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 clinicopathologic factors on overall survival, 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 on the overall survival 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 experienced the operation (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 . 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 . 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 similar to the reported results despite the limited number of corresponding patients. According to the regular CT surveillance protocol, we could find it was within the first two years after the curative-intent surgical section that the most recurrences or disease progression appeared, 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 investigated and validated in case of excessive medical treatment or delayed the illness 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 needed more 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 modalities for patients having stage I NSCLC, previous studies have reported the 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 clinicopathological variables on overall survival and overall recurrence in stage I NSCLC and identified a number of risk factors: 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) were significantly associated with worse overall survival. 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 . Shimada et al demonstrated that liver metastasis (P＜0.001) and bone metastasis (P=0.001) were independently and significantly correlated with worse PRS. 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 . Hung et al reported that the higher incidence of distant metastasis occurred in adenocarcinoma and higher probability of local recurrence existed in non-adenocarcinoma . Zhang et al confirmed that adenocarcinoma histology, compared to squamous cell carcinoma, had the higher incidence of bone or brain recurrence . 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 also facilitated the quality of life and survival benefit . 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 three limitations. First, the retrospective nature of the current study had its limitation 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.