The role of the surgeon in the management of oligometastatic non-small cell lung cancer: a literature review

Introduction

Lung cancer is worldwide the second most common type of cancer and one of the leading causes of cancer-related deaths (1). In Europe, non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer diagnoses, and around 60–70% of these patients present with advanced stages at time of diagnosis (2,3). Generally, patients with late-stage NSCLC are treated with systemic or palliative therapies, including chemotherapy, radiation therapy (RT), or both. The 5-year overall survival (OS) rates of NSCLC are 26% for stage IIIb, 10% for stage IVa, and 1% for stage IVb (4). Previously, patients with these advances stages of diseases were not considered to be amenable for curative-intent treatments due to their poor prognoses. However, advances in imaging modalities and screening strategies in more recent years have substantially increased tumor detection rates and have resulted in a shift towards earlier diagnosis of NSCLC (5). Furthermore, the identification of new molecular alterations and the discovery of their respective targeted treatments, such as for anti-epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and ROS1, have resulted in an almost exponential emergence of new treatment modalities for advanced stages of NSCLC (6). When applied in carefully selected treatment populations, these treatments can provide major improvements in disease-free survival (DFS) and OS rates in these patients (6-8).

These developments have led to an increasing number of patients with a limited number of metastatic lesions at only a few sites, often referred to as oligometastatic disease (9). This is also reflected in the 8^th edition of the Tumor, Node, Metastasis (TNM) classification published by the International Association for the Study of Lung Cancer (IASLC) which included oligometastatic disease as a separate category for the first time since its introduction. In this latest TNM classification, patients with metastatic disease are divided into three distinct subgroups: stage M1a: involvement of the lung alone; M1b: single extrathoracic metastasis; and M1c: multiple extrathoracic metastases in one or more organs (10). Recent studies have suggested that patients with oligometastatic disease have better OS rates compared to patients with more disseminated diseases, and that they may benefit from a combination of systemic treatment and local treatment aimed at the metastatic site(s) (5,11-13). However, the specific role of surgical therapies in the treatment of oligometastatic disease remains a controversial and challenging subject with many unanswered questions regarding topics such as long-term treatment outcomes and patient selection criteria. In this review, we aim to summarize the most recent and relevant data on the surgical management of oligometastatic NSCLC. We present the following article in accordance with the Narrative Review reporting checklist (available at https://dx.doi.org/10.21037/tlcr-21-58).

Methods

The PubMed/MEDLINE database and the Cochrane database were searched to identify relevant articles regarding oligometastatic NSCLC. Specifically, articles regarding definitions of oligometastatic disease, oligometastatic tumor biology, diagnosis, and the treatment of oligometastatic disease were identified. Narrative reviews, clinical trials, systematic reviews, meta-analyses, and guidelines written in English and from the period of 2015–2021 were included in this study. Studies published before 2015 that were deemed vital to the review were also included.

Definition of oligometastatic disease

The term “oligometastasis” is a composite derived from the Greek words “oligo”, meaning “a few” and “metastasis”, meaning “removal” or migration”. In 1995, Hellman and Weichselbaum introduced the term oligometastasis to refer to a state of limited systemic metastatic disease in which local treatments could be curative (14). This resulted in a paradigm shift where cancer metastasis was no longer viewed as a binary concept in which a tumor is either localized and curable, or disseminated and, by definition, incurable. Rather, the behavior of metastatic disease is more likely to represent a spectrum in which, initially, patients have limited disease in one or a few sites before the metastases becomes more disseminated (15). This spectrum theory of tumor metastasis posits that differences in metastatic potential are rooted in the molecular features of cancers which determine its metastatic virulence. Many of these features were not characterized yet at the time of Hellman and Weichselbaum’s first description of oligometastatic disease. However, more recent studies have identified several biological mechanisms that support this theory (16).

A number of molecular markers have been proposed to play a significant role in the differentiation between oligometastatic and polymetastatic disease. For example, analysis of microRNA expression in cancer patients has allowed the identification of potential “oligomiRs” that could help identify oligometastatic phenotypes (17). In a study performed by Lussier et al., the authors analyzed patterns of microRNA expression in tumor samples from patients with oligometastatic disease that were treated with high-dose RT. Their study results showed that patients who did not develop polymetastases were characterized by unique features of microRNA-200c, a top prioritized microRNA (18). Earlier studies have shown that several members of the microRNA-200 family are involved in metastatic disease (19). Lussier et al. demonstrated that microRNA-200c enhancement in an oligometastatic cell line resulted in conversion from oligo- to polymetastases. In a subsequent study by Lussier et al., the authors investigated the role of microRNA expression patterns in patients with oligometastatic NSCLC patients (<5 initial metastases) that were treated with curative-intent surgery. Their results showed that microRNA expression patterns were distinctly different between patients with high and low rates of progression. Furthermore, these prioritized microRNAs were associated with rate of progressive disease and survival in an independent dataset. The authors concluded that oligo- and polymetastatic disease are distinct entities, both at clinical and a molecular level (20). Additional studies have shown that predicted target genes for a number of oligomiRs are involved in the molecular pathways that are vital to tumor adhesion, epithelial–mesenchymal transition, invasion, and migration (21,22). Other molecular features that may determine metastatic potential include copy number alterations (CNA), driver mutations, and intratumor heterogeneity (16).

Studies have suggested that cancer biology can be variable between patients, with some cancers progressing more slowly than others, resulting in variable progression patterns over time (23,24). These variations in progression phenotypes may be associated with different expression patterns in microRNA (20). The incidence of oligometastases in patients with NSCLC is estimated to range between 26–50%, depending on which definition is used (i.e., number of metastatic lesions and oligometastatic subtype) (25). In NSCLC, the most common (oligo)metastatic site is the brain, accounting for approximately 35.5%, followed by multi-organ metastases to the contralateral lung (33.6%), adrenal glands (10%), bone (8.5%), and the liver (2.4%) (11). Several subtypes of oligometastatic disease have been described, which are classified according to the initial diagnosis and/or their response to systemic therapy. In synchronous or “de novo” oligometastasis, patients present with oligometastases at the time of initial detection of the primary tumor. In contrast, metachronous oligometastatic disease refers to the development of a limited number of metastases after initial diagnosis and treatment of the primary tumor (26). Two other terms that are frequently used in this setting are “oligoprogression” and “oligopersistence”. While the first two terms are entities that are more closely related to tumor biology, oligoprogression and oligopersistence are generally used to describe oligometastases that are induced as a result of treatment with systemic therapies such as targeted therapies, immunotherapy, and, sometimes, chemotherapy (Figure 1). Patients treated with tyrosine kinase inhibitors (TKIs) are particularly susceptible to oligoprogression and oligopersistence due to acquired resistance through phenotypic transformation. In oligoprogression, patients develop a limited number of new metastases in one or a few sites after an initial favorable response to systemic treatments, usually targeted therapy, immunotherapy, or a combination of chemo- and immunotherapy. Often, progression in these cases occurs at a limited number of anatomic sites. It has been proposed that these patterns of progression are caused by intratumoral and intertumoral genetic heterogeneity. Oligopersistence refers to a situation in which patients have residual metastatic disease at a few sites after a favorable response to initial systemic therapy (15). Table 1 shows an overview of the most important definitions regarding oligometastatic disease.

Figure 1 Overview of different subtypes of oligometastatic disease in NSCLC. (A) Synchronous oligometastatic disease with the primary lung tumor and metastatic lesions appearing at the same time; (B) metachronous oligometastatic disease with a metastatic (brain) lesion appearing after initial treatment for the primary lung tumor; (C) oligoprogression with new metastatic lesions appearing after initial treatment for oligometastatic NSCLC; (D) oligopersistence with persistent metastatic lesions after initial treatment for oligometastatic NSCLC. NSCLC, non-small cell lung cancer.

Table 1 Definitions of different terms related to oligometastatic diseases
Full table

Currently, there is no consensus on which threshold should be used to define oligometastatic disease in terms of the number of sites and lesions involved. There is a wide range of different eligibility criteria used in studies involving oligometastatic disease, both in terms of sites/organs involved and the number of lesions. However, in the majority of the available trials, a large proportion of patients enrolled have only 1 or 2 lesions, even in studies where more than 1–2 lesions are permitted. This suggests that investigators in these trials favor patients with fewer lesions. Furthermore, this means that the limited outcome data that is available is mainly based on treatment outcomes of patients with just 1 or 2 lesions (27,28). In a systematic review by Giaj-Levra et al., the authors found no consensus with regards to a definition of oligometastatic disease, however, the majority of studies included in their analysis adopted a threshold of no more than five lesions (29). This heterogeneity makes it quite difficult to create evidence-based guidelines for oligometastatic disease. To overcome these difficulties, the European Organization of Research and Treatment of Cancer (EORTC) established a pan-European multidisciplinary group with the goal of developing a consensus definition of oligometastatic disease. In their published consensus findings, the authors explained that the maximum number of lesions and organs involved depend on whether it is possible to offer a radical intent treatment strategy to the patient. They further stated that, based on their data, a maximum of five metastatic lesions and three organs are used as definition for oligometastatic NSCLC. In addition, the authors clarified that all organs are allowed, except for bone marrow involvement and diffuse serosal metastases (meningeal, pericardial, pleural, and mesenteric), due to the fact that these metastases cannot be treated with radical intent (30).

In order to accurately identify oligometastatic disease, a careful and complete radiological work-up is necessary. In addition to standard computed tomography (CT) scans, a large number of studies advocate the use of brain magnetic resonance imaging (MRI) and ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) in the staging of NSCLC. This is also the general consensus in the publications of major scientific societies such as the European Society for Medical Oncology (ESMO), National Comprehensive Cancer Network (NCCN), and EORTC (9,29,31,32). Earlier data has shown that MRI is superior to CT for detecting brain metastases (33). Furthermore, ¹⁸F-FDG PET/CT-scans are generally used to diagnose systemic disease and mediastinal lymph node status, with sensitivity and specificity rates ranging between 79–85% and 87–92%, respectively (34). The additional use of ¹⁸F-FDG PET/CT-scans is associated with improved treatment outcomes as stage migration may occur. This is due to higher rates of metastasis detection with PET/CT compared to the use of CT-scans alone. It is estimated that around 15% of all NSCLC patients initially staged as stage I–III with conventional CT-imaging, are upstaged to stage IV with PET/CT (9,35). This upstaging can obviate the use of aggressive local therapies in patients that are not likely to benefit from them. In a retrospective study by Tönnies et al., patients who underwent preoperative staging using ¹⁸F-FDG PET-CT scans were compared to patients that were staged using conventional spiral CT-scans. The authors found a significant difference in 5-year survival rates, with an OS of 58% in the PET/CT group, compared to 33% in the CT group (36).

There is still some controversy regarding mediastinal staging and the need for pathological confirmation. Most studies agree on the fact that PET-CT is required for mediastinal lymph node staging, however, the issue of pathological confirmation is still hotly debated (29,30). The role of mediastinal node involvement in oligometastatic disease is still not clear and it is still uncertain whether a positive mediastinal lymph node status should be viewed as metastatic disease. In the 8^th TNM classification, involvement of mediastinal lymph nodes is defined as locally advanced disease, and not as metastasis (4). The EORTC consensus group clarifies that pathological confirmation of mediastinal nodes is only indicated if it influences treatment strategy. In addition, the EORTC states that pathological confirmation of at least one metastatic lesion is required, especially in patients with a solitary metastasis or if the results may change the treatment strategy. However, it is required that the benefits of the pathological confirmation outweigh the risks (30).

Surgical treatment of oligometastatic disease

According to the EORTC consensus group, the main goal in the treatment of oligometastatic disease is to gain long-term disease control using a radical treatment that is technically feasible and has acceptable toxicity. The term “cure” was not used as the authors stated that patients could still benefit from radical therapies resulting in long-term disease control, even if they are not cured. However, technical feasibility is an important element in this definition, due to the fact that radical treatment may not be possible due to the location of the metastatic lesion or the patient’s comorbidities, even in cases with a limited number of metastatic lesions. The type of radical treatment is not included in this definition, only the feasibility. As a result, genomic background and histologic subtype are not taken into account as well (30). One of the most important elements in the treatment selection for oligometastatic NSCLC is to identify patients that are most likely to benefit from radical metastasis-directed treatments. Only a relatively small subset of oligometastatic patients (15–25%) will have an extended disease-free interval (DFI) after local treatment of metastases, thus necessitating careful patient selection in order to prevent administering futile therapies. Several prognostic factors associated with survival have been identified, such as: age, sex, number of metastases; involvement of mediastinal lymph nodes, DFI, tumor histology, performance status, pathological T stage, location of the metastasis/metastases, treatment type of the primary lesion, and the biomolecular profile (9,37).

Traditionally, surgical treatment has been the main modality in oligometastatic NSCLC patients, with approximately 55% of all patients receiving surgical treatment (38). The indications for surgical treatment depend on a number of metastasis-related factors such as the number, size, and location of metastases, and on patient-specific factors such as age, performance status, comorbidities, and prognosis (9,25,26). Both brain and adrenal oligometastases have shown to have relatively good prognoses after radical treatment with surgery, with 5-year OS rates of approximately 20% and 20–30%, respectively (39). The 2013 American College of Chest Physicians (ACCP) guidelines state that in patients with a synchronous resectable cN0,1 primary NSCLC and an isolated brain or adrenal metastasis with no other metastatic sites, resection of the primary lesion and the isolated brain/adrenal metastasis is advised (40). Furthermore, the NCCN guidelines recommend local therapy for patients with oligometastatic disease, and multidisciplinary treatments (including systemic therapies) for primary lesions in patients with isolated brain metastases (41). However, clinicians should be aware that these guidelines are mostly based on expert opinions than on high quality data, and can thus include bias.

There are two main surgical treatment approaches for treating oligometastatic NSCLC. The first approach involves an initial resection of the primary tumor, followed by control of distant lesions using surgery or RT, and control of micrometastases using systemic therapy. The second approach involves initial treatment with systemic therapy, followed by adjuvant local treatment with surgery or RT for those patients that have responded to drug therapy, but have residual, localized tumors. The latter approach is often called the salvage (surgery) approach (42). In a study by Wang et al., the effect of initial surgical resection of the primary lesion in oligometastatic NSCLC was analyzed. In their retrospective study, 172 NSCLC patients with oligometastatic disease were divided into two groups: one group received primary surgical treatment followed by adjuvant chemotherapy, while the other group received neoadjuvant chemotherapy followed by local RT. Median survival times in the primary surgery group and neoadjuvant therapy group were 48 months and 18 months, respectively. Furthermore, 5-year OS rates were 21.1% and 7.6%, respectively. The authors concluded that upfront surgical treatment of primary tumors significantly increased median survival times and 5-year OS in patients with oligometastatic NSCLC (43). However, it should be noted that selection bias is expected in this retrospective study. For example, patients in the neoadjuvant chemotherapy group may have had bulkier diseases than the primary surgery group.

Treatment outcomes of a salvage surgery approach in oligometastatic NSCLC were evaluated in a relatively recent phase II, multi-center, randomized controlled trial (RCT) by Gomez et al. Patients with pathological confirmation of stage IV NSCLC and three or fewer metastases after first-line systemic therapy were included. The sites of oligometastatic lesions in this study were: brain [10], bones [10], adrenal gland [8], pleura [7], lung [6], cervical lymph node [4], liver [2], spleen [2], retroperitoneal lymph node [1], paraspinal [1], and kidney [1]. The first-line therapy consisted of ≥4 cycles of platinum doublet therapy or ≥3 months of either EGFR or ALK inhibitors for patients that the respective mutations. After inclusion, patients were randomized and assigned to either local consolidative treatment (RT or surgical resection of all metastatic lesions) with or without subsequent maintenance treatment, or to maintenance treatment alone. The type of maintenance treatment was chosen by the treating physician(s) and included pemetrexed, bevacizumab, erlotinib, crizotinib, and observation (close surveillance without any cytotoxic therapies). The trial was terminated early after randomization of 49 patients (25 patients in the local consolidative therapy arm and 24 in the maintenance treatment arm) after an interim analysis demonstrated that the local consolidative arm extended progression-free survival (PFS) when compared to the maintenance therapy alone. The median PFS in the local consolidative therapy arm was 11.9 months, versus 3.9 months in the maintenance treatment arm. Of the 25 patients in the local consolidative therapy arm, six patients (24%) received a combination of surgery and RT, and one patient (4%) received surgery to all sites. No grade 3 or 4 toxicities were reported in this study. The authors concluded that, in patients with three or fewer NSCLC metastases, aggressive local therapy with or without maintenance therapy resulted in improved PFS rates compared to maintenance treatment alone (12).

Despite an increasing amount of research in the field of NSCLC, there is a lack of data on the outcomes of local consolidative therapy in the setting of oligoprogressive disease. However, the limited amount of evidence that is available supports the notion that local treatment of one or a few sites of progression in patients that have demonstrated a good response to systemic treatment is feasible, safe, and associated with favorable treatment outcomes (15). In a retrospective analysis by Yu et al., a total of 18 patients with oligoprogression after EGFR TKI therapy received local consolidative therapy (surgery, radiofrequency ablation, or stereotactic RT). Of the 18 patients, 11 (61%) underwent surgery (wedge resection in 7 patients, lobectomy in 3 patients, and a pneumonectomy in 1 patient). Local therapy was well tolerated in all patients, and 85% of patients were able to restart TKI therapy within 1 month after the local therapy. Furthermore, median time to progression after local therapy was 10 months, and the median time until a subsequent change in systemic treatment was 22 months. Median OS from local therapy was 41 months. The authors concluded that local consolidative therapy followed by continuation of EGFR TKI therapy is well tolerated and associated with long OS and PFS rates (44). A study by Weickhardt et al. regarding EGFR- or ALK-positive NSCLC showed similar results, with a median time to progression after local therapy of 6.2 months (45).

Future perspectives

In recent years, there has been a significant increase in the use of less invasive ablative techniques such as stereotactic body radiation therapy (SBRT) (25). Technological advances in imaging and radiation technologies have made it feasible to administer high ablative doses of RT with precision, without damaging surrounding tissues. These high-dose treatments can be given in fewer fractions, resulting in shorter treatment durations than conventional RT schedules. SBRT is currently mainly used for (oligo)metastatic lesions that are unresectable or for patients that are deemed unfit for surgical treatment due to comorbidities (46,47). However, the notion that SBRT is only suitable for unresectable oligometastatic lesions or patients that are medically unfit for surgical treatment is erroneous. Several studies have been published in recent years with the aim of evaluating long-term outcomes of SBRT in oligometastatic NSCLC. A number phase I or II trials have been conducted as well in order to investigate the feasibility, safety, and efficacy of SBRT in patients with oligometastasis from NSCLC. All of them have shown that SBRT is feasible and safe in selected patient populations with favorable local control rates and treatment outcomes (13,48-51). One notable trial is the randomized Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Disease (SABR-COMET) trial which enrolled 99 patients with controlled primary solid tumors and up to 5 metastatic lesions. Patients were randomized to standard of care (SOC) or to SOC + SBRT to all metastatic lesions. OS was 28 months in the SOC arm and 41 months in the intervention arm (P=0.09). PFS was 6 months in the SOC arm and 12 months in the intervention arm (P=0.001) (52). The phase III SABR-COMET-10 is currently investigating the impact of SBRT in patients with 4–10 metastatic cancer lesions. Other notable ongoing trials are the NRG-LU002 and ETOP CHESS trials. The randomized phase II/III NRG-LU002 will assess the role of consolidative ablative therapies on OS. The multi-center single arm phase II ETOP CHESS-trial aims to assess the efficacy of immunotherapy, chemotherapy plus SBRT to oligometastases followed by definitive surgery or RT to the locoregional primary tumor in patients with histologically-confirmed synchronous oligometastatic NSCLC (53). Several other trials investigating the effects of SBRT and/or surgery on oligometastatic NSCLC are still ongoing. An overview of these trials is found in Table 2. However, despite an increasing number of promising studies, no RCTs comparing SBRT to surgery have been published as of yet. This means that, for the foreseeable future, treatment strategies must be based on individual prognostic factors and require a rigorous work-up and a multidisciplinary approach. In the future, integration of clinical and molecular staging will hopefully allow a more personalized treatment approach across the wide spectrum of (oligo)metastatic diseases (Figure 2). More data from multi-center prospective trials will likely shed light on which therapeutic modalities are most suitable for the heterogeneous population of patients with oligometastatic NSCLC.

Table 2 Overview of ongoing trials using SBRT and/or surgery as treatment for oligometastatic disease
Full table

Figure 2 Overview of the spectrum theory of malignant diseases showing oligometastatic disease as an intermediate state between localized and disseminated disease. The benefit of local ablative therapy gradually decreases as the disease state progresses along the spectrum, while the reverse is seen for systemic treatments. In addition, progression along the spectrum is associated with higher risk diseases.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Maurizio Infante & Thierry Berghmans) for the series “Oligometastatic NSCLC: definition and treatment opportunities” published in Translational Lung Cancer Research. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://dx.doi.org/10.21037/tlcr-21-58

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/tlcr-21-58). The series “Oligometastatic NSCLC: definition and treatment opportunities” was commissioned by the editorial office without any funding or sponsorship. PEVS serves as an unpaid editorial board member of Translational Lung Cancer Research from July 2019 to July 2021. 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.

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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