The three-year OS of 61.5% with a median OS of 50 months from lung surgery after the TKI therapy for initially unresectable Stages III and IV NSCLC is encouraging. This value generally exceeded the two-year OS and a median OS of Stages III and IV, 7–55% and 6–29 months, respectively. 5, Apart from the effective TKI remedy, the contribution of lung resection should be highlighted to achieve this milestone.
Patients gain extraordinary responses to treatment with less toxicity with the development of molecular-targeted therapy. Therefore, the advanced NSCLC patients are expected to live longer with improved treatment options and maintained Eastern Cooperative Oncology Group (ECOG) status, particularly in oligometastatic NSCLC, as observed in our cohort. Oligometastasis is defined as five or fewer metastases and involves three or fewer organs and has a better prognosis than the general Stage IV cohort, with a five-year OS of 30% vs 0–10%.5,, Hence, oligometastatic NSCLC deserves aggressive treatment, including primary lung resection.
Gomez et al. demonstrated comprehensive local consolidation therapy (LCT) after systemic therapy in which local therapy applied to primary and metastatic lesions of NSCLC showed significantly longer PFS and OS than those of the maintenance therapy and observation groups: 14.2 vs 4.4 months and 41.2 vs 17.7 months, respectively. Mitchell et al. compared the LCT for primary lung lesions treated with surgery vs radiotherapy for oligometastatic NSCLC patients and observed superior five-year OS in the surgery group (48.0% vs 24.2%). Compared to radiation and ablation therapy, surgery has the following advantages: obtaining a valuable specimen for the complete assessment of tumor response to treatment, exploring the resistance mechanism, and evaluating actionable biomarkers to direct subsequent treatment, overcoming the issue of acquired resistance, reducing the amount of circulating tumor cells and tumor heterogeneity, and enhancing the subsequent systemic therapy effect.,
Evidence of lung surgery after TKI therapy is scarce, as shown by the limited number of patients reported in most published papers (Table 4):,,, the median PFS and OS values ranged from 10–15 and 17–68 months, respectively. Compared to previous studies, our median PFS was higher (17 months), whereas our median OS was within the range. Pulmonary resection after TKI therapy is technically challenging because of the dense-scarring tissue formed at the pleura and hilum as a sequela of the tissue reaction to the treatment. Consequently, extended operating hours and postoperative morbidity are anticipated. The complication and mortality rates observed in our study are compatible with reported VATS lobectomy (10.5 vs 10–20% and 0 vs 0–2%, respectively)., The favorable perioperative outcome was attributed to the good ECOG status, low toxicity profile of TKI, case selection, improvements in perioperative care, prevention of pneumonectomy, and minimally invasive surgery. Overall, lung surgery after TKI is feasible and safe with appropriate patient selection.
The National Health Insurance of Taiwan approved the prescription of osimertinib, a third-generation EGFR-TKI, as the treatment for acquired resistance to EGFR T790M mutation at the end of the study period in 2020. Before then, the T790M test was not widely performed. As only one patient in the cohort tested T790M-positive, we could not evaluate the benefit of surgery for the acquired resistance compared to the osimertinib treatment alone.
Several studies have shown that regressed disease is a better predictor for favorable OS and PFS than a stable disease., Although our study revealed that regressed disease had a better OS than regrowth disease, the disparity between regressed and regrowth diseases (89.5% and 10.5%, respectively) in a small study cohort made the comparison tenuous. Hence, a study with large cohorts is required to validate the findings.
Five patients with unresectable Stage III NSCLC at diagnosis received TKI as neoadjuvant therapy for a median duration of 2.5 months, followed by radical resection. All achieved R0 resection. The three-year OS showed superior results compared to the PACIFIC trial, in which a similar group of patients received durvalumab after a standard CCRT therapy (66.7% vs 56.7%). Wu et al. reported median and maximum time to response values of 1.7 and 3.9 months, respectively.29 Takeda et al. reported a median time to response of 1 month with most patients achieving complete response and a partial response within two months.30 We deduced that TKI is safe and effective for administration for 1–4 months as neoadjuvant before undergoing radical resection.
Evidence of TKI as adjuvant therapy is rare. Riely et al. advocated the continuation of TKI after failed TKI treatment, owing to some tumor cells remaining sensitive to EGFR inhibition. All these issues should be solved after complete resection, and logically, TKI should be discontinued. However, our study showed that TKI continuation after the lung surgery significantly prolonged PFS, compared to non-TKI adjuvant. It is believed that TKI works as cytostatic instead of cytotoxic, and it cannot eliminate micrometastatic cancer cells. Hence, the continuation of TKI after surgery helps control subclinical micrometastatic cancer cells. The ADAURA trial studied on osimertinib as adjuvant therapy for resectable Stages IB–IIIA EGFR-mutant NSCLC showed a significantly longer two-year disease-free survival than with placebo (90% vs 44%). These results enlightened the role of TKI as adjuvant therapy, and further research is justified.
The limitations of this study include: retrospective investigation from a single center, single arm, small sample size, short follow-up, highly selected patients, and heterogeneity of patients’ characteristics and clinical course. All Stage IV patients were clinically downstaged to M0 before surgery. All regrowth tumors exhibited solitary progression. Only those with a favorable response to TKI treatment were recruited, and those with an inadequate response were excluded. All these lead to a better prognosis. A prospective study with a larger sample size and a nonsurgical control group for comparison is required to validate the role of lung surgery in this context.
Lung surgery for initially unresectable NSCLC after TKI therapy is feasible, safe, helps to solve the issue of acquired resistance, and prolongs survival by local control and directed consequential treatment through the analyzed surgical specimen. Surgery should be considered a part of multimodality treatment, particularly for patients with an excellent response to TKI treatment.