Salvage lung resection: if you’re not first, you’re last

Lung cancer remains the leading cause of cancer-related death in the US and worldwide, and is unsurprisingly associated with high rates of persistence, progression, and recurrence (1). Although a number of guidelines exist to inform the initial management of lung cancer, data to guide clinical decision making become scarce when considering salvage therapies (2,3). This is particularly true for salvage lung resection performed after initial non-operative treatment. For instance, a recent review of all published studies from 2000–2019 identified a total of only 200 patients treated via salvage lung resection after initially receiving definitive chemo-radiation for stage III non-small cell lung cancer (NSCLC) (4). These aggregate data demonstrated a longer recurrence free-survival for salvage surgery vs. average data for chemotherapy or radiotherapy in similar populations, implying a potential benefit for salvage lung resection.

Recently, Dunne and colleagues provided a valuable contribution to this literature (5). They described outcomes of a single-center, prospectively accrued, cohort of patient who underwent lung resection after initial non-operative treatment for NSCLC. These authors retrospectively identified 120 patients, over a 12-year period, with NSCLC and an initial plan for non-operative therapy who subsequently underwent lung resection. This group of patients fared remarkably well after surgery, both in the perioperative setting and long term, with a 3% 90-day mortality. The median age was 61 years old and the majority (69%) had a robust functional status [Eastern Cooperative Oncology Group (ECOG) 0] highlighting the importance of careful patient selection in this population. The authors also performed a multivariate analysis for overall survival, demonstrating dramatic increases in the hazard ratio for patients that previously received radiation therapy or had lymphovascular invasion on pathologic evaluation.

Major perioperative complications predominantly occurred in patients who received radiation treatment. Although not presented in the current study, recent data argue that this may be a modifiable risk factor. A review of salvage lobectomy after radiation from the National Cancer Database found a decreased overall survival when surgery was performed less than three months after radiation (6).

Importantly, an R0 resection was achieved in 88% of patients, commonly with a minimally invasive approach. The proportion of surgeries that were performed minimally invasively also increased over time. Just over half of patients experienced a recurrence at 3 years, with the majority being a distant recurrence. Unfortunately, data on re-staging procedures are not available and it is unclear if a standard imaging approach [computed tomography (CT), positron emission tomography (PET)-CT, and/or magnetic resonance imaging (MRI)] was used or if invasive mediastinal re-staging [endobronchial ultrasound (EBUS), endoscopic ultrasound (EUS), or mediastinoscopy] was performed to rule out contralateral mediastinal lymph node involvement prior to salvage surgery.

A strikingly large percentage of the cohort (45%) received targeted therapy and many continued to receive targeted therapy after resection. The duration of prior treatment could be of special importance in this population given the inevitable development of drug resistance. At the same time the interval between stopping treatment and resection may impact the difficulty of the operation. In one study of nine patients who underwent salvage surgery after targeted therapy, half of the patients initially planned for a minimally invasive approach required conversion to an open procedure due to bleeding. Importantly, median duration of targeted therapy was 6 months with the operation occurring between 5 and 14 days after last targeted therapy (7). Earlier resection (sooner after the initiation of treatment) also has the potential to achieve cytoreduction, reducing the “at-risk” population of malignant cells available to develop resistance.

In contrast to the large number of patients who received targeted therapy, only 17% of the patients in the study received immunotherapy. Interestingly, among the group of 19 patients who were classified as long-term survivors (patients with at least 5 years of follow-up and no known recurrence) a disproportionate number received immunotherapy (6/19 vs. 20/120). This observation raises several questions regarding the benefit of salvage lung resection for patients receiving immunotherapy. Certainly potential benefit will depend on accurate patient selection utilizing longitudinal clinical imaging. Unfortunately, it is not possible to perform additional subgroup analysis in this heterogeneous cohort but we will likely have more data in the future with the increasing utilization of immunotherapy.

The authors also compared the survival of patients with stage IV NSCLC treated with salvage lung resection to a convenience cohort treated with salvage radiation or chemotherapy enrolled at the same center. Although the patients that underwent salvage surgery demonstrated a significantly longer overall survival, this analysis is limited by selection bias, significant differences in baseline age and performance status, and a dramatically higher proportion of patients on targeted therapy.

While the mortality and morbidity were low, and minimally invasive approaches were often achieved, it would also be of interest to investigate the quality-of-life impact of surgery on these patients. These metrics were not tracked in the prospective database. Many of the patients also went on to receive additional therapy as well, which is a risk factor for prolonged opioid use after lung resection (8). One recent study with 19 patients who were initially unresectable and were subsequently operative after immunotherapy did track patient reported outcome measures, with cough reported most commonly, as well as shortness of breath, as bothersome symptoms 30 days after surgery, which did decrease by the one year mark from surgery (9). There is always room for improvement in the care of these complicated patients, and they certainly require extensive support services. A nursing-led continuity of care model with pre-treatment, online, telephone, and home visits was shown to improve both quality of life, adverse treatment reactions, and overall survival in a study group that looked at patients with NSCLC being treated with targeted therapy (10).

We congratulate Dunne and colleagues on this valuable contribution to the literature. These data expand our understanding of the safety of salvage lung resection for NSCLC. With increasing use and types of both immunotherapy and targeted therapies, we anticipate that more patients will be reconsidered for surgery after initial treatment. Further research which helps define both optimal duration of initial treatment and time between treatment cessation and resection may help improve efficacy and minimize risk.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Current Challenges in Thoracic Surgery. The article has undergone external peer review.

Peer Review File: Available at https://ccts.amegroups.com/article/view/10.21037/ccts-24-10/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://ccts.amegroups.com/article/view/10.21037/ccts-24-10/coif). C.M.K. received grant funding to institution, Intratumoral Therapy from Johnson and Johnson and received grants to study pulmonary nodules and perform tissue biopsies to grow lung cancer cells from National Institutes of Health. He is also the Chair of the External Advisory Board in Interventional Oncology of Johnson and Johnson. He serves as an unpaid Board of Directors of the American Association of Bronchology and Interventional Pulmonology. He performs research consulting for companies interested in intratumoral therapy for lung cancer (and owns a 5% equity share in QIS). The other author has no 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA Cancer J Clin 2022;72:7-33. [Crossref] [PubMed]
2. Ettinger DS, Wood DE, Aisner DL, et al. Non-Small Cell Lung Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2022;20:497-530. [Crossref] [PubMed]
3. Remon J, Soria JC, Peters S, et al. Early and locally advanced non-small-cell lung cancer: an update of the ESMO Clinical Practice Guidelines focusing on diagnosis, staging, systemic and local therapy. Ann Oncol 2021;32:1637-42. [Crossref] [PubMed]
4. Hamada A, Soh J, Mitsudomi T. Salvage surgery after definitive chemoradiotherapy for patients with non-small cell lung cancer. Transl Lung Cancer Res 2021;10:555-62. [Crossref] [PubMed]
5. Dunne EG, Fick CN, Tan KS, et al. Lung resection after initial nonoperative treatment for non-small cell lung cancer. J Thorac Cardiovasc Surg 2023; Epub ahead of print. [Crossref] [PubMed]
6. Afshari S, Anker CJ, Kooperkamp HZ, et al. Trends and Outcomes of Salvage Lobectomy for Early-stage Non-Small Cell Lung Cancer. Am J Clin Oncol 2023;46:271-5. [Crossref] [PubMed]
7. Song W, Di S, Liu J, et al. Salvage surgery for advanced non-small cell lung cancer after targeted therapy: A case series. Thorac Cancer 2020;11:1061-7. [Crossref] [PubMed]
8. Brescia AA, Harrington CA, Mazurek AA, et al. Factors Associated With New Persistent Opioid Usage After Lung Resection. Ann Thorac Surg 2019;107:363-8. [Crossref] [PubMed]
9. Mohamed S, Bertolaccini L, Casiraghi M, et al. Predictors, surrogate, and patient-reported outcomes in immunotherapy and salvage surgery for unresectable lung cancer: a single-center retrospective study. Updates Surg 2023;75:2355-63. [Crossref] [PubMed]
10. Min Y, Zhu Y, Ye M, et al. Life quality improvement of patients with non-small cell lung cancer undergoing targeted therapy: A case study of continuous care. Medicine (Baltimore) 2023;102:e35678. [Crossref] [PubMed]