that patients with lung cancer with preexisting ILD or pulmonary fibrosis have a high risk of developing exacerbation after anticancer therapy,
It is very important to establish an optimal treatment, which is considered to be safe and effective, for patients with lung cancer with ILD or IPF.
To our knowledge, this is the first study to evaluate the risk of cytotoxic chemotherapy-related ILD based on pretreatment chest CT patterns. In clinical practice, patients with lung cancer with ILD have been carefully treated with cytotoxic chemotherapy. Nevertheless, it is unknown what type of ILD has a high risk for exacerbation of ILD. In this study, patients with lung cancer with UIP pattern on CT findings demonstrated a high risk of exacerbation of ILD, compared with those with non-UIP pattern. This result suggests that chest CT patterns could be a risk factor for the development of chemotherapy-related exacerbation of ILD. Although age (<70 years) was also shown to be a risk factor, these patients might tend to receive multiple drugs for longer periods than elderly patients.
As there have been few reports about chemotherapy for patients with lung cancer with ILD, the optimal agent remains controversial. From Japan, a prospective study to evaluate the safety and efficacy of weekly paclitaxel in combination with carboplatin for advanced NSCLC with IIPs was reported.
The safety and efficacy of weekly paclitaxel in combination with carboplatin for advanced non-small cell lung cancer with idiopathic interstitial pneumonias.
One of 18 patients enrolled in this prospective study developed exacerbation of IIPs. Our study also showed that carboplatin and paclitaxel were relatively safe for patients with lung cancer with ILD, for whom this regimen might be one of the optimal regimens for those patients. Our results suggested that vinorelbine might also be relatively safe for patients with ILD. Nevertheless, we could not completely rule out the influence of biopsy for lung cancer diagnosis, before chemotherapy and before radiotherapy. It is known that the long-term survival in IPF shows poor prognosis compared with non-IPF, such as nonspecific interstitial pneumonia and other subgroups of IIPs.
In this study, although the UIP pattern on CT was significantly associated with the exacerbation of ILD, in patients with NSCLC with UIP pattern OS was not significantly different from those with non-UIP pattern. On the other hand, OS was significantly shorter in patients with SCLC with UIP pattern than in those with non-UIP pattern, and the type of ILD might influence the prognosis of patients with SCLC with ILD. Sixty-three percent of exacerbation of ILD in patients with SCLC occurred during the first-line chemotherapy, and they could not receive subsequent chemotherapy. On the other hand, approximately 70% of exacerbation of ILD in patients with NSCLC occurred during the second or subsequent line of chemotherapy and completed first-line chemotherapy. Thus, the rate of failure in first-line chemotherapy might contribute to poor prognosis in SCLC.
A major limitation of this retrospective analysis was that the diagnosis of ILD was based on CT findings and not on histologic diagnosis. In addition, the diagnosis of exacerbation of ILD was also based on CT findings, and we could not confirm histologically the exacerbation of ILD. Although we tried to exclude infection by bacteriological examination and heart failure by physical examination or echocardiography, we cannot completely exclude pulmonary infection, pulmonary embolism, or heart failure. Nevertheless, their clinical and radiological courses were consistent with exacerbation of ILD. It was reported that in clinical practice, surgical lung biopsies were performed in 8 to 12% of patients,
European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias
This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001.
Moreover, the ability of high-resolution computed tomography scanning to diagnose IPF has reported sensitivities of 43 to 78% and specificities of 90 to 97% for confident radiological diagnosis.
Thus, we consider that it is appropriate to diagnose IPF using the clinical and radiological findings in clinical practice. Further studies are needed to clarify the relationship between the radiological patterns and pathological patterns of ILD for patients with lung cancer.
In conclusion, our study indicated that in patients with lung cancer with UIP pattern on CT findings, the risk of exacerbation of ILD was significantly higher than in those with non-UIP pattern. In particular, greater care is required when administering cytotoxic chemotherapy agents for patients with lung cancer with UIP pattern on CT findings.
REFERENCES
King Jr, TE
Clinical advances in the diagnosis and therapy of the interstitial lung diseases.
European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias
This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001.
The safety and efficacy of weekly paclitaxel in combination with carboplatin for advanced non-small cell lung cancer with idiopathic interstitial pneumonias.
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