1 INTRODUCTION

In 1995, Hellman proposed the “spectral theory,” which stated that tumor metastasis is the progression from local lesions to systemic lesions, and there are some intermediate states with clinical significance between early metastasis and widespread metastasis. Subsequently, Hellman and Weichselbaum¹ proposed the concept of oligometastases, a term that is used to describe this special form of advanced tumor metastasis, because the number of metastases and the organs involved are relatively limited. According to a systematic review, it is defined as a maximum of five metastases and three organs, and the presence of diffuse serum metastasis or bone marrow involvement is excluded.² Oligometastasis is a period of relatively mild biological tumor invasiveness. It exists in the transitional stage between the formation of the localized primary tumor and extensive metastasis. Because of the limited tumor burden, it does not have the tendency to spread widely throughout the body despite the occurrence of distant metastasis for a long time. In 2011, Weichselbaum and Hellman³ conducted a conceptual update, proposing that oligometastasis has the potential to be cured. According to them, the survival time of actively treated patients with oligometastasis can be substantially prolonged.

2 THE CLASSIFICATION OF OLIGOMETASTASES

In 2020, Guckenberger et al. and other experts from Europe⁴ defined 17 characteristic factors for oligometastatic diseases in four categories. They used the second round of the Delphi method to clarify the classification of oligometastatic diseases. The characteristic factors included: descriptive tumor characteristics (features of the primary tumor, history of cancer progression, history of treatment of the primary tumor, previous systemic treatment before diagnosis, staging, and violation of organs), number of metastatic lesions (number of lesions and involved organs, number of lesions in affected organs, and maximum diameter of metastases), characteristics of disease development (whether a history of more or less metastasis in the past exists, whether oligometastasis within half a year after the diagnosis of lung cancer was observed, whether previous diagnosis was oligometastasis during the systemic treatment of the primary tumor, and if oligometastatic progress was observed in the existing images), and features related to oligometastasis (Was any such lesion observed before diagnosis? Can the lesion be cured?)

According to whether there is a history of multiple diseases before the diagnosis of oligometastasis, oligometastases are categorized as induced oligometastasis and true oligometastasis. However, on the basis of whether disease history of a lesser metastatic event was observed, true oligometastasis is further divided into repetitive oligometastasis (previously diagnosed oligometastatic disease) and de novo oligometastasis (initially diagnosed oligometastatic disease). De novo oligometastasis is divided into synchronous oligometastasis and metachronous oligometastasis according to the time when the oligometastasis appears. Synchronous oligometastasis refers to the diagnosis of primary lung tumors and the discovery of oligometastasis at the same time, the oligometastasis of other organs before diagnosis of the primary tumor, or oligometastases that occur soon after the treatment of the primary tumor (usually within 6 months).⁵ Metachronous metastasis refers to situations in which the primary lung lesions metastasize to other parts of the lung after a period of standardized treatment. Finally, considering whether the patient is actively treated when oligometastasis occurs and whether there is progress in the current imaging, oligometastases can be categorized as oligorecurrence, oligoprogression, or oligopersistence. Oligorecurrence refers to patients whose systemic disease recurs after systemic treatment. Oligoprogression refers to patients with limited multiple metastases in residual lesions after systemic treatment or patients with only one lesion that has progressed after systemic treatment.

3 SITES OF OLIGOMETASTASIS

With the recent rapid development of imaging technology, the tumor detection rate has dramatically increased. In “Tumor, Lymph Node, and Metastasis,” published by the International Association for the Study of Lung Cancer (8th edition), oligometastatic disease was mentioned for the first time. According to the prognosis of patients, cancers can be divided into M1a (where the lesion only exists in the lungs); M1b (where a single metastasis exists outside the chest); and M1c (where multiple extrathoracic metastases occur).⁶ Studies have shown that the survival time of patients with single metastasis was longer than those of patients with multiple metastases.^{6, 7} In a meta-analysis, it was found that most patients with non-small cell lung cancer (NSCLC) have oligometastasis sites in the brain or lung, followed by the adrenal glands, bone, other sites, liver, and lymph nodes.⁸ However, metastatic NSCLC is a heterogeneous state that is characterized by different clinical manifestations and prognoses depending on the anatomical location and number of metastases.⁹

4 THE TREATMENT OF OLIGOMETASTATIC NSCLC

Since the seminal paper by Hellman and Weichselbaum described the intermediate state between patients with local cancer and patients with obvious distant metastases, increasing studies on the treatment of oligometastasis have been observed. Several retrospective studies into oligometastatic NSCLC^{8, 10} showed that, compared with historical data, local treatment (LAT) could significantly improve the overall survival (OS) and progression-free survival (PFS) of patients. It is worth noting that, because the concept of oligometastases is often mentioned in association with NSCLC patients, the treatment of these patients has become increasingly important, particularly during the past decade. The latest developments in immunotherapy and targeted therapy have been remarkable, and at the same time, image-guided percutaneous thermal ablation has also been used more widely.

5 RADICAL SURGERY

Previous studies have confirmed the existence of oligometastases in NSCLC¹¹ and have shown the significant effect of LAT on improving the OS. Traditionally, surgery is the most commonly used treatment for oligometastatic NSCLC. In 2012, Congedo et al.¹² conducted statistical analysis of data obtained from 53 patients with oligometastatic NSCLC, except for 39 patients with brain metastases. As observed, the most common metastatic site was the adrenal gland (7), followed by the bone (3), vertebral body (3), liver (1), and the contralateral supraclavicular lymph node (1). Subsequently, all patients with extracranial metastases underwent surgery for the primary disease with or without metastases. Results showed that the 5-year survival rate was 24%. In 2016, He et al.¹³ also conducted a related trial to explore the impact of surgery on patients with NSCLC experiencing oligometastases in the lung. The study included 11 surgical patients; the average survival period was 37 months. According to statistics, the 5-year survival rate of understudied patients was 18.2%. Likewise, in 2017, Lodeweges et al.² conducted a relevant analysis on 68 patients who underwent surgical resection of pulmonary oligometastases and showed that the 5-year survival rate of surgical patients was 41%. Moreover, in 2020, Casiraghi et al.¹⁴ discussed the efficacy of surgery in patients with oligometastasis, with the most common site of oligometastatic NSCLC being the brain (61%), followed by the bone (21%), adrenal gland (11%), skin (4%), eye (2%), and the contralateral lung (2%). Subsequently, all patients received multidisciplinary treatment, including surgical resection of the primary tumor, local metastases treatment, and systemic drug therapy. Results showed that while the median OS was 30 months, the 2-, 3-, and 5-year OS were 57%, 50%, and 30%, respectively. Meanwhile, they also showed that OS and PFS did not correlate with both metastatic sites and number of metastases (1 vs. 2).

Radical surgical resection of the lesion is the first choice for treating patients with oligometastasis. Approximately 55% of patients can receive surgical resection,¹¹ and surgery can prolong the survival time of patients. However, even if the lesion is completely removed, the 5-year survival rate remains lower than 50%.^{15, 16} Furthermore, within 2 years after surgical resection, approximately 80% of patients experience a relapse. Therefore, recurrence after surgery can considerably reduce the life expectancy of patients.^{17, 18} It had been reported that the median survival time of patients after recurrence is approximately 11.5 months.

6 SYSTEMIC THERAPY

Systemic chemotherapy is usually used as the main treatment method for metastatic stage IV lung cancer with metastases. Many studies have shown that it can prolong the survival time and improve the quality of life of patients with advanced NSCLC. In 2016, Gomez et al.¹⁹ conducted a phase II trial reporting that of all understudied 49 patients who developed oligometastases after first-line chemotherapy, 25 received local therapy, whereas the other 24 patients received maintenance therapy or observation. With a median follow-up of 11.32 months, the PFS in the local consolidation therapy group was also considerably prolonged: (local consolidation therapy vs. maintenance therapy group, 11.93 vs. 3.9 months).

In addition, with a gradual and thorough understanding of oligometastatic NSCLC, oligometastasis and oligoprogress are considered unique subgroups. In 2019, Jiang et al.²⁰ conducted a clinical study of epidermal growth factor receptor (EGFR)-mutant NSCLC patients with liver oligometastasis or oligoprogress. Among the patients with oligometastasis, 20 patients received EGFR-tyrosine kinase inhibitor (TKI) treatment and 23 patients received EGFR-TKIs combined with LAT. The PFS and OS after combined treatment were higher (12.9 and 36.8 months) than those for the EGFR-TKIs alone treatment group (7.9 and 21.3 months). Among patients with oligoprogression, 24 patients continued to receive EGFR-TKI combined with local therapy, and 25 patients received chemotherapy. While the median PFS and OS of the combination group were 13.9 and 28.3 months, respectively, the median PFS and OS of the targeted therapy group alone were 9.2 and 17.1 months, respectively. However, for patients with oligometastatic or oligoprogressive, targeted therapy for NSCLC with EGFR mutations had substantial effects. Nevertheless, although these targeted drugs were effective at the early stage of treatment, many patients experience weakened treatment effects after 1–2 years of treatment.^21-24

Recently, immunotherapy has brought new hope to patients with metastatic NSCLC. In 2019, Bauml et al.²⁵ conducted a phase II clinical trial to evaluate whether adding pembrolizumab after LAT can enable patients to achieve a longer survival time. The trial included 51 patients with oligometastasis, including 45 who underwent LAT on all lesions, followed by those who were administered pmebrolizumab. The median PFS-L (PFS from the start of LAT) improved from 6.6 to 19.1 months, with the PFS of pembrolizumab being 18.7 months, and the median OS being 41.6 months. In 2019, Theelen et al.²⁶ conducted a similar study. Forty people were randomly assigned to the control group, after which the remaining 36 people were assigned to the experimental group. While 37 patients in the control group received only pembrolizumab immunotherapy, 35 patients in the experimental group received local radiotherapy before immunotherapy. Results showed that the median OS of the control group was 7.6 months, whereas that for the experimental group was 15.9 months. These results show that for patients with oligometastasis of NSCLC, supplementation with immunotherapy after LAT can increase the patient's PFS without causing toxic side effects. However, there are relatively few clinical trials for immunotherapy for patients with oligometastatic NSCLC, and a lack of statistical significance. Therefore, this treatment requires further testing in randomized clinical trials.

7 STEREOTACTIC ABLATIVE RADIOTHERAPY

Research has shown that oligometastases represent a minimal metastatic state, and radical LAT can cure or prolong the survival of these patients. Stereotactic radiotherapy (SABR) is usually recommended for older patients, those with poor physical condition, poor central location of lung nodules, or intolerance of surgery. In 2020, Poon et al.²⁷ conducted a large-scale international multicenter study, which included 1033 patients with oligometastasis and 1416 patients with lesions who underwent SABR. Afterward, all patients were followed up for an average of 24.1 months. The median OS, PFS, and widespread progression (WSP) were 44.2, 12.9, and 42.5 months, respectively. As observed, the 5-year OS rate was 35.2%. Furthermore, although 260 patients had oligometastasis of NSCLC in this sample, the median OS was 32 months. In another study, 1422 patients with oligometastasis from 17 hospitals in UK were enrolled.²⁸ The most common oligometastatic site was the lung. All patients were treated with SABR. The 1-year OS rate was 92.3%. However, the 2-year OS rate was 79.2%. Among these patients, 64 had oligometastatic NSCLC. The 1-year OS rate was 80.2%, whereas the 2-year OS rate was 65.4%.

In 2019, Palma et al.²⁹ conducted a phase II study. Among the 99 understudied patients, 33 were allocated to the control group (care treatments alone), after which the remaining 66 people were placed in the SABR group. Patients in the SABR group received SABR at all metastatic sites, with a median follow-up of 25–26 months. Results showed that the median OS of the control group was 28 and 41 months in the SABR group. However, the median PFS in the control group was 6.0 months, whereas that in the SABR group was 12 months.

In 2018, Iyengar et al.³⁰ conducted a phase II trial to explore the efficacy of maintenance chemotherapy combined with SABR in patients with oligometastatic NSCLC who did not have EGFR or ALK mutations. In an interim analysis, the PFS of the SABR combined with maintenance chemotherapy group was 9.7 months, while that of the maintenance chemotherapy group alone was 3.5 months. Recently, two randomized phase III clinical trials reported that the PFS of patients with low metastasis who received combined therapy was longer than those of patients who received chemotherapy alone.^{31, 32}

In these clinical studies, SABT had a better effect on patients with early-stage, inoperable NSCLC.³³ Recently, a survey conducted by more than 1000 oncologists from 43 countries³⁴ found that the use of SABT in oligometastatic NSCLC is gradually increasing. With brain metastases treated with SBRT, the percentage of radiation necrosis was approximately 5–25%, which mainly manifested as headache, convulsions, nausea, or memory loss.³⁵

8 THERMAL ABLATION

With the advancement in modern medical technology, image-guided percutaneous thermal ablation has also been noted to influence the treatment of lung cancer. CT-guided thermal ablation therapy for lung tumors was first reported 20 years ago.³⁶ Thermal ablation is a type of energy ablation that is minimally invasive. It targets one or more tumor lesions in a certain organ, and the biological effect of heat directly causes irreversible damage or coagulative necrosis of the tumor cells in the lesion tissue. At present, thermal ablation has widely been used in patients with NSCLC whose lesions cannot be surgically removed at an early stage, or those having advanced-stage NSCLC with oligometastasis.^{37, 38} The most commonly used methods are radiofrequency ablation (RFA) and microwave ablation (MWA). Additionally, cryoablation has been used recently in treating cancer patients. However, owing to the lack of clinical data, technologies, such as laser ablation, have not been widely used in the treatment of lung tumors.³⁹

9 CONCLUSION

NSCLC oligometastasis is clinically regarded as an advanced stage of lung cancer. However, it differs from traditional advanced lung cancer in biological behavior and treatment strategies. The number of clinically oligometastatic NSCLC patients is relatively limited, and prospective randomized controlled studies are still lacking. However, the existing research data confirm that effective LAT combined with systemic treatment can significantly improve the prognosis of patients. In the occurrence, development, diagnosis, and treatment of oligometastatic. Thermal ablation has the advantages of less trauma, good curative effect, short treatment time, and low cost. Therefore, combining thermal ablation technology with other treatment methods can increase the local control rate and improve OS. Thus, it will be more widely used in the treatment of oligometastatic NSCLC in the future.

In clinical practice, it is necessary to fully understand the timing and complications of the combined application of multiple treatment methods in order to bring the ultimate benefit to patients. It is unreasonable to blindly emphasize one method while ignoring the comprehensive application of multiple methods. It is necessary to emphasize the importance and necessity of multidisciplinary cooperation in the treatment of cancer to prevent the various drawbacks caused by the excessive application of certain methods.

CONFLICT OF INTEREST

The authors have no conflict of interest to declare.