Although previous studies have reported molecular and clinicopathologic variables for the recurrence for NSCLC after initial resection especially in LUAD [28,29], the recurrence pattern of LUSC, LASC or other NSCLC subtypes still needs to be investigated. To our knowledge, this present study is the first to comprehensively explore the influence of clinicopathologic factors on OS, overall recurrence and post-recurrence survival based on a largest cohort of patients with NSCLC having LUAD, LUSC, LASC and other subtypes. The median follow-up period of all resected lung cancer patients was more than 60 months.
The prognostic value of the new IASLC/ATS/ERS classification system in the OS and the overall recurrence has been reported and discussed in several previous studies [15,16,21,30]. Warth et al reported that solid-, micropapillary-, and papillary-adenocarcinoma patients who underwent the surgery (the frequencies: 37.6%, 6.8%, and 4.7% respectively), compared to lepidic- and acinar-predominant histologic patterns (the frequencies: 8.1% and 42.5%, respectively), were significantly related with lower disease-free survival (DFS) and poorer OS [15]. Yoshizawa et al showed that LUAD patients with stage I having high-grade tumors including solid- and micropapillary-predominant subtypes were significantly associated with worse overall survival and a higher incidence of recurrence [21]. Hung et al demonstrated that LUAD patients with resected stage I-III owing the high architectural grade including solid- (13.6%) and micropapillary- (19.5%) predominant patterns, compared with papillary- (27.1%), acinar- (33.7%), and lepidic- (6.1%) predominant subtypes, were remarkably associated with worse overall survival, poorer disease- specific survival and higher incidence of recurrence [16,31]. Our outcomes also demonstrated that the solid-predominant patients of LUAD had the higher possibility of recurrence similarly to the reported results despite the limited number of corresponding patients. According to the regular CT surveillance protocol, we found that most recurrences or disease progression appeared within the first two years after the curative-intent surgical section, which indicated that the regular CT surveillance was of great significance for the postoperative lung cancer patients. However, the best interval time for postoperative follow-up is still to be warranted to be investigated and validated in case of excessive or delayed medical treatment due to insufficient diagnosis. In addition, the current study also demonstrated that high architectural grade including solid-predominant LUAD was significantly associated with poor PRS, which highlights the need for medical care for the postoperative clinical contact.
The present study also investigated the clinicopathological factors influencing the PRS of stage I NSCLC patients. Although surgical resection with curative intent is the most effective treatment modality for patients having stage I NSCLC, previous studies have reported an incidence of recurrence in stage I NSCLC ranging from 14% to 36%, with 1- and 2-year PRS rates of 38%-88%, and 19%-72.3% respectively (Table 3). In this study, overall incidence of recurrence during the postoperative 5 years was 20.2% and median PRS time was 25.5 months. We examined the impact of clinicopathological variables on OS and overall recurrence and identified a number of risk factors that were significantly associated with worse OS including the older age (P=0.036), p-stage IB (P=0.001), sublobar resection(P<0.001), histologic subtype (P<0.001), and lymphovascular invasion (LVI) (P=0.042). Smoking history (P=0.043), non-adenocarcinoma (P=0.013), high architectural grade of LUAD (P= 0.019), EGFR wild status (P=0.002), bone metastasis (P=0.042) and brain metastasis (P=0.040) were marginally correlated with worse PRS. Some risk factors such as sublobar resection and high architectural grade of LUAD were consistent with previous studies.
Previous research reported that the recurrence sites might be a risk factors for PRS, which was consistent with our findings. Yoshino et al showed that bone metastasis was reported to be the remarkably significant unfavorable factor for PRS in the NSCLC patients with resected stage I-III [32]. Shimada et al demonstrated that liver metastasis (P<0.001) and bone metastasis (P=0.001) were independently and significantly correlated with worse PRS [6]. Ujiie et al showed that solid predominant adenocarcinoma was marginally associated with higher recurrence or metastasis incidence of brain (P=0.007), adrenal gland (P=0.034), and liver (P=0.038) than the non-solid predominant tumors [5]. Hung et al reported that the higher incidence of distant metastasis occurred in adenocarcinoma and higher probability of local recurrence existed in non-adenocarcinoma [33]. Zhang et al confirmed that adenocarcinoma histology, compared to squamous cell carcinoma, had the higher incidence of bone or brain recurrence [34]. The present study also indicated that the non-LUAD histology, brain metastasis and bone metastasis were significantly associated with worse PRS.
With the rapid development of management of lung cancer, molecular target therapy of tyrosine kinase inhibitors (TKI) has exerted survival benefit for the NSCLC patients with EGFR mutations [35, 36]. Shimada et al demonstrated that epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), compared with platinum-based doublet chemotherapy, were significantly associated with favorable PRS (HR=0.460, 95%CI 0.245-0.862, P=0.015), which improved the quality of life and survival benefit [6]. The current study also suggested that NSCLC patients with EGFR mutations, having received the EGFR-TKIs, obtained a favorable PRS. However, since no EGFR mutations accounts for the majority of the lung cancer, the most appropriate treatment modality for resected lung cancer with no mutations is needed to be investigated.
Nonetheless, the present study had some limitations. First, the retrospective nature hinders us to assess the influence of clinicopathological factors on the post-recurrence survival. Prospective randomized controlled trials (RCTs) are more appropriate in this regard. Second, our sample may not be largely representative because all patients involved in the study were Chinese. A multi-center investigating targeting non-Asian populations will certainly validate the results. Finally, not all LUADs had the predominant histologic subtypes due to insufficient records data. Despite these limitations, this current study is, to our knowledge, the first to investigate comprehensively the impact of clinicopathologic factors on post-recurrence survival based on the largest cohort of patients diagnosed with NSCLC with a median follow up of more than 5 years.