INTRODUCTION
Interstitial lung disease (ILD) refer to heterogenous diseases in which acute and/or chronic inflammation as well as fibrosis develop in the lung parenchyma, mainly involving the interstitium [1]. Among these, idiopathic pulmonary fibrosis (IPF) is the most prevalent and lethal. IPF is defined as chronic progressive fibrosis of the lungs of unknown etiology [2]. Although the disease course may vary across patients, the prognosis is often grave due to the progression of fibrosis leading to respiratory failure. The median survival of patients diagnosed with IPF is 3 to 5 years [2,3].
Lung cancer is the most commonly diagnosed cancer worldwide and imposes significant burdens on society and healthcare resources [4]. In 2022, approximately 2.5 million individuals were newly diagnosed with lung cancer. Furthermore, it has the worst prognosis among all cancers, with a 5-year survival rate of only 10% to 20% [5]. Hence, it was the leading cause of cancer-related mortality in 2022, attributing to the death of 1.8 million individuals.
Lung cancer is also a common comorbidity of IPF. Patients diagnosed with IPF have a three to seven times increased risk for developing lung cancer compared with the general population [6]. The concurrence of these two major detrimental respiratory diseases not only impose huge health burdens but also pose challenges for clinicians in the management of affected patients. This narrative review discusses the current knowledge regarding the epidemiology, clinical characteristics, and management of lung cancer in patients diagnosed with IPF.
RISK FOR LUNG CANCER DEVELOPMENT IN PATIENTS DIAGNOSED WITH IPF
The reported prevalence of lung cancer in patients with IPF ranges from 4.4% to 48% [7,8]. The wide range in prevalence may be attributed to differences in the inclusion criteria of studies. In a study by Matsushita et al. [7], which reported a prevalence of 48%, the investigators reviewed 3,712 consecutive autopsy cases and identified 83 cases with usual interstitial pneumonia (UIP) pattern, in whom lung cancer arose in 40. The analysis of autopsy cases may have impacted the reported prevalence by detecting those with minimal fibrosis and cancer lesions, as well as by including only patients who died and underwent autopsy. Most studies have reported a prevalence of 10% to 20% [6]. Given the broad prevalence range due to the heterogeneity of study populations, incidence data may provide more helpful information. In a single-center study from South Korea, we found that lung cancer occurred in 135 of 938 (14.5%) patients with IPF who did not have evidence of lung cancer at the time of IPF diagnosis [9]. The cumulative incidence rates at 1, 3, 5, and 10 years were 1.1%, 8.7%, 15.9%, and 31.1%, respectively. Similarly, a retrospective study by Ozawa et al. [10], who reviewed data from 103 patients diagnosed with IPF at their center, reported 1-, 5-, and 10-year cumulative incidence rates of lung cancer of 3.3%, 15.4%, and 54.7%, respectively. These results are comparable with those reported in European countries. In a retrospective multicenter study involving 3,178 patients with IPF from seven European countries, the 5- and 10-year cumulative incidence rates were 14.1% and 26.6%, respectively [11].
However, an explanation for the increased risk for lung cancer among patients with IPF remains unclear. Shared risk factors for disease, such as smoking may, in part, have influenced frequent development. However, in a recent systematic review, IPF was found to be an independent risk factor for lung cancer, even after accounting for smoking [12]. Another possible explanation involves the genetic and epigenetic mechanisms underlying these diseases. Numerous epigenetic alterations found in cancer have also been identified in IPF [13,14]. For example, partial similarity in the alteration of global methylation patterns in cancer was observed in IPF, suggesting a similar pathogenic mechanism in both diseases [15]. Furthermore, genetic mutations associated with carcinogenesis, including telomere shortening and telomerase expression, have been described in familial and sporadic IPF [16]. However, the mechanisms underlying the vulnerability of those with IPF to the development of cancer have not been fully elucidated. In addition, some epigenetic alterations exhibit contradictory directionalities; as such, further research is necessary to fully understand the association between IPF and lung cancer.
CLINICAL CHARACTERISTICS OF LUNG CANCER IN IPF
Studies involving patients diagnosed with lung cancer and concurrent IPF have demonstrated that most were older males with an ongoing or history of smoking [9-11]. In our previous study [9], the mean age of 135 patients with IPF and lung cancer was 65.2 years and 94.8% were male. Sixty (44.4%) patients were current smokers and 74 (54.8%) were ex-smokers. Squamous cell carcinoma was the most common histological type, followed by adenocarcinoma [9,11,17,18]. We found that 32.6% of the study population had squamous cell carcinoma, while 28.1% had adenocarcinoma (28.1%). Small-cell carcinoma was identified in 27 (20%) patients. In another study from South Korea [18], squamous cell carcinoma accounted for 48.4%, while adenocarcinoma was diagnosed in 32% of patients. In a study from the United States involving 31 patients, most of whom were Caucasian (97%), Yoon et al. [17], reported that 11 (41%) and 7 (26%) were diagnosed with squamous cell carcinoma and adenocarcinoma, respectively.
Several studies have investigated the radiological features of lung cancer in patients diagnosed with IPF. Although one study reported a predominance of tumor lesions in the upper lobe and non-fibrotic area [19], most others reported that the tumor tended to be located within the area or abutting the fibrosis (Fig. 1) [9,20,21]. The majority of tumors were located in the lower lobes, likely reflecting the predilection of the lower lobes for the development of fibrosis in IPF.
PROGNOSIS OF LUNG CANCER IN IPF
The prognosis of patients with concomitant lung cancer and IPF is worse than that for those with IPF or lung cancer alone. In our study involving patients diagnosed with lung cancer and IPF, the median survival was 3.4 years compared with 9.8 years in those with IPF without lung cancer [9]. Similarly, Tomassetti et al. [22] reported a median survival of 38.7 months for patients with IPF and lung cancer and 63.9 months for those diagnosed with IPF alone. In a multicenter retrospective study from Europe [11], patients with IPF and coexisting lung cancer were at an increased risk (hazard risk, 1.51) for allcause mortality compared with IPF patients without lung cancer. Interestingly, in a study by Ozawa et al. [10], no difference in survival was observed between patients with IPF with and without lung cancer. However, patients with IPF and lung cancer exhibited better lung function than those without lung cancer, and the interval between IPF diagnosis and lung cancer development was relatively long (120 months). These factors may have influenced the observations.
Coexisting IPF worsens the prognosis of those diagnosed with lung cancer. In a study from South Korea, Kim et al. [18] investigated patients with lung cancer and reported that the 5-year survival rate of those with IPF and lung cancer was significantly shorter than that of those with lung cancer alone (14.5% vs. 30.1%). In another study from Korea, Lee et al. [23] analyzed data from 33 patients with IPF and lung cancer who underwent surgery and matched these with 66 patients diagnosed with lung cancer but without IPF. The 5-year survival rate was 38% in patients with lung cancer and 73% in those without IPF.
Poor survival rates among patients diagnosed with both lung cancer and IPF has been consistently reported in the literature. Although respiratory failure due to IPF and cancer progression are the major causes of death in these patients, treatment- or diagnosis-related complications have a significant effect on poor outcomes. In one study, the cause of death was attributed to complications resulting from treatment or diagnostic procedures in 17% of patients with lung cancer and IPF [22]. Analysis of our IPF and lung cancer cohort revealed that 23% of deceased patients died of treatment-related complications [9].
Previous studies have shown that patients diagnosed with lung cancer and IPF are at high risk for developing treatment-related complications (Fig. 2). Watanabe et al. [24] analyzed 858 patients with primary lung cancer who underwent surgery, including 56 and 802 patients with and without IPF, respectively. Acute postoperative exacerbation of interstitial pneumonia and acute respiratory distress syndrome were more common in patients with IPF. Furthermore, the rate of mechanical ventilation was higher in patients with IPF. Surgery-related hospital mortality was also higher in patients with IPF than in those without IPF (7.1% vs. 1.9%, P= 0.030). The postoperative 5-year survival for pathological stage I lung cancer was 61.6% in patients with IPF and 83.0% in those without IPF (P= 0.019). In a Japanese study involving patients with stage IA non-small cell lung cancer who received surgical treatment [25], 10 (35.7%) in the IPF group experienced pulmonary complications, including pneumonia and prolonged air leakage, whereas 41 (12.7%) in the non-IPF group developed pulmonary complications. Three (10.7%) patients developed acute exacerbation (AE) of IPF. Ninety-day mortality was 3.6% for the IPF group and 0.3% for the non-IPF group. Notably, respiratory failure as the cause of death was more common in the IPF group than in the non-IPF group (14.3% vs. 1.2%, P< 0.0001). Regarding radiotherapy, our group has shown that grade ≥ 3 radiation pneumonitis develops more often in patients with IPF following definitive radiotherapy for lung cancer than in patients with combined pulmonary fibrosis and emphysema (CPFE), chronic obstructive pulmonary disease, or in controls (31.8%, 6.3%, 2.3%, 1.6%, respectively; P< 0.001) [26]. IPF and CPFE were independent risk factors for mortality. Similarly, Ueki et al. [27] reported that grade ≥ 2 radiation pneumonitis occurred in 52.4% of patients with pretreatment ILD who underwent stereotactic body radiation therapy for lung cancer (11 with UIP pattern and nine with other than UIP pattern) and 13.1% without ILD. The rates of grade ≥ 3 radiation pneumonitis were 10.0% and 1.5% in patients with ILD and non-ILD, respectively. Nevertheless, overall survival did not differ between patients with and without ILD. With regard to chemotherapy, few studies have evaluated treatment-related complications of chemotherapy in patients with IPF and lung cancer. In addition, most available studies did not exclusively evaluate patients with IPF but investigated those diagnosed with ILD including those with IPF. Furthermore, a large proportion of studies had a small, single-arm, retrospective design. Given these limitations, the reported incidence of pneumonitis or AE of interstitial pneumonia varies widely, from 4.3% to 29.4% [28].
CONSIDERATIONS IN THE TREATMENT AND PREVENTION OF LUNG CANCER IN IPF
Although the prognosis of patients with lung cancer and IPF is poor, and fatal treatment-related complications are common, specific treatment guidelines for this patient population have yet to be developed. Although general treatment strategies for lung cancer may be adopted for IPF, several points should be considered during decision making. First, the nature of progressive fibrosis in IPF inevitably results in worsening of lung function. Treatment for lung cancer—typically surgery— may lead to temporary or permanent loss of additional lung function. Whether to treat a patient and which treatment modality to use should be carefully considered before therapy. For patients with early-stage lung cancer, radiation therapy can be an alternative to surgery in those who cannot tolerate surgical treatment [29]. Lung function trajectory after radiation therapy remains unclear in patients with IPF. However, in a prospective study of patients with IPF and lung cancer treated with proton therapy, the decline in lung function was largest at 7 months after treatment [30]. Nevertheless, lung function in the patients recovered to pretreatment levels after 1 year.
More importantly, the risk for developing treatment-related complications, such as AE and pneumonia, which may lead to mortality, is increased; therefore, this should be evaluated thoroughly. The high risk for treatment-related complications poses a significant challenge to clinicians, especially in patients with early-stage lung cancer. Surgical resection may offer a cure for these patients; however, the development of treatment-related complications may result in mortality. In our cohort of patients who underwent surgical resection as a curative treatment, the median survival of those who developed postoperative complications was only 17 months, compared with 30 months among those who did not (unpublished data). Therefore, whether surgery should be indicated for patients with IPF and lung cancer has long been controversial. Calculating the risk for postoperative complications may help clinicians and patients weigh the risks for complications and curative benefits of surgery. A scoring system to predict the 30-day risk for AE after surgical treatment (history of AE, surgical procedure, UIP pattern on computed tomography, male sexgender, postoperative steroid use, elevated serum KL-6 level, and low vital capacity) has also been published [31]. Nonetheless, it has not been validated. Further research aimed at developing a reliable tool for precisely calculating the risk for complications and mortality that can be used in decision making is warranted.
Because treatment-related complications can be fatal, researchers have attempted to identify methods to reduce them and improve outcomes. In this regard, whether antifibrotic agents, which have been confirmed to decrease the decline in lung function in IPF, play a role in preventing the development of complications is of great interest. Several retrospective and prospective studies have examined the effects of pirfenidone on the occurrence of postoperative AE of IPF in patients who underwent surgical treatment. In a retrospective analysis on 50 patients with IPF and lung cancer, of whom 31 received pirfenidone at least 4 weeks before surgery and 19 did not receive pirfenidone, Iwata et al. [32] reported that the incidence of AE of IPF within 90 days postoperatively was lower in the pirfenidone group (3.2% vs. 21.1%, P= 0.04). In a propensity score-matched study involving 631 patients with IPF and lung cancer (121 treated with pirfenidone) in Japan, the risk for severe respiratory complications was lower in the pirfenidone group than in the control group (odds ratio, 0.24; P= 0.015) [33]. An ongoing phase III clinical trial is evaluating the preventive effects of perioperative pirfenidone in patients with IPF undergoing surgical treatment for lung cancer [34]. The results of this study will provide a better understanding of the role of pirfenidone in reducing complications in surgical patients with IPF and lung cancer. Few studies have analyzed the preventive role of antifibrotics in patients with IPF treated with radiation therapy or chemotherapy for lung cancer. However, a recent phase III trial from Japan (J-SONIC study), an open-label randomized study that evaluated 243 patients with chemotherapy-naïve non-small cell lung cancer and IPF, may shed light on the role of nitedanib [35]. The investigators compared the outcomes of groups receiving carboplatin with nab-paclitaxel, with and without nintedanib. Although exacerbation-free survival did not differ between the two groups, the median progression-free survival for patients in the nin-tedanib group was 6.2 months compared with 5.5 months in the group without nintedanib. In addition, nintedanib improved overall survival in patients with non-squamous histology (hazard risk, 0.61) and in those with gender-age-physiology (GAP) stage I (hazard risk, 0.61), suggesting that nintedanib may be beneficial in improving survival in a specific subset of patients, despite its potential to reduce AE. Based on the results of previous studies, antifibrotic therapy is a possible option for preventing post-treatment complications and/or improving survival. However, further investigation is necessary to confirm these findings.
Several studies have reported the benefits of antifibrotic therapy on the mortality of patients with IPF and lung cancer (Table 1). In a recently published study, Naoi et al. [36] reviewed multicenter data and analyzed 345 patients with IPF and lung cancer. Among them, 189 patients received antifibrotics (137 received pirfenidone and 52 received nintedanib), whereas 156 did not receive any antifibrotic agents. Lung cancer-related mortality in patients who received antifibrotic agents was 1.61% compared with 15.2% in patients who did not receive antifibrotic agents. The risk ratio was 0.16 (95% confidence interval, 0.025 to 0.450). In another retrospective, multicenter, study from Europe by Karampitsakos et al. [11], the authors compared the survival of patients with IPF and lung cancer with and without antifibrotic therapy. Patients treated with anti-fibrotic therapy exhibited better survival rates (hazard ratio, 0.61; P= 0.006). Antifibrotic therapy was associated with improved survival after adjusting for potential confounding factors.
CONCLUSION
IPF and lung cancer are two major respiratory diseases that commonly coexist. Patients diagnosed with IPF have a 3- to 7-fold increased risk for developing lung cancer compared with the general population. Patients diagnosed with both lung cancer and IPF are typically older males with a history of smoking. Lung cancer accompanied by IPF tends to be located in the lower lobes and areas abutting or within the fibrosis. The most common histological type is squamous cell carcinoma, followed by adenocarcinoma. The prognosis of patients diagnosed with IPF and lung cancer is poorer than that of those with either lung cancer or IPF alone. Treatment-related complications, IPF, and cancer progression are the major causes of poor prognosis in these patients. Thorough evaluation of the risk for complications is necessary during the decision-making process. Antifibrotics may help prevent complications and improve patient survival. Further research to develop a reliable tool to predict complications and mortality, as well as to identify methods to prevent complications, is necessary to establish optimal treatment strategies for patients diagnosed with both IPF and lung cancer.
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