Redefining the role of surgery in advanced lung cancer: a new paradigm of adjuvant lung surgery to systemic therapy

Lung cancer remains the leading cause of cancer-related mortality globally, with advanced-stage disease historically associated with poor outcomes (1). Traditionally, surgery was limited to early-stage, resectable tumors as the only curative-intent surgical option, whereas advanced cases are typically classified as unresectable. However, breakthroughs in lung cancer treatment, including targeted therapy, immunotherapy, and the introduction of antibody-drug conjugates (ADCs), have fundamentally altered the therapeutic landscape, significantly improving patient survival rates. Under the frameworks of adaptive medicine, the treatment of advanced lung cancer no longer relies on a single modality but rather combines systemic and local therapies to achieve better therapeutic outcomes, with the goal of prolonging survival and improving quality of life (2,3).

Based on this, we propose the concept of adjuvant lung surgery, as a paradigm shift for advanced lung cancer. Unlike conventional surgery targeting resectable early-stage tumors, adjuvant lung surgery is specifically designed for patients with initially unresectable advanced disease (e.g., stage IIIb/IV) who demonstrate tumor response or stable disease after systemic therapy. This approach prioritizes systemic therapy as the cornerstone, with surgery serving as a precision adjunct to address residual lesions that may harbor resistant clones or molecular heterogeneity. And adjuvant lung surgery is a broad framework that includes multiple surgical strategies such as local tumor resection, metastasectomy to reduce burden, or en-bloc biopsy for genomic profiling. Especially with the advancements in minimally invasive techniques, such as video-assisted thoracoscopic surgery (VATS) and tubeless surgery, the integration of adjuvant lung surgery with systemic therapies offers the potential to optimize treatment outcomes, prolong survival, and enhance quality of life. We herein present the background and clinical significance of adjuvant lung surgery to systemic therapy, analyze its challenges, and provide insights into its future development.

In recent years, significant progress has been made in the treatment of advanced lung cancer. For non-small cell lung cancer (NSCLC), a deeper understanding of its molecular biology, combined with advances in new drugs and technologies, has made systemic therapy more precise and effective (4,5). In the treatment of small cell lung cancer (SCLC), despite its historical reputation as difficult to cure, breakthroughs in genomics and transcriptomics have opened up new therapeutic avenues and provided directions for optimizing treatment strategies (6). With continuous advancements in treatment technologies and diagnostic methods, more advanced-stage patients are achieving long-term survival. Treatment goals have gradually shifted from merely extending life to improving quality of life and achieving effective long-term survival management (4,7).

Historically, surgery was primarily used for curative interventions in non-metastatic lung cancer patients, with advanced lung cancer considered largely incurable. However, with the progress of systemic therapies, many patients previously deemed inoperable (such as those with stage IIIb disease) are now considered for surgical intervention following favorable systemic therapy (8,9). Simultaneously, the rapid development of minimally invasive techniques, particularly the maturation of VATS in thoracic surgery, has significantly reduced surgical trauma and postoperative complications, providing patients with faster recovery opportunities (10,11). The emergence of tubeless surgery further advances the concept of minimal invasion (12). Tubeless surgery emphasizes maintaining spontaneous breathing during surgery, avoiding the use of traditional endotracheal intubation and chest drainage. A study has shown its significant advantages in reducing trauma and accelerating postoperative recovery (13). Single-port tubeless surgery is an exemplary model of this concept, allowing surgery through a single small incision, further reducing both physiological and psychological burdens on the patient (14). These technological advances have created new opportunities for the effective combination of surgery as a local treatment with systemic therapy, offering more possibilities for the treatment of advanced lung cancer.

As an innovative treatment paradigm, adjuvant lung surgery is redefining the role of surgery in stage IV/IIIb lung cancer in some cases. Its core concept lies in utilizing surgery as an adjunct to systemic therapy, enhancing overall treatment efficacy through local intervention (15). For example, VATS-based en-bloc biopsy is a typical application of adjuvant lung surgery to systemic therapy, aiming to resect the tumor via minimally invasive surgery to obtain high-quality tissue samples for genetic testing while reducing tumor burden. An ongoing study from our center has shown that en-bloc biopsy not only significantly improves the success rate of genetic testing but also provides high-quality tissue samples for precision treatment, enhancing the effect of systemic therapy. Removal of tumor heterogeneity and cancer stem cell (CSC) properties is a critical aspect of adjuvant lung surgery. Tumor heterogeneity refers to the genetic and phenotypic diversity within a tumor, which can lead to treatment resistance and disease progression. CSCs are a subpopulation of tumor cells with self-renewal and differentiation capabilities, playing a key role in tumor initiation, metastasis, and recurrence. By integrating adjuvant lung surgery with systemic therapies, surgical interventions can target and reduce tumor heterogeneity, thereby diminishing the CSC population and enhancing treatment efficacy. Furthermore, the median overall survival (OS) of the en-bloc biopsy group was significantly higher than that of the traditional biopsy group, particularly in patients receiving targeted therapy, where survival benefits were even more pronounced. These results suggest that en-bloc biopsy not only optimizes the local treatment effect but also enhances the precision of systemic therapy by providing reliable genetic testing results, thereby significantly prolonging patient survival.

It is important to note that en-bloc biopsy is just one application scenario for adjuvant lung surgery. As a novel treatment paradigm, adjuvant lung surgery’s core idea is to use surgery as an adjunct to systemic therapy rather than a curative intervention, aiming to further optimize overall treatment outcomes through local surgery [reach complete response (CR)]. Beyond en-bloc biopsy, adjuvant lung surgery includes various other surgical forms, such as local tumor resection, metastatic site resection, and palliative surgery, all of which may play important roles in different clinical settings. For instance, in patients with oligometastatic lung cancer, combining local tumor resection with systemic therapy has been shown to significantly extend progression-free survival (PFS) and OS (15-17). The success of en-bloc biopsy provides important technical support and theoretical basis for adjuvant lung surgery, but its application should not be limited to the biopsy field. Future research should further explore the applicability and potential benefits of adjuvant lung surgery in different clinical contexts, including but not limited to oligometastatic lung cancer, locally advanced lung cancer, and specific genetic mutation patient populations. Through multidisciplinary collaboration and technological innovation, adjuvant lung surgery holds the potential to bring hope for treatment to more lung cancer patients.

We propose the adjuvant lung surgery concept for the first time, emphasizing the importance of a multidisciplinary team (MDT) and promoting the synergistic effects of multimodal treatment, ensuring effective integration of local and systemic therapies. Surgery, as an adjunct to systemic therapy, reduces tumor burden through resection, while systemic therapies can eliminate micrometastases. The interaction between these two approaches significantly enhances treatment effects, providing patients with more opportunities for survival prolongation and quality of life improvement. It should be noted that adjuvant lung surgery is not applicable to all advanced lung cancer patients. A retrospective study has shown that primary tumor resection can be effective for certain metastatic NSCLC patients, with potential benefits closely related to individual patient characteristics (18). Future studies should prioritize prospective multicenter trials to validate the efficacy, safety, and optimal timing of adjuvant lung surgery. While adjuvant lung surgery holds transformative potential, like any other surgical intervention, it carries inherent risks. Its success depends on meticulous patient selection and strict adherence to well-defined criteria that balance therapeutic benefits with the minimization of morbidity.

As minimally invasive technologies continue to advance, the use of robotic surgery and metaverse-based precision localization techniques may further improve the safety and efficacy of adjuvant lung surgery. The application of liquid biopsy or volatile organic compound (VOC) breath metabolomics technologies may help monitor tumor dynamics in real-time, enabling timely adjustments to treatment plans (19). Global collaboration and data sharing will promote the widespread application of adjuvant lung surgery, offering better treatment options for patients worldwide.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article has undergone external peer review.

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-232/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-232/coif). The authors have no conflicts of interest to declare.

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