Introduction
Interstitial lung diseases (ILDs), also called interstitial lung abnormalities (ILA) or interstitial pneumonia (IP), are characterized by diffuse pulmonary interstitial abnormalities that often lead to fibrosis (Borchers et al.
2011). Recent evidence has shown that preexisting ILD is associated with shorter survival in patients with advanced non-small cell lung cancer (NSCLC) (Kinoshita et al.
2012; Nishino et al.
2015). In a study of NSCLC patients receiving chemotherapy, 22 of whom had idiopathic interstitial pneumonia (IIP), IIP was found to be a significantly unfavorable factor for progression-free survival (PFS) (95.0 vs. 199.5 days) and overall survival (OS) (163.0 vs. 400.0 days) (Kinoshita et al.
2012). In another study, NSCLC patients with high ILA scores according to computed tomography (CT) findings had shorter OS (
n = 17, 7.2 months) than those without ILA (
n = 103, 14.8 months) (Nishino et al.
2015).
Idiopathic pulmonary fibrosis (IPF), the commonest type of ILD (Borchers et al.
2011), is defined as a specific form of chronic, progressive fibrosing IP of unknown cause, occurring primarily in older adults, limited to the lungs, and associated with the histopathologic and/or radiologic patterns of usual interstitial pneumonia (UIP) (Raghu et al.
2011). IPF was recently reported to be a poor prognostic factor in patients with surgically treated NSCLC (Goto et al.
2014; Lee et al.
2014). Only one study has focused on the efficacy of chemotherapy in advanced NSCLC with IPF (Watanabe et al.
2013). The authors reported that 21 patients with IPF had an overall response rate (RR), PFS, and OS of 42.9 %, 5.4, and 11.4 months, respectively (Watanabe et al.
2013). No published studies have compared the survival of IPF and non-ILD patients with advanced NSCLC.
Because there is limited clinical information regarding advanced NSCLC patients with IPF, we retrospectively compared the efficacy of chemotherapy and survival in NSCLC patients with ILD or IPF with that in patients without ILD. In addition, we investigated the incidence, risk factors, and outcome of acute exacerbations (AEs) after receiving chemotherapy.
Discussion
In the present study, we demonstrated that (1) characteristics of ILD/IPF patients differed significantly from those of non-ILD patients; in particular, no IPF patients had EGFR mutation-positive tumors; (2) the presence of either IPF or ILD was associated with shorter PFS and OS in patients with advanced NSCLC who received chemotherapy; (3) DCR was significantly lower in ILD and IPF patients than in non-ILD patients, even those with EGFR-WT; and (4) AEs of ILD occurred more frequently after docetaxel-containing regimens than after other regimens.
The present study clearly demonstrated several differences in the characteristics of non-ILD and ILD/IPF patients. Most ILD and all 34 IPF patients were male smokers and had
EGFR-WT. It is particularly interesting that no IPF patients had
EGFR mutation-positive cancers, which has been shown for the first time although a previous study has reported a correlation between preexisting ILD and
EGFR-WT adenocarcinoma (Fujimoto et al.
2013). In that study, only one of 31 ILD patients with lung adenocarcinoma had an
EGFR mutation; this patient had a non-UIP radiographic pattern (Fujimoto et al.
2013). The current study extended this finding in that our one ILD patient with
EGFR mutation also had a radiologic pattern inconsistent with UIP pattern. The frequency of squamous cell carcinoma was higher in IPF than in non-ILD patients (35 vs. 13 %). In ILD patients, most tumors reportedly develop in the area affected by ILD (Fujimoto et al.
2013; Kanaji et al.
2015). The current study provides evidence that carcinogenesis in IPF differs from that in non-ILD patients in that it is not associated with
EGFR mutation.
Consistent with previous studies (Borchers et al.
2011; Watanabe et al.
2013), IPF was the commonest type of ILD (34/53 patients; 64 %). Even in patients with
EGFR-WT, PFS and OS were significantly shorter in IPF than in non-ILD patients. These findings indicate that the presence of IPF predicts an extremely poor prognosis in patients with advanced NSCLC. Lower %VC (<80 %) was also associated with shorter survivals (120 vs 196 days for PFS,
P = 0.0043, and 266 vs 538 days for OS,
P = 0.0023, respectively, data not shown). Shorter survival in lower %VC has been reported in patients with NSCLC and ILD who underwent surgical resection (Sato et al.
2015).
Another important finding of the current study is regarding response to chemotherapy/molecular targeted therapy. RR and DCR in ILD/IPF patients were lower than that in non-ILD patients. EGFR mutation was not identified in any of the 34 IPF patients, whereas 32 % of non-ILD patients harbored EGFR mutations. Because the response to EGFR-TKI is much better in tumors with EGFR mutation than in EGFR-WT, the lower RR in IPF patients may be associated with the absence of EGFR mutations. Indeed, the difference in RR was not significant for EGFR-WT patients; interestingly, however, a difference in DCR was observed, even in patients without EGFR mutations.
There are several possible mechanisms that could explain the lower DCR and shorter survival of ILD/IPF patients. First, ILD/IPF patients may experience adverse events more frequently. Indeed, adverse events, including AEs, and PD were the main reasons for discontinuing first-line therapy within three cycles in patients with ILD/IPF, suggesting that AEs of ILD/IPF may have made an important contribution to the lower DCR and shorter survival. Consistent with this, coexisting ILD is reportedly associated with a high risk of developing chemotherapy-induced ILD (Sakurada et al.
2015). Chemotherapeutic strategies that do not induce AEs or deterioration of ILD are needed.
Second, an altered drug delivery system may lead to the lower response and shorter survival of ILD/IPF patients. Histological features of the UIP pattern include marked pulmonary fibrosis and architectural distortion (Raghu et al.
2011). Alveolar epithelial cell damage, dysregulation of fibroblasts, and vascular injury and aberrant angiogenesis related to vascular remodeling are key elements of lung fibrosis (Selman and Pardo
2006; Wémeau-Stervinou et al.
2012). Destruction of normal vasculature would logically reduce the local delivery of chemotherapeutic agents to a tumor.
Third, acquired drug resistance may result in lower DCR and shorter survival in ILD/IPF patients. In this regard, transforming growth factor (TGF)-
β may have a role. Many cytokines and growth factors, including TGF-
β, are reportedly associated with the development of ILD/IPF (Das et al.
2014; Kanaji et al.
2014). TGF-
β concentrations are higher in bronchoalveolar lavage fluid obtained from IPF than from control patients (Khalil et al.
2001). TGF-
β is reportedly associated with chemoresistance in colon cancer (Li et al.
2015). Additionally, TGF-
β is a major regulator of epithelial–mesenchymal transition in the alveolar epithelia (Kasai et al.
2005; Miyazono
2009). In epithelial–mesenchymal transition, cancer cells seemingly acquire chemoresistance in lung and other types of cancers (Jiang et al.
2015; Li et al.
2014; Wang et al.
2015). Thus, increased TGF-
β in the lung’s microenvironment may be a causative factor for lower DCR and shorter survival in NSCLC patients with ILD/IPF.
Regarding AEs of ILD, several studies have reported docetaxel-induced AE (Tamiya et al.
2012; Watanabe et al.
2015). In 35 patients with NSCLC and IP treated with docetaxel monotherapy, the incidence of AEs of IP was 14.3 % (5/35 patients). Three of the five patients who developed AEs of IP died (Watanabe et al.
2015). In another study, deterioration of ILD was observed in 7/27 patients (25.9 %) with NSCLC and preexisting ILD (Tamiya et al.
2012). In contrast, 6/309 patients (1.9 %) without preexisting ILD reportedly developed it after receiving docetaxel (Tamiya et al.
2012). In the current study, there was also a higher incidence of AEs of ILD/IPF after docetaxel-containing chemotherapy. Of note, AEs also occurred in 3/15 patients with radiographic possible UIP pattern (20 %). Several studies have reported that possible UIP pattern often corresponds with pathologically confirmed UIP (Sumikawa et al.
2014; Raghu et al.
2014). Radiographic possible UIP pattern should be considered clinically similar to UIP when choosing treatment strategies for patients with advanced NSCLC. Administration schedule also affects the incidence of AEs (higher incidence in a weekly than in triweekly administration) (Chen et al.
2006). Anti-microtubule activity by taxanes itself seems not to be related in the development of AE because the incidence of AE in paclitaxel is different from that in docetaxel. Thus, factors other than anticancer activity might be associated with docetaxel-related AE although an actual mechanism has never been reported.
No optimal chemotherapeutic regimen for patients with advanced NSCLC and underlying ILD has been established (Watanabe et al.
2015). A combination of carboplatin and weekly paclitaxel may be a treatment option for NSCLC with ILD (Minegishi et al.
2011). Eighteen patients with ILD, including six with IPF, treated with carboplatin and paclitaxel achieved PFS and median survival time of 5.3 and 10.6 months, respectively (Minegishi et al.
2011). Only one patient (5.6 %) with IPF developed an AE (after four cycles of chemotherapy). However, in another study 4/15 patients with NSCLC and ILD who received carboplatin and paclitaxel developed grade 3 or higher pneumonitis (27 %) (Shukuya et al.
2010); this high incidence cannot be ignored. In a phase III trial, administration of albumin-bound paclitaxel (nab-paclitaxel) as first-line treatment in patients with advanced NSCLC without ILD was effective and resulted in a higher RR than conventional solvent-based paclitaxel (Socinski et al.
2012). Currently, several clinical trials are assessing a combination of carboplatin and nab-paclitaxel for advanced NSCLC with ILD.
Nintedanib is a multiple tyrosine kinase inhibitor, and INPULSIS-2 trial demonstrated that nintedanib reduced the time to first AE compared with placebo (Richeldi et al.
2014). In addition, a combination of docetaxel and nintedanib showed a benefit on OS over docetaxel monotherapy as second-line treatment (Reck et al.
2014). The addition of nintedanib to cytotoxic agents such as docetaxel may be more effective with fewer adverse events.
The prevalence of ILD and IPF in this study was 24.3 and 15.6 %, respectively, and seems to be higher than in previous reports (7.3–14 %) (Kinoshita et al.
2012; Nishino et al.
2015). However, among 387 patients who received surgical resection, 65 (16.8 %) were confirmed as underlying IPF (Goto et al.
2014). Location of the institution would greatly influence the prevalence of ILD and IPF as well as smoking status.
The limitations of this study are as follows. First, this was a retrospective, single-center study; a prospective, multicenter large study including both non-ILD and ILD patients is desirable to further investigate clinical differences in response to chemotherapy. Second, all patients were Japanese: Some studies have shown ethnic differences in incidence of drug-induced lung injury and other pulmonary diseases (Azuma et al.
2008; Natsuizaka et al.
2014). The incidence of AEs of ILD/IPF may vary between different ethnicities.