Role of adjuvant treatment in stage IB non-small cell lung carcinoma

We thank Lee and Hsu for showing interest in our study, and raising the limited role of adjuvant chemotherapy in stage IB non-small cell lung cancer (NSCLC) (1).

The effectiveness of adjuvant cytotoxic chemotherapy in patients with completely resected stage IB NSCLC has been controversial in previous studies (2,3). The National Comprehensive Cancer Network guidelines suggest an optional strategy for adjuvant chemotherapy in patients with stage IB NSCLC who have high-risk factors, such as moderate to poorly differentiated neuroendocrine tumors, vascular invasion, wedge resection, visceral pleural involvement, and unknown lymph node status (4). However, most of the evidence underlying the recommendation included retrospective studies in which the stage was defined by the Tumor, Node, and Metastasis (TNM) Atlas, 7^th edition.

The pathologic stage of the present study, the APICAL trial (5), was based on the TNM 7^th edition. As the T2a classification (3–5 cm, IB TNM 7^th edition) was revised to T2a (3–4 cm, IB) and T2b (4–5 cm, IIA) in the TNM 8^th edition (6). Accordingly, some of the stage IB tumors in the present study can be translated into stage IIA of the TNM 8^th edition. The present study was a phase II trial that had no control arm comparable to adjuvant chemotherapy. The prediction of adjuvant chemotherapy’s effectiveness in the stage IB population was limited. However, to date, adjuvant chemotherapy is a perioperative treatment with an overall survival (OS) benefit in completely resected NSCLC, even if the efficacy is modest (7). Given that a prospective study involving the overall population of stage IB NSCLC is unlikely to materialize in the immediate future, a trial involving patients who would benefit from and the exclusion of patients who could be harmed by adjuvant chemotherapy is warranted.

A recent retrospective study by Choi et al. demonstrated that adjuvant chemotherapy had benefits in recurrence-free survival (RFS) and OS for high-risk patients with stage IB (<4 cm) tumors as defined by TNM 8^th edition (8). The authors highlighted that adjuvant chemotherapy may be useful for patients with visceral pleural involvement, even if the tumor size is less than 3 cm. However, the effectiveness of adjuvant chemotherapy in this population must be validated in a prospective trial, and safety profiles should be considered for patients with high-risk factors.

As mentioned in the present study (5), adjuvant chemotherapy in patients with resected early-stage NSCLC harboring an epidermal growth factor receptor (EGFR) mutation was not effective. Several randomized clinical trials (RCTs) of adjuvant EGFR tyrosine kinase inhibitors (TKIs), such as ADJUVANT/CTONG1104 (9), IMPACT (10), EVAN (11), and EVIDENCE (12), involved patients with completely resected stages II to IIIA EGFR-mutated NSCLC randomly assigned to first-generation EGFR-TKIs or standard platinum doublet chemotherapy (vinorelbine plus cisplatin). The additive effect of adjuvant chemotherapy upon adjuvant EGFR-TKIs could not be investigated, even in patients with stage IB cancer.

The ADAURA trial was designed to compare adjuvant osimertinib versus placebo in patients with resected stage IB to IIIA NSCLC, and 60% of enrolled patients received adjuvant chemotherapy before osimertinib or placebo (13). In the ADAURA trial, higher disease recurrence rates and shorter disease-free survival (DFS) times were observed in patients with stage IB cancer with osimertinib or placebo who received antecedent adjuvant chemotherapy compared to those without adjuvant chemotherapy. The significant differences in DFS between osimertinib and placebo were consistent in patients with stage II and IIIA cancer, regardless of receiving adjuvant chemotherapy (14). The ADAURA trial was not randomized or stratified by the use of adjuvant chemotherapy and applied TNM 7^th edition guidelines at the time of randomization. Adjuvant chemotherapy in stage IB EGFR-mutated NSCLC is discouraged, even though it was used less often in patients in stage IB than those in stages II to IIIA (26% versus 71–80%).

Adjuvant immune checkpoint inhibitors (ICIs) are promising strategies to improve the survival of patients with resected early-stage NSCLC. The IMpower010 trial showed a DFS benefit with atezolizumab versus best supportive care (BSC) after the mandatory adjuvant chemotherapy in patients with resected stage II–IIIA NSCLC (15). The hazard ratio (HR) for DFS in stage IB was not described in the report. The DFS benefit was consistent in the randomized intention-to-treat (ITT) population, including stage IB patients [HR 0.81, 95% confidence interval (CI): 0.67–0.99], even if the effect was modest.

In the PEARLS/KEYNOTE-091 trial, adjuvant pembrolizumab treatment significantly improved DFS compared with placebo in patients with completely resected stage IB–IIIA (≥4 cm, T2b in TNM 8^th edition) NSCLC (16). In the PEARLS/KEYNOTE-091 trial, antecedent adjuvant chemotherapy was not mandatory, and 14% of enrolled patients did not receive this treatment. In a subgroup analysis, the DFS benefit of pembrolizumab was not significant in stage IB patients (HR 0.74, 95% CI: 0.47–1.37). However, the stage IB population was relatively small (14%). It is unclear whether the diminished efficacy of adjuvant ICI treatment in patients in stage IB originated from ineffective adjuvant chemotherapy or ICI. Among the overall population, the subgroup who received adjuvant chemotherapy demonstrated a significant DFS benefit to pembrolizumab, while those without adjuvant chemotherapy did not show any difference. Therefore, even if the effect was modest in stage IB NSCLC, adjuvant ICI treatment following chemotherapy may be considered in selected patients in stage IB NSCLC given the synergistic effects of cytotoxic chemotherapy and immunotherapy.

The detection of minimal residual disease (MRD) reflects the presence of tumor cells in a patient after definitive treatment and a lack of any clinical and radiological signs of recurrence or metastasis (17). MRD has been applied to develop a biomarker for the use of postoperative adjuvant treatment. In the exploratory analysis of IMpower010, the circulating tumor DNA (ctDNA) levels of 600 patients were analyzed after surgery but before adjuvant chemotherapy. ctDNA was positive in 9% for stage IB to 29% for stage IIIA (18). ctDNA-positive patients with stage II–IIIA showed a worse prognosis than ctDNA-negative patients, and improved DFS with atezolizumab versus BSC was seen in both groups. Approximately 62% of postoperative ctDNA-positive patients were cleared at the post-chemotherapy state, which was associated with improved DFS (19). Furthermore, atezolizumab treatment improved DFS regardless of ctDNA clearance post-chemotherapy and maintained ctDNA levels in a longitudinal assessment. Although the survival outcome of resected stage IB NSCLC according to the presence of ctDNA was not reported, ctDNA detection after surgery may be a biomarker utilized in the decision to perform adjuvant chemotherapy.

In summary, although most of the RCTs and prospective studies were conducted based on the TNM 7^th edition, adjuvant chemotherapy showed survival benefits in selected patients with resected stage IB NSCLC, excluding EGFR-mutated NSCLC. However, the potentially harmful effects of chemotherapy should be considered in older patients, those with multiple comorbidities, or individuals exhibiting poor performance. It is reasonable to select or exclude patients with risk factors considering tumor size, histologic type, driver mutations, visceral pleural involvement, and ctDNA status, if possible. Adjuvant chemotherapy’s effectiveness in patients in stage IB defined by TNM 8^th edition, including a tumor size less than 4 cm, should be verified in a larger prospective trial. Lastly, most of the primary endpoints in previously mentioned RCTs were DFS or RFS, not OS. The utility of adjuvant chemotherapy in the stage IB population can be determined after confirmation of the OS.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Lung Cancer Research. The article did not undergo external peer review.

Conflicts of Interest: The authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2023-1/coif). All authors report that they received honoraria for presentations from AstraZeneca, Yuhan, Boehringer Ingelheim, MSD, Takeda, Ono BMS, Amgen, Novartis, Johnson and Johnson, and Pfizer. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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