Acute exacerbation (AE) is characterized by diffuse and rapid alveolar damage superimposed on a background of preexisting fibrotic change, which most likely occurs as a result of a massive lung injury due to some unknown etiologic agents. Some unknown etiologic agents of AE can be induced by pulmonary resection. Several investigators have reported on possible AE risk predictors, such as low DLCO [6], low %VC [17, 18], high KL-6 [19], high CRP [20], high LDH [18], poor performance status [7], and positive intraoperative water balance [20]. However, all these previous studies were single institutional retrospective studies, and their sample size were less than 100, which were too small to draw any conclusions.

AE has been shown to be the major cause of death for lung cancer patients after pulmonary resection in a report cumulating over 10,000 cases from the Japanese Joint Committee for Lung Cancer Registration and in the 2009 annual report of the Japanese Association for Thoracic Surgery [21, 22]. It was for reason that we first conducted a large-scale multi-institutional retrospective cohort study at the initiative of the Japanese Association for Chest Surgery starting from 2010 [23]. The original data for analysis were obtained from non-small cell lung cancer patients who had undergone pulmonary resection and presented with a clinical diagnosis of ILDs between January 2000 and December 2009 at 64 institutions throughout Japan. The primary end point for outcome analysis was postoperative AE of interstitial pneumonitis within 30 days after pulmonary resection. Medical records of the patients were reviewed for about 80 clinicopathological factors.

Diagnoses of ILDs were confirmed based on a combination of clinical and radiologic findings according to the clinical criteria proposed by the Japanese Respiratory Society [17], which are consistent with the guidelines of the American Thoracic Society in 2011 [12]. The cases were categorized into two groups according to their radiological appearance on CT scan: (1) usual interstitial pneumonia (UIP) pattern, characterized by the presence of basal-dominant reticular opacities and predominantly basal and subpleural distribution of honeycomb lesions, with multiple equal-sized cystic lesions of 2–10 mm diameter with a thick wall; and (2) non-UIP pattern, characterized by the presence of basal-predominant ground-glass opacities and infiltrative shadows inconsistent with UIP patterns.

AE caused by pulmonary resection was defined based on criteria proposed by Yoshimura et al. and ATS Guidelines [12, 24]. These criteria were (1) onset within 30 days after pulmonary resection, (2) intensified dyspnea, (3) increase in the interstitial shadow on chest radiograph and chest CT scan, (4) decrease in arterial oxygen tension of more than 10 mmHg under similar conditions, (5) no evidence of pulmonary infection, and (6) exclusion of alternative causes such as cardiac failure, pulmonary embolism, or other identifiable causes of lung injury. Exacerbations occurring from 31 days onward were defined as chronic exacerbations.

Data were obtained from 1,763 patients with surgically treated lung cancer with ILDs. Among these, 164 patients (9.3 %) developed postoperative AE within 30 days after the operation. The majority of the patients developed AE within 10 days after operation, with postoperative day 4 showing the highest frequency of AE. Within the patients developing AE, 72 of them (43.9 %) died.

With multivariate analysis, the following seven independent risk factors of AE were identified: surgical procedures, male sex, history of exacerbation, preoperative steroid use, serum sialylated carbohydrate antigen KL-6 levels, usual interstitial pneumonia appearance on CT scan, and reduced percent-predicted vital capacity (Table 15.1). Surgical procedures showed the strongest association with AE. The lobectomy/segmentectomy group and the bilobectomy/pneumonectomy group were both more likely to develop AE than the wedge resection group, with ORs of 3.83 and 5.70, respectively. Neoadjuvant treatment and video-assisted thoracoscopic surgery showed no association with AE in our study. The effect of perioperative prophylactics such as steroids and sivelestat was not confirmed in this study.

Achieving long-term survival after surgical resection for lung cancer patients with ILDs is not easy due to several reasons. Firstly, AE may occur in early postoperative period as shown in the previous section. Secondly, ILD itself has poor prognosis in general. Especially, the median survival of the patients with IPF reportedly ranges only 2–4.2 years from the date of diagnosis [12, 25, 26]. Thirdly, cancer arising from ILDs may have aggressive nature.

Because of these considerations, determining the surgical indication for lung cancer patients with ILDs is not easy. Besides their impaired pulmonary reserve, it is not clear whether pulmonary resection is beneficial or harmful for each individual. Although there is a general understanding that the prognosis of lung cancer patients with ILDs is poor, existing evidence to support these conclusions used to be based on a few studies with comparatively small number of patients (14–56 cases) [5, 14, 16, 27–30]. In our previous report using data from 61 institutes in Japan on 1,763 lung cancer cases who had ILDs, we studied the morbidity and mortality rate of pulmonary-resected patients and identified seven risk factors for postoperative acute exacerbation of pulmonary fibrosis [23]. Using the same cohort, we have analyzed their long-term survival and the probable factors influencing their survival [31].

The overall 5-year survival after surgical resection for lung cancer patients with ILDs was 40 %. The leading cause of death was cancer recurrence (50.2 %), followed by respiratory failure (26.8 %). The 5-year survivals were 59 %, 42 %, 43 %, 29 %, 25 %, 17 %, and 16 % for patients with p-stage Ia, Ib, IIa, IIb, IIIa, IIIb, and IV, respectively. These were substantially poorer than the recent figures reported by the Japanese Joint Committee for Lung Cancer Registration for general patients (Table 15.2) [32]. These poorer survival rates are likely due to the high incidence of cancer recurrence, combined with the poor survival rate of ILD itself.

Multivariable analysis revealed that the type of surgical procedure, percent-predicted vital capacity (%VC), and tumor locations were independent predictors for survival (Table 15.3). Long-term survival of stage Ia patients who had undergone wedge resections was poorer than that of lobectomy patients (Fig. 15.2). The estimated survival curve of the wedge resection group crossed that of the lobectomy group 1 year after the surgery, and the survival of the wedge resection group was significantly poorer than that of the lobectomy group (log-rank test, p = 0.0008). These observations can be explained by the fact that the wedge resection group was less likely to develop AE, but had a higher cancer recurrence rate than that of the lobectomy group. The 5-year survival of the stage Ia patients with %VC < or = 80 % was 20 %, whereas those with %VC > 80 % was 64.3 % (log-rank test, p < 0.0001). For patients with poor predictors of survival, such as predicted percent vital capacity of 80 % or less, surgical resection should be limited.