This study was a retrospective analysis of 293 patients who had a histopathological diagnosis of stage IB lung adenocarcinoma predominant according to the 8th UICC staging system and underwent lobectomy. After a sufficient follow-up period of 66 months, the 5-year RFS was 78.0% and the 5-year OS was 83.5%. These outcomes were better than the results obtained by the Japanese Joint Committee of Lung Cancer Registry in 2004 (OS 73.9%) and 2010 (OS 76.7%) [15,16]. The outcomes of lung cancer treatment have been improving, but the main reason for the good results may be the selection of patients; the subjects were limited to patients who were ≤75 years of age at the time of surgery, and the procedure was limited to lobectomy. In this study, adenocarcinoma predominant of stage IB according to the latest edition of the staging system was an independent prognostic factor not only for RFS, but also for OS. To examine the role of adjuvant chemotherapy, adenocarcinoma predominant was matched using the propensity score-matching test. Overall, adjuvant chemotherapy was not associated with an effect on OS or RFS. However, when focusing on adenocarcinoma predominant, lepidic predominant showed excellent RFS and OS regardless of the presence or absence of adjuvant chemotherapy. Adjuvant chemotherapy is not necessary for this subgroup of patients. In other non-lepidic predominant subgroups, adjuvant chemotherapy tended to show slightly, but not significantly better RFS. A difference may not have been detected owing to the small number of patients. On the other hand, the OS curves overlapped in non-lepidic predominant, and there was no apparent difference. This may be related to the remarkable progress in systemic treatment including EGFR-TKI for EGFR mutant disease. When focusing on the outcomes of 35 patients with recurrence, the 5-year OS was significantly better in mutant disease mainly treated by EGFR-TKI. In advanced lung cancer, EGFFR-TKI showed a positive effect in improving survival in patients with EGFR-mutant disease [17,18]. Even after recurrence, patients can survive for a long period with effective treatment. Evidence showing that EGFR-TKI decreases the postoperative recurrence rate is still not available, and no other study has shown that adjuvant chemotherapy other than UFT is effective in stage IB lung cancer. Although the present study did not show a statistically significant decrease in recurrence, the tendency may be beneficial for patients even if it does not affect OS. UFT is relatively inexpensive (treatment with 400 mg/day of UFT costs 300 US dollars per month), and adverse reactions of grade ≥3 were reported in a few percent of patients [10]. Although the present study could not demonstrate a statistically significant advantage of adjuvant chemotherapy in patients with stage IB disease according to the current TNM staging system, the results of previous randomized clinical trials suggest that UFT administration cannot be omitted [9,10]. Thus, for non-lepidic predominant cases of stage IB lung cancer, adjuvant chemotherapy with UFT after complete resection remains a standard treatment in Japan.
On high resolution CT, lung adenocarcinoma is sometimes accompanied by ground glass opacity (GGO) around the tumor. GGO pathologically shows alveolar replacement growth, which corresponds to the lepidic component; it was considered a non-invasive part of lung cancer. The new, 8th UICC staging system was introduced in 2017 [19-21]. Lepidic component was omitted when the pathological tumor size was measured; only invasive size was set as the tumor size. This made it possible to predict outcomes more precisely than the previous edition of the staging system [19,21].Moreover, tumors with an invasion size of greater than 4 cm was was set at T2b, which is a higher stage than IB. These were large changes, and the population of stage IB in the 7th staging system differed from that in the 8th edition. When the 7th edition of the staging system was launched in 2010, pleural invasion became a factor to upstage to IB. Before then, a small size tumor of ≤3 cm with pleural invasion was staged as IA. Of course, accurate prognostic information is an extremely important factor for developing a more appropriate treatment strategy. In this study, patients with pathological stage IB disease according to the 8th staging system were examined, and the most important prognostic factor was the adenocarcinoma predominance. In particular, lepidic predominant showed excellent outcomes. However, when adenocarcinoma predominant was grouped according to the malignant degree, the intermediate-grade group (lepidic + acinar + papillary) was reported to show fair outcomes [12,22]. However, the lepidic predominant group has also been reported to have better outcomes than other predominant groups in the intermediate-grade group [23-25]. A solid appearance tumor without GGO on high resolution computed tomography has been reported to have higher malignant potential than tumors with GGO [26]. Another study showed that the presence of small micropapillary components had a greater negative effect on outcomes than the absence of such components [27]. Tumors with high-grade fatal adenocarcinoma component, which is a rare subtype, have also been reported to have poor outcomes [28]. Further studies are needed to evaluate the impacts of adenocarcinoma predominant and subtype components on outcomes.
Clinical trials are conducted to develop better treatment strategies. The TNM staging system is fundamental to deciding a patient’s treatment plans and predicting outcomes. However, when the TNM staging system is greatly updated, several problems may occur clinically. Especially, if it is difficult to interpret the results of past clinical trials using the new TNM staging system, serious problems might occur because the current standard therapy becomes unknown. In Japanese guidelines for lung cancer, adjuvant chemotherapy with UFT is standard treatment for pathological stage IB lung cancer. This is based on the results of clinical trials reported in the early 2000s. The staging system has been revised several times since these results were published. Of course, if new prognostic information becomes available or very effective new drugs are developed, standard therapy has to be updated. However, costly and laborious prospective clinical trials cannot be performed every time the staging system is updated. A retrospective analysis may be inferior to prospective trials in terms of the reliability and interpretation of the results because potential selection bias cannot be excluded. The propensity score-matching test is one effective statistical analysis technique that increases the accuracy of comparisons based on data gathered in the past [29]. By further developing statistical analysis techniques, more precise results are likely to be obtained from randomized control trials. It will be important to gather wider and more detailed information when clinical trials are performed.
Limitations
This was a retrospective study, and potential bias can occur, even when propensity score matching is performed. The most common reasons why patients did not receive adjuvant chemotherapy were the TNM update and the patients’ will. Before 2010, a small tumor size of ≤3.0 cm was staged as IA, regardless of pleural invasion status. In addition, adverse effects of UFT were the second reason to terminate treatment soon after it began, but there may be unclear reasons why many patients did not receive adjuvant therapy.