Lung cancer is by far the leading cause of cancer-related death (1). Complete surgical resection of the tumor provides a hope for a cure for those patients with resectable disease (2). However, post-operative recurrence poses a main problem of the treatment (3). Therefore, identifying populations who may benefit from additional treatment after surgery may improve the clinical outcomes in those patients with resectable lung cancer.

Several randomized clinical trials reported the efficacy of adjuvant chemotherapy following surgery in patients with resectable lung cancer (4–8). The pooled analysis of 5 trials of cisplatin-based adjuvant chemotherapy revealed benefit of adjuvant chemotherapy in completely resected lung cancer patients at an overall hazard ratio (HR) of 0.89 (95% CI, 0.82-0.96; p=0.005). In further subgroup analysis, the benefit is restricted to patients with stage II or IIIA disease. There was no significant improvement of survival in patients with stage IB or IA lung cancer (9). Another study, Cancer and Leukemia Group B (CALGB) 9633, a randomized controlled trial, was designed to solve the unmet need. Patients enrolled had pathologically confirmed T2N0 (according to the International System for Staging Lung Cancer edition in 1997) (10) non-small-cell lung carcinoma (NSCLC) undergoing complete surgical resection. The study showed a significant survival benefit of adjuvant chemotherapy for patients with tumors 4 cm or larger in diameter (HR, 0.69; 95% CI, 0.48- 0.99; p=0.043) (11).

Tumors larger than 4 cm, but 5 cm or less in size without lymph node metastasis are now classified as T2bN0 stage IIA lung cancer, according to AJCC staging system 8^th edition (12). Their benefits of adjuvant chemotherapy are mentioned above (11). On the other hand, for patients with T2aN0 stage IB lung cancer, benefits of adjuvant chemotherapy remain unclear. Though several studies advocated the benefit of adjuvant chemotherapy for patients with stage IB lung cancer (8, 11, 13–16). the cancer staging was based on the 5th, 6th, or 7th international staging criteria (10, 17). Furthermore, prior randomized controlled trials enrolled NSCLC patients and did not subdivide them according to histology types. Nevertheless, there is increasing evidence that different histology types (lung adenocarcinoma vs. non-adenocarcinoma) presented with different clinical outcomes (18, 19). A meta-analysis partially answered the above-mentioned questions. The author pooled the studies regarding the impact of adjuvant chemotherapy in stage IB NSCLC in the context of the 8th TNM staging system. Subgroup analysis by histology indicated that adjuvant chemotherapy conferred more favorable survival to both squamous cell carcinoma and adenocarcinoma. However, the eligible studies were retrospective and with population heterogeneity, and subgroup analysis according to tumor size (e.g., tumor <=3 cm vs. tumor >3 but <=4 cm) was not performed (20). Apart from tumor size, other high-risk histopathologic features (e.g., tumor differentiation, vascular invasion, visceral pleural involvement) and surgical factors (e.g., sublobar resection, unknown lymph node status) are presumably indications for adjuvant chemotherapy (21). Little evidence is available to support these indications. Here, we conducted a retrospective cohort study on a nationwide population database in Taiwan, aiming to determine benefits of adjuvant chemotherapy for patients with completely resected T2aN0 stage IB lung adenocarcinoma.

In this study, we found that the benefit of adjuvant chemotherapy was associated with tumor size amongst patients with T2aN0 stage IB lung adenocarcinoma. Adjuvant chemotherapy improved survival for those with tumors larger than 3 cm, but 4 cm or less in size. For patients with tumors 3 cm or less with VPI, adjuvant chemotherapy had no survival benefit.

Tumor size is a topic of research in predicting the benefit for resectable lung cancer patients treated with adjuvant chemotherapy. For tumors larger than 4 cm, a survival advantage has been reported in association with adjuvant chemotherapy (11, 19, 25). Therefore, we focused our study on tumors 4 cm or less without nodal involvement and found the benefit of adjuvant chemotherapy was dependent on tumor size only.

For tumors 3 cm or less with VPI, we found no survival benefit with adjuvant chemotherapy. In a previous study using the Surveillance, Epidemiology and End Results (SEER) database, adjuvant chemotherapy does not improve survival in patients with tumors 4 cm or less with VPI. However, that study did not perform exploratory analysis focusing on tumors 3 cm or less (19). Pathak et al. conducted a cohort study using data from the National Cancer Database (NCDB) of the United States to assess the association between adjuvant chemotherapy and survival in patients with node-negative early-stage NSCLC. In subgroup analysis in 2,813 patients with tumors 3 cm or less with VPI, only 297 (10.6%) had received adjuvant chemotherapy. Adjuvant chemotherapy is not associated with a survival benefit in the population (HR, 0.90; 95% CI, 0.72-1.14; p=0.38) (25). Another study using NCDB evaluated the role of adjuvant chemotherapy in patients with tumors 4 cm or less with VPI. In subgroup analysis, 6,785 patients with tumors 3 cm or less with VPI and 608 (9.0%) of them received adjuvant chemotherapy. Adjuvant chemotherapy does not provide overall survival benefit (26). Our findings are consistent with prior studies that adjuvant chemotherapy is not associated with survival benefit for tumors 3 cm or less with VPI. Compared with prior research on patients with a low adjuvant chemotherapy rate, our present study had the highest proportion (39.1%) receiving adjuvant chemotherapy for patients with tumors 3 cm or less with VPI.

For patients with tumors larger than 3 cm, but 4 cm or less in size, we found that adjuvant chemotherapy had improved their OS and CSS even in the absence of risk factors. In a cohort study based on NCDB, patients with tumors larger than 3 to 7 cm were analyzed to evaluate the role of adjuvant chemotherapy. In subgroup analysis, there were 10,587 patients with tumors >3 cm, but <=4 cm and 1,608 (15.2%) of whom had received adjuvant chemotherapy. Adjuvant chemotherapy is associated with improved OS in the population with a hazard ratio of 0.75 (95% CI, 0.70-0.86; P <0.0001) (27). In aforementioned Pathak’s study, 7,501 patients with tumors >3 cm, but <=4 cm were analyzed, and 896 (11.95%) of them had received adjuvant chemotherapy. In that population, adjuvant chemotherapy is not associated with an increase in OS (HR, 0.90; 95% CI, 0.78-1.03; p=0.21). On the other hand, adjuvant chemotherapy provides benefit only amongst patients who had received sublobar resection (HR, 0.72; 95% CI, 0.56-0.93; p=0.004) (25). In the present study, adjuvant chemotherapy was administered to 68.8% of patients with tumors >3 cm, but <=4 cm. Survival advantages in both OS and CSS were found in these patients regardless of the presence of risk factors. The difference in results across these studies may be related to differences in the studied population, chemotherapy regimen, and proportion of patients receiving adjuvant chemotherapy. Furthermore, performance status and smoking habits were not captured in the NCDB. The decision to offer adjuvant chemotherapy and survivals may be influenced by these factors. In contrast, these factors above were comprehensively recorded in the National Taiwan Cancer Registry database. Besides, CSS was unable to be evaluated in the NCDB, whereas the survival information was available in our database. With regard to the time to initiate adjuvant chemotherapy, we recommended starting adjuvant chemotherapy within 8 weeks following surgery according to prior randomized controlled trials (5, 7, 11).

The demographic characteristics of early lung cancer in Taiwan differ from that in non-Asian countries (28, 29). In our cohort, there were more female and non-smoking patients. Besides, the prevalence of EGFR mutation in lung cancer patients in Taiwan is higher than that in the western population (30). For patients with EGFR-mutant lung cancer experienced better response to EGFR-TKI or chemotherapy as compared to those with EGFR wild-type one if the patients suffered from disease recurrence into advanced stage (31–34), this may partly explain the discrepancy in results between our research and prior studies. Worldwide, the 5-year survival in pathologic stage IB is 73% (35), however they were 91.1% and 77.9% even in group 1 and group 2 stage IB without adjuvant chemotherapy in our study. Furthermore, according to the results from ADAURA trial, osimertinib is now standard-of-care therapy for stage IB EGFR-mutant lung cancer (36). This will make major improvement in survivals for stage IB EGFR-mutant lung cancer patients in the near future. As lung cancer is a highly heterogeneous disease, the treatment should be personalized and genetic testing could be encouraged for patients with stage IB lung adenocarcinoma. Further studies to clarify the role of driver gene mutations, immune status, and other novel treatments in adjuvant therapy following surgical resection for stage IB lung adenocarcinoma may be warranted.

There are some limitations of our study. First, it was a retrospective study. Second, the status of lymphovascular invasion, proposed as a high-risk histopathologic feature, was not recorded in the National Taiwan Cancer Registry. Third, the detailed information on adjuvant chemotherapy regimens was not collected in our cancer registry database. The regimen type, dose, and duration may influence treatment outcomes. Fourth, the treatment strategies could differ across health care institutions. Amongst patients treated in regional hospitals, the chemotherapy rates were similar between those with tumors >3 cm, but <=4 cm and those with tumors 3 cm or less (51.0% vs. 49.2%). On the other hand, in medical centers, patients with tumors >3 cm, but <=4 cm more likely to have received adjuvant chemotherapy as compared with those having tumors 3 cm or less (74.1% vs 36.7%). The inconsistency of treatment strategies across health care institutions may have introduced selection bias for adjuvant chemotherapy.

In conclusion, for patients with T2aN0 stage IB lung adenocarcinoma, the benefit of adjuvant chemotherapy depended on tumor size. Adjuvant chemotherapy within 8 weeks following surgery improved survival in those with tumors larger than 3 cm, but 4 cm or less in size. For patients with tumors 3 cm or less with VPI, adjuvant chemotherapy had no survival benefit.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

This study was approved by the Research Ethics Committee of the National Taiwan University (NTU-REC No.202101HM030), with waiver of informed consent owing to the lack of personal information and use of secondary data in the study. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for observational studies was used in the revision of this article. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

Study concepts: P-HL, G-CC; Study design: C-JC, G-CC, Y-HH, J-ST; Data acquisition: C-JC, Y-HH, K-CC, K-HH; Quality control of data and algorithms: P-HL; Data analysis and interpretation: C-JC, P-HL, Z-RZ, C-HC; Statistical analysis: C-JC, W-CL; Manuscript preparation: P-HL; Manuscript editing: J-ST, T-WL; Manuscript review: G-CC, T-YY, J-YH. All authors contributed to the article and approved the submitted version.