Current status of surgical treatment for lung cancer oligometastases

Introduction

In 1995, Hellman et al. proposed the concept of oligometastases (1). This refers to an advanced stage of cancer with a limited number of metastatic lesions. It represents an intermediate disease state between locally advanced cancer and widespread systemic metastasis and includes a group of cases that can potentially be cured. Based on this concept, a multidisciplinary treatment strategy combining systemic and local therapies has been explored. Radiotherapy is the primary modality for local treatment of oligometastases. In addition to pursuing curative outcomes, radiotherapy is highly significant from the perspective of complementing and synergizing with systemic therapies. In Japan, stereotactic body radiotherapy (SBRT) for oligometastases has been covered by health insurance since April 2020.

However, reports on the efficacy and validity of surgical treatment for oligometastases are limited. Except for certain metastatic organs, the resection of distant metastases in lung cancer has been considered a deviation from the standard treatment. However, in clinical practice, surgical treatment is prioritized over local therapy, such as wedge resection of isolated pulmonary metastases in patients with interstitial pneumonia after lung cancer surgery. The treatment of oligometastases can be systematized by the elucidating the indications for surgical treatment. This article introduces the current evidence and consensus on lung cancer oligometastases and provides an overview of the effectiveness and prospects of surgical treatment.

Reasons why oligometastases are currently receiving attention

Since the concept of oligometastases was first proposed in 1995, research on oligometastases declined from the late 1990s to the early 2000s. This was partly because both the systemic and local treatments were still in their developmental stages and were not sufficiently effective. In other words, the groundwork for accepting treatment strategies that pursue curative intent for advanced cancer had not yet been established. However, in 2006, Niibe et al. reported the outcomes of radiotherapy for isolated para-aortic lymph node recurrence after curative treatment of cervical cancer (2). The concept of oligo-recurrence (oligometastases with primary control) proposed by Niibe was a pioneering idea on the global stage (2-4). Since the beginning of 2010, the development of treatments for lung cancer oligometastases began to advance, particularly in North America and Europe.

In a randomized phase II trial reported by Gomez et al. in 2016, the additional effects of maintenance drug therapy and local treatment (resection or radiotherapy) were compared in patients with non-small cell lung cancer (NSCLC) who had three or fewer metastatic lesions and no disease progression for 3 months following initial chemotherapy (5). The interim analysis of 49 randomized patients revealed that progression-free survival (PFS) was significantly prolonged in the local treatment group, with a hazard ratio of 0.35 (11.9 vs. 3.9 months, 90% confidence interval: 0.18–0.66, P=0.006). According to long-term follow-up reports, the median overall survival (OS) was 41.2 months in the local treatment group, showing a favorable trend compared with 17.0 months in the maintenance therapy group. In addition, adverse events were similar between the two groups (6).

In a single-institution randomized phase II trial reported by Iyengar et al. in 2018, patients with NSCLC who had stable disease after four to six cycles of platinum-based chemotherapy, lacked epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) fusion genes, and had up to five metastatic lesions (with no more than three lesions in the lungs or liver) were included (7). The study compared the effects of maintenance drug therapy alone versus the addition of SBRT. In an interim analysis of 29 enrolled patients, PFS was significantly prolonged in the local treatment group, with a hazard ratio of 0.30 (9.7 vs. 3.5 months, 95% confidence interval: 0.11–0.82, P=0.01).

In a randomized phase II trial targeting solid tumors (SABR-COMET trial), the additional effect of SBRT was compared to maintenance therapy in patients with up to five metastatic lesions, including the primary tumor, who had their disease controlled for more than 3 months with drug therapy (8). Among the participants, 18% had NSCLC. The results from 99 randomized patients demonstrated that OS was significantly prolonged, with a hazard ratio of 0.57 (41 vs. 28 months, 95% confidence interval: 0.30–1.10, P=0.009). However, grade 2 or higher adverse events occurred in 19 patients (29%) in the SBRT group and 3 patients (9%) in the maintenance therapy group. In addition, treatment-related deaths were observed in three patients (4.5%) in the SBRT group, whereas no such deaths were reported in the maintenance therapy group (9).

For synchronous oligometastatic disease, in which stable disease has been achieved with drug therapy, the results of randomized controlled trials suggest that the addition of local therapy can potentially extend patient prognosis. As of August 2024, several phase III trials targeting oligometastases in lung cancer are underway. Although no reports have been published yet, Iyengar et al. presented findings at the 2024 American Society of Clinical Oncology (ASCO) annual meeting from a randomized phase II/III trial comparing maintenance therapy alone versus local consolidation therapy plus maintenance therapy for oligometastatic NSCLC (NRG-LU002) (10). Intermittently, the phase II portion of the trial revealed no differences in PFS between the two groups, leading to the closure of the study to further accrual. The primary reasons for this outcome likely include the heterogeneous population in the study, such as genuine oligometastatic cases with fewer initial metastatic sites and induced oligometastatic cases, where systemic therapy initially induced an oligometastatic state but started with diffuse metastasis.

Currently, targeted next-generation sequencing testing for cancer is being conducted as part of routine clinical practice, and multiple molecular targeted therapies and immune checkpoint inhibitors are being used. The advent of effective drug therapies and the introduction of precision medicine have improved the outcomes of systemic treatment for patients with advanced NSCLC compared with the time when the aforementioned clinical trials were conducted. However, only a subset of patients has been managed to avoid recurrence or progression. When systemic therapy fails to control micrometastases, or when systemic therapy alone can achieve a cure, the significance of local therapy is limited. However, the current state of systemic treatment has room for improvement, making it suitable to evaluate the survival benefits of local therapies for oligometastases. The attention paid to oligometastases across different cancer types in recent years can be attributed to advancements in diagnostic techniques, improvements in systemic treatments, and the widespread use of high-precision radiotherapy and minimally invasive surgeries. In addition, increased awareness of the state of oligometastatic disease, driven by clinical trials and several other reports, has contributed to this focus.

Lung cancer oligometastases and consensus

In previous clinical trials on lung cancer oligometastases, the definition of oligometastases varied across studies, making it challenging to compare and interpret the results. To address this issue, several consensus guidelines have been reported, primarily by North American and European radiotherapy groups, to establish standardized definitions, diagnoses, and classifications of oligometastases. In 2019, the European Organisation for Research and Treatment of Cancer (EORTC) Lung Cancer Group proposed a consensus useful for standardizing eligibility criteria in clinical trials and comparing clinical trial data (11). According to this consensus, synchronous oligometastatic NSCLC is defined as having up to five metastases in a maximum of three organs, all of which can be treated with local therapy.

In 2020, the European Society for Radiotherapy and Oncology (ESTRO) and EORTC consensus introduced a decision tree that uses five questions to classify oligometastatic disease into nine different categories based on factors such as the presence or absence of polymetastatic disease, whether the primary tumor was diagnosed within 6 months, whether systemic therapy was ongoing at the time of oligometastatic disease diagnosis, and whether there were progressing lesions during systemic therapy (Figure 1) (12). This decision tree facilitates the development of treatments specific to each disease state and is also valuable for the efficient conduct of clinical trials.

Figure 1 Decision tree for classification of oligometastatic diseases from the ESTRO/EORTC consensus (Guckenberger et al. 2020, Lancet Oncol) (12). OM, oligometastases; OR, oligo-recurrence; OPR, oligoprogression; OPE, oligopersistence; ESTRO, European Society for Radiotherapy and Oncology; EORTC, European Organisation for Research and Treatment of Cancer.

In the same year, the ESTRO and the American Society for Radiation Oncology (ASTRO) produced a consensus on the definition of oligometastatic disease to ensure that all metastatic lesions can be safely treated. Furthermore, the 2021 edition of the Lung Cancer Clinical Practice Guidelines includes a section on oligometastatic disease, recommending that local therapy should be considered for patients with stage IV NSCLC who have a limited number of synchronous oligometastatic lesions and whose disease is stable with drug therapy (13).

Is surgical resection effective for lung cancer oligometastases?

In the consensus and clinical practice guidelines, curative local treatment generally refers to metastases-directed radiotherapy with a primary focus on radiotherapy. Among the randomized phase II trials mentioned earlier, the only study that allowed surgical treatment was by Gomez et al. However, even in this study, only 28% of the cases involved surgery. The criteria for selecting between radiotherapy and surgery as the preferred local therapy have not yet been clearly defined. Even in ongoing randomized phase III trials of oligometastases, a few studies have considered surgical treatment as a local therapeutic option. However, this does not imply that the surgical treatment of oligometastases should be avoided. In contrast, reports on the surgical treatment of lung cancer oligometastases are increasing. Table 1 presents recent retrospective studies on the surgical treatment of synchronous oligometastases (14-21).

Opitz et al. conducted a study of 124 patients with advanced NSCLC who had five or fewer metastatic lesions.14 The results demonstrated that systemic therapy was administered to 82% of patients, and metastasectomy (surgical removal of metastases) was performed in 72% of cases. The 5-year OS rate was 36% for the entire cohort. In addition, factors associated with poor prognosis included age ≥60 years, lymph node metastasis, and bone metastasis. In a multicenter study by Spaggiari et al. in 2021, 281 patients with NSCLC and five or fewer metastatic lesions were included.17 Among these, 61% underwent metastasectomy, and the median OS for the entire group was 40 months. Furthermore, the study found that patients aged <65 years, those with a single metastasis, and those with contralateral lung metastases had better prognoses. Joosten et al. reported 28 patients with NSCLC who exhibited oligoprogression after systemic drug therapy (21). Among these 28 patients, 12 underwent primary tumor resection, and 16 underwent metastasectomy. The median PFS after resection was 7 months.

When considering the indications for surgical treatment of lung cancer oligometastases, it is essential to thoroughly evaluate the status of the primary tumor and metastatic lesions (including whether systemic therapy has been administered, whether it is a postoperative recurrence, number and location of metastases, and tumor size) and assess the patient’s surgical tolerance. Decisions regarding such treatment strategies must be made carefully by a multidisciplinary treatment team that cover difference specialties. Surgical treatment is typically categorized into three scenarios: cases in which radiotherapy is preferred, cases in which either radiotherapy or surgery can be selected, and cases in which surgery is prioritized. This article focuses on the latter two categories of oligometastases and discusses the indications and risk assessment for lung resection based on the state of the primary tumor and metastatic lesions, along with an evaluation of surgical tolerance (Figure 2).

Figure 2 The risk assessment of pulmonary resections and operable indication for oligometastatic non-small cell lung cancer. LN, lymph node; ASA, American Society of Anesthesiologists; FEV1, forced expiratory volume at one second; CT, computed tomography; COPD, chronic obstructive pulmonary disease; PPO FEV1, predicted postoperative forced expiratory volume at one second; PPO DLCo, predicted postoperative diffusing capacity of the lungs for carbon monoxide; SWT, shuttle walk test; SCT, stair-climbing test; CPET, cardiopulmonary exercise testing; VO₂max, maximum rate of oxygen consumption; RTx, radiation therapy.

Examples of surgical indications include isolated pulmonary metastasis in a patient with interstitial pneumonia after lung cancer surgery, isolated abdominal lymph node metastasis where radiotherapy poses a risk of gastrointestinal exposure, and brain metastasis with symptoms of increased intracranial pressure requiring urgent resection by a neurosurgeon. However, several of these situations involve exploratory interventions, making safety a paramount concern. Therefore, when considering lung resection for oligometastases, more attention should be paid to assessing surgical tolerance and managing complications than in standard lung cancer surgeries. Treatment strategies for oligometastases generally involve multimodal therapies with systemic treatment often administered before, after, or in conjunction with local treatments. Systemic therapy is likely to be administered in the event of disease recurrence or progression. The surgical treatment of oligometastases differs conceptually from salvage surgery, which is typically performed when no other options are available. Specifically, in cases of lung resection, highly invasive procedures such as pneumonectomy, bilobectomy, combined resection of adjacent organs, or bronchovascular reconstruction should be avoided whenever possible.

Postoperative oligo-recurrence in lung cancer

Lung cancer oligometastases eligible for curative local treatment include not only stage IV advanced cancer but also postoperative recurrence cases. In the case of postoperative oligo-recurrence in lung cancer, because the primary tumor has already been resected, there is no need to consider the control of the primary site, resulting in a lower overall tumor burden (4). Metastatic lesions are often discovered during regular postoperative follow-ups, leading to a higher likelihood of “true oligometastases”, which are lesions that appear isolated but do not represent a state of impending multiple metastases, where imaging findings and biological characteristics are consistent.

Table 2 presents studies that have examined the effectiveness of surgical treatment for postoperative oligo-recurrence in lung cancer (22-28). Hishida et al. conducted a survival analysis of 768 patients with NSCLC who experienced postoperative recurrence after complete resection (24). Among the 162 patients with three or fewer metastatic lesions, the 5-year post-recurrence survival rate was 32.9%, which was significantly better compared to patients with more than three metastatic lesions. Sonoda et al. analyzed post-recurrence survival in 118 patients with NSCLC with oligo-recurrence after complete resection, categorizing them based on the presence or absence of EGFR gene mutations (27). They found that local treatment of metastatic lesions significantly prolonged survival in patients without or with unknown EGFR mutations, whereas the effect was not observed in those with positive EGFR mutations. According to these studies, postoperative oligo-recurrence accounts for 21% to 53% of all recurrence cases, indicating that it is not an uncommon condition.

When evaluating postoperative oligo-recurrence against the previously mentioned ESTRO/EORTC consensus, it is classified as synchronous oligometastatic disease because it involves patients with no previous history of systemic treatment for recurrence (genuine oligometastatic disease). It is the first diagnosis of oligometastases (de novo oligometastatic disease), and it represents metachronous metastasis. Such conditions are considered more homogeneous, making it easier to establish objective criteria for selecting between surgical treatment and radiotherapy.

Conclusions

As both systemic and local therapies have advanced, there is a growing interest in investigating whether oligometastases in lung cancer can be cured. Although radiotherapy remains the primary modality for local treatment, there are situations in clinical practice where surgical treatment is prioritized. Defining the role of surgical treatment within the context of local therapy is essential for systematizing the treatment of lung cancer oligometastases, which could expand treatment options.

When considering the indications for surgical treatment of lung cancer oligometastases, it is necessary to assess the patient’s surgical tolerance in light of the condition of the resected organ and metastatic lesions. Although not covered in this article, understanding the biological characteristics of oligometastases and establishing precision medicine will also require identifying minimally invasive biomarker discovery through liquid biopsy and the examination of resected specimens.

Acknowledgments

We would like to thank Editage (www.editage.com) for English language editing.

Funding: None.

Footnote

Provenance and Peer Review: This article is a secondary publication. This article is based on a study first reported in the Japanese Journal of Lung Cancer 2023;63:850-856. The article did not undergo external peer review.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://ccts.amegroups.com/article/view/10.21037/ccts-24-35/coif). Y.S. serves as an unpaid editorial board member of Current Challenges in Thoracic Surgery from February 2024 to December 2025. The author has no other conflicts of interest to declare.

Ethical Statement: The author is 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/.

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