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Oligometastatic non-small cell lung cancer

Oligometastatic non-small cell lung cancer
Literature review current through: May 2024.
This topic last updated: Dec 22, 2023.

INTRODUCTION — As cancer treatments have evolved, some metastatic non-small cell lung cancer (NSCLC) patients with a limited burden of disease may be able to achieve long periods of disease control or potentially even cures.

For patients with stage IV NSCLC with one or a limited number of metastases, an emerging approach has been to use definitive treatment modalities in an attempt to render them disease free. The eighth edition Tumor, Node, Metastasis (TNM) staging system (effective in the United States as of January 1, 2018) distinguishes between patients with a single extrathoracic metastasis and those with multiple such metastases, reflecting that some patients with oligometastatic disease may receive more aggressive local and metastasis-directed therapy in addition to systemic treatment and have the potential for prolonged survival (table 1) [1]. (See "Tumor, node, metastasis (TNM) staging system for lung cancer".)

This topic reviews the basis of the oligometastatic clinical state and discusses outcomes among patients with oligometastatic NSCLC.

Related discussions on the approach to patients with brain metastases from NSCLC, stereotactic body radiation therapy, as well as topics regarding systemic therapy in NSCLC are found elsewhere.

(See "Brain metastases in non-small cell lung cancer".)

(See "Stereotactic body radiation therapy for lung tumors".)

(See "Initial systemic therapy for advanced non-small cell lung cancer lacking a driver mutation".)

(See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor".)

(See "Anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer".)

(See "Subsequent line therapy in non-small cell lung cancer lacking a driver mutation".)

THE OLIGOMETASTATIC STATE

Definition — The clinical state of oligometastasis describes patients with metastases limited in number and organ sites, who may have a more indolent biology. Additionally, the disease may be either without widespread metastases or with widespread metastases that are microscopic and able to be eradicated with systemic therapy. A particular challenge in defining the oligometastatic state is determining what specific criteria constitute "disease limited in number and organ sites." For the purposes of this topic, select patients with three or fewer metastases seem best-suited to metastasis-directed therapy (although the European Consensus definition is up to five metastases from three sites [2]). The rationale for metastasis-directed therapy to treat multifocal and asymptomatic disease becomes less justifiable as the number and/or bulk of lesions to treat increases. (See 'Selection of patients for local treatments' below.)

Presentation — The oligometastatic state can occur in several different settings:

Patients who presented with limited metastases at the time of initial cancer diagnosis, "de novo oligometastases" or "synchronous oligometastases" [3].

Oligorecurrence (or metachronous oligometastases) occurs in patients who have undergone curative-intent treatment to locoregional disease that remains controlled in the setting of new metastatic disease.

Patients with multiple metastases who are rendered oligometastatic from an effective response to systemic treatment that "eradicated" most metastases but failed to destroy one or a limited number of treatment-resistant tumor foci, called "induced oligometastases" [3].

Oligoprogression occurs when one or a limited number of metastases (generally five or fewer) recur or progress while systemic therapy continues to control the primary site and most areas of metastatic disease [4]. Such a situation has been frequently observed in the setting of acquired resistance to targeted therapies after a prolonged tumor response. In this setting, ablation of all progressive (ie, growing) metastases could potentially eradicate the metastases resistant to systemic therapy, allowing for continued delivery of systemic agents that are providing clinical benefit at other sites.

Whether or not the outcomes between these clinical situations differ with respect to tumor response or survival is not clear. In this review, all clinical scenarios with metastases limited in number and extent are considered as "oligometastases."

Incidence — Oligometastasis is relatively common in NSCLC, although the precise incidence is not clear. Improvements in diagnostic imaging (eg, positron emission tomography [PET], PET/computed tomography [CT], magnetic resonance imaging [MRI]) may allow detection of metastases in patients who otherwise have been thought to be free of metastases, or it may detect widespread metastases in patients thought to have oligometastatic disease.

As examples of reported incidence rates, in a Japanese study of patients with resected NSCLC (mostly adenocarcinoma), of those who developed distant recurrences in the absence of locoregional recurrence, 55 percent had limited disease (one to three metastases) [5]. Similarly, in a United States study, long-term follow-up of surgically managed, early-stage NSCLC found that greater than 50 percent of patients eventually developing metastases did so in three or fewer locations [6], although lower rates of oligometastases (26 percent) have also been reported [7].

These data are derived from the era before routine use of targeted therapy in patients with oncogene-driven NSCLC, so it remains unknown if the oligometastatic state is more or less common in oncogene-driven NSCLC.

Although earlier data are also available, they largely antedate the use of newer imaging modalities [8,9].

SELECTION OF PATIENTS FOR LOCAL TREATMENTS — While many patients develop limited metastases from NSCLC, only a relatively small percentage (on the order of 15 to 25 percent) experience long-term disease-free intervals following ablative treatment to all known metastases. Identification of the patients who are most likely to benefit from definitive treatment of oligometastases is of the utmost importance in deciding whether or not to offer metastasis-directed therapy. Our typical approach is to offer ablative therapy to all known metastases (and the primary tumor, if present) in patients with good performance status and limited metastases (one to three sites). Those who have had long disease free intervals (in the case of oligorecurrent disease) are more likely to derive benefit. Additionally, for patients who are not candidates for, or decline, systemic therapy, noninvasive ablative therapy can be considered as a means to afford control of the treated sites.

Presumably there is a relationship between increasing number of metastases and diminishing efficacy of metastasis-directed therapy. With ablative radiation therapy (RT), <5 lesions have been used as a cut-off in many studies because RT to more lesions might increase toxicity risks. In a patient with more than five lesions and low-volume disease, ablative RT might still be feasible, which is now often done in patients with brain metastases. (See "Overview of the treatment of brain metastases", section on 'High tumor burden or multiple large tumors'.)

Similarly, surgery may also be possible in some patients with more than five lesions, such as hepatic lobectomy containing more than five metastases. However, outcomes in such cases may not be as good as compared with those with a more limited number of metastases. Other factors that influence outcomes among those with oligometastatic disease are discussed below. (See 'Prognostic features' below.)

INCORPORATION OF SYSTEMIC THERAPY WITH LOCAL THERAPIES — Systemic therapy is the standard palliative treatment for patients with NSCLC initially presenting with metastatic disease or after relapsing to distant sites. The benefit of treating patients with systemic therapy for NSCLC with oligometastases amenable to resection or ablative therapies is not well understood, but in extrapolating from the benefit of systemic therapy for locoregionally advanced and metastatic NSCLC, we generally offer systemic therapy in addition to local therapies to those with oligometastatic NSCLC. However, for patients who are not candidates for, or decline, systemic therapy, noninvasive ablative therapy alone can be considered as a means to afford control of the treated sites.

The choice of systemic therapy is influenced by molecular studies and would be the same as the existing standard of care for stage IV disease. For those lacking a "driver mutation," immunotherapy, with or without chemotherapy, is more effective than older regimens. For patients who progress after first-line chemotherapy, additional chemotherapy agents are less effective, with response rates ranging around 10 percent with median survivals of seven to eight months [10]. Immunotherapy is now US Food and Drug Administration approved alone or in combination with chemotherapy for patients with NSCLC and has been evaluated after locally ablative therapy for oligometastatic disease [11]. (See "Initial systemic therapy for advanced non-small cell lung cancer lacking a driver mutation" and "Subsequent line therapy in non-small cell lung cancer lacking a driver mutation", section on 'Patients treated with initial chemoimmunotherapy'.)

Patients with an activating mutation in the epidermal growth factor receptor (EGFR) gene, rearrangements of the anaplastic lymphoma kinase (ALK) gene, or c-ROS oncogene 1 (ROS1), and others, are now typically treated initially with specific inhibitors, and other potential targets are being identified. Ablation of limited progressive metastases typically leads to longer duration of targeted systemic therapies, which in some reports (including a randomized trial) is associated with improved survival [12-14]. This is often followed by very limited progression in a single focus of disease (either intracranial or extracranial). (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

For patients with oligometastatic recurrence or progression while on targeted therapy, temporarily holding systemic therapy perioperatively or during radiation may reduce adverse effects; however, resuming some form of targeted therapy upon completion is typically recommended. A second-line agent is often chosen after local treatment, although if the site of treated oligometastatic disease was intracranial only, it would be appropriate to continue the original targeted agent. (See "Brain metastases in non-small cell lung cancer", section on 'Brain metastases upon progression on TKI' and "Brain metastases in non-small cell lung cancer", section on 'Brain metastases upon progression on TKI'.)

The optimal timing of ablative treatment with systemic therapy is not known. Because the initial appearance of oligometastatic disease or oligoprogression may merely be a harbinger of subsequent diffuse metastatic disease, favorable outcomes with local therapy for metastatic disease are more likely if limited metastatic disease remains oligometastatic over time. In this setting, we typically suggest that systemic therapy be administered for at least three months prior to local therapies, although we recognize that practice in this regard varies. The benefit of systemic therapy initially is that it may allow metastatic disease to "declare itself" as truly oligometastatic versus more widely metastatic disease, for which local therapies would likely not have been of benefit. Alternatively, ablative therapy while deferring systemic therapy until patients develop radiographically evident widespread metastatic progression can be considered, particularly in the setting of oligorecurrence or oligoprogression (as opposed to treatment-naïve disease). A hypothesis-generating study of 25 patients with oligometastatic NSCLC treated to all metastases reported that prior systemic therapy was associated with worse outcomes [15]. However, with upfront ablative therapy, the response to systemic therapy cannot be accurately gauged in patients whose disease remains controlled (ie, disease may have been controlled by ablative therapy, systemic therapy, or both).

There are no data to guide the duration of systemic therapy after local therapy, and this should be individualized based on how well the patient is tolerating treatment and the anticipated probability of subsequent relapse (based on the extent and pace of progression of metastatic disease prior to local therapy).

OTHER CONSIDERATIONS FOR LOCAL THERAPIES — Patients with oligometastatic NSCLC do not always develop progression to widespread metastases [8]. Therefore, there may be appropriately selected patients with respect to disease bulk/burden and number of metastases who can be treated with metastasis-directed surgical or ablative procedures. Locally ablative treatment directed to known metastases may render such patients disease free, possibly for a protracted interval. (See 'Efficacy' below.)

Treatment of both primary and metastatic sites — When treating patients with an untreated primary NSCLC and newly diagnosed oligometastases, there appears to be a benefit to treating all sites of malignancy with surgical or ablative therapies.

For example, in one study, 78 patients with newly diagnosed oligometastatic NSCLC were treated with definitive radiotherapy (RT) to both the primary site and ≤5 metastatic sites [16]. For all patients, the 1- and 3-year overall survival (OS) rates were 62 and 25 percent, respectively. Smaller tumor volume, better performance status, and an RT dose ≥63 Gy to the primary tumor were associated with improved OS. The site(s) of metastases were not prognostic.

Definitive treatment of the primary NSCLC tumor as well as sites of oligometastases is also supported by a systematic review that identified favorable prognostic factors [17]. Additionally, an individual patient meta-analysis indicated that patients treated with surgical management of the primary tumor in addition to all metastases had improved survival [18].

Efficacy

Overall — Data regarding efficacy for patients with oligometastatic NSCLC receiving any form of local therapy and for those specifically undergoing surgery or RT are discussed below. (See 'Radiation therapy' below and 'Surgery' below.)

While many patients develop limited metastases from NSCLC, only a relatively small percentage (on the order of 15 to 25 percent) experience long-term disease-free intervals following ablative treatment to all known metastases. Whether the disease-free benefits (and in some studies, overall survival benefits) seen in some patients with oligometastases are a result of the treatment to all metastases or due to more indolent biology is unclear. Although available data suggest a benefit from treatment, data to date come from retrospective and small phase II studies [19-23], including randomized phase II studies [23-26]. As examples of available data:

In a multicenter, randomized phase II study including 49 patients with three or fewer metastatic sites after first-line therapy for metastatic NSCLC, those assigned to local consolidative therapy of residual disease (stereotactic body RT [SBRT], hypofractionated RT, or resection), with or without maintenance systemic therapy, had a better progression-free survival (PFS) than those assigned to maintenance therapy alone (14.2 versus 4.4 months) [24]. Time to the appearance of a new lesion was longer for those receiving local consolidative therapy (14 versus 6 months). There was also a substantial OS benefit with local consolidative therapy (median, 41 versus 17 months, respectively). Approximately two-thirds of patients in this study had only primary disease or a single metastatic focus after first-line therapy, and such patients may derive the greatest benefit.

The SABR-COMET trial was a randomized phase II study of 99 patients with cancer of a variety of primary tumors and up to five metastatic lesions to any site. Overall, SBRT versus standard palliative care demonstrated improvement in OS that met predefined statistical significance (41 versus 28 months; hazard ratio 0.57, 95% CI 0.30-1.10), although only 18 percent on this trial had lung cancer [25]. This trial is discussed in further detail elsewhere. (See "Stereotactic body radiation therapy for lung tumors", section on 'Lung metastases'.)

However, not all trials have shown overall survival benefits. In an open label phase II trial including 106 patients with either oligometastatic breast or NSCLC, among the 59 patients with lung cancer, the addition of SBRT to standard of care treatment improved median PFS (10.0 versus 2.2 months), but failed to show an overall survival benefit [26].

Retrospective data also suggest an improved outcome with local consolidative therapy. These have included patients with both synchronous and metachronous metastases, various sites of metastases (both intracranial and extracranial), and patients treated with multiple treatment modalities (surgery, conventional RT, and/or SBRT). For example, a retrospective series analyzed outcomes for 61 patients with 1 to 3 synchronous metastases (intra- and extracranial) from NSCLC [22]. Most patients had a single metastasis (82 percent). Metastasis-directed treatments included surgical resection, conventional RT, and/or SBRT. The two-year PFS and OS rates were 8 and 38 percent, respectively.

Despite the limitations of these studies, they provide indirect evidence that definitive therapy of all sites of disease can result in prolonged disease-free survival in a subset of patients. Moreover, the finding of a significant improvement in time to new metastatic lesions or OS in a subset of these studies suggests that local therapies can alter the trajectory of the systemic progression of oligometastatic NSCLC. Ongoing trials including the National Cancer Institute-sponsored cooperative group NRG LU002 and the United Kingdom's SARON trial will provide further evidence [27,28].

Efficacy among specific subsets

Efficacy among those with oncogene-driven NSCLC – Among those with oncogene-driven NSCLC, there also appears to be a benefit to the addition of local therapies to systemic agents in appropriately selected patients.

The SINDAS trial randomly assigned 133 patients with previously untreated epidermal growth factor receptor (EGFR)-mutated NSCLC, with one to five oligometastases and no brain metastases, to upfront radiotherapy to the primary tumor, involved regional nodes, and oligometastases followed by a tyrosine kinase inhibitor (TKI) or to a TKI alone [14]. Upfront radiotherapy improved PFS (median 20 versus 13 months) and OS (median 26 versus 17 months).

In a Chinese study of 145 patients with stage IV EGFR-mutant oligometastatic (one to five sites) NSCLC, the median OS in patients undergoing local therapy (surgery or RT) to all sites of disease was 40.9 months compared with 34.1 months in those undergoing local therapy to some sites of disease and 30.8 months for those not undergoing RT [29].

Two retrospective studies were limited to patients with NSCLC who were treated with RT for extracranial metastases only. In one series, the five-year survival of 38 patients with up to eight metastases from NSCLC treated with SBRT was 14 percent [30]. Another series reported on 25 patients with limited metastatic disease (<5 sites; median, 2) who were treated with SBRT. The median survival was 22 months, and 28 percent were disease free at last follow-up [15]. Adverse prognostic factors included greater than two treated sites, prior systemic therapy, progression after systemic therapy, and nonadenocarcinoma histology.

Efficacy among those with intracranial disease – The presence of intracranial metastases, even those limited in number and treated with ablative therapies, is associated with worse PFS [18]. The efficacy of local treatments among those with intracranial disease involvement is discussed elsewhere. (See "Overview of the treatment of brain metastases".)

Choice of technique — The primary treatment options for definitive therapy of oligometastases are surgery and/or RT. Both surgery and modern RT techniques appear to control metastases equally well when selected by experienced practitioners, as shown in a single-institution analysis of outcomes of patients with pulmonary metastases [31].

Decisions between RT and surgery, or potentially how to combine them are usually made in a multidisciplinary tumor board. Situations in which surgery would be preferred include:

Metastases causing symptoms from mass effect

Bone metastases at risk of impending fracture

Metastases that would require biopsy for diagnosis and/or molecular testing, when resection would likely cause similar risks as a biopsy would (ie, intracranial malignancy)

Situations in which definitive doses of RT are likely to be prohibitively toxic (ie, abdominal metastasis compressing small bowel)

RT would be preferred for patients in whom resection would potentially be too morbid or who are not surgical candidates due to comorbidities, although we acknowledge that RT is also associated with morbidity and mortality [25]; additionally, patients with multiple lesions within one organ, with surgery expected to cause loss of function, may be better suited for RT. For some patients, a combination of surgery to some sites and RT to others may be offered as well.

Contraindications for RT (relative or absolute) include prior RT, active collagen vascular disease, and certain conditions including ataxia-telangiectasia and neurofibromatosis.

Surgery or RT may also be combined with systemic therapy. Other ablative modalities do not have an established role but may be useful in selected cases.

Surgery — We suggest a surgical approach to appropriately selected patients with oligometastatic disease. The benefit of surgery is that it can be considered for any metastatic site, but supporting data are largely observational.

As an example, in a Japanese study of 93 patients (14 with brain metastases) who underwent resection of recurrent metastatic NSCLC, the two- and five-year survival rates after recurrence were 44 and 39 percent [20]. Overall, however, studies specifically analyzing outcomes after resection of extracranial metastases from NSCLC are limited. Additionally, some studies also include patients receiving SBRT or other ablative therapies, in addition to surgery [17-19]. Many studies specific for metastasectomy for NSCLC include heterogeneous cohorts with respect to timing of metastases and metastatic sites [16-19,32-36], which often comprise a large percentage of patients with brain metastases [16-19,33-36].

Over the last decade, the rate of metastasectomy for patients with NSCLC is increasing, mainly driven by increasing resection for lung, brain, and adrenal metastases. These are being increasingly performed in patients with comorbid illness. Fortunately, over the same time period, perioperative mortality following metastasectomy is decreasing, with minimally invasive surgical approaches to metastasectomy and improved perioperative surgical care [37].

Radiation therapy — A number of studies have investigated RT with or without chemotherapy to treat oligometastatic NSCLC as a noninvasive means of achieving tumor eradication [38]. Most, but not all, studies treating patients with oligometastatic NSCLC with RT, similar to surgery studies, are retrospective. Furthermore, most have included various RT dosing schedules including conventionally fractionated RT and stereotactic techniques for both intracranial and extracranial metastases.

Stereotactic techniques deliver a single or limited number (most often five or fewer) of image-guided, precisely targeted, and high doses of RT that are associated with high rates of local tumor control. The use of these technologies, developed originally for intracranial targets, has been extrapolated extracranially and are commonly termed stereotactic body RT (SBRT). SBRT in particular has become widely used for the treatment of limited metastases with increasing utilization [39]. (See "Stereotactic body radiation therapy for lung tumors", section on 'Lung metastases' and "Radiation therapy techniques in cancer treatment", section on 'Stereotactic radiation therapy techniques'.)

As examples, in a single-institution study, 29 patients with limited metastatic NSCLC (primary plus up to five metastatic sites) without targetable mutations were randomly assigned to maintenance chemotherapy alone versus RT (hypofractionated RT to primary site as needed and SBRT to metastatic sites) followed by maintenance chemotherapy [23]. This study was closed early due to PFS endpoint being met prior to planned accrual. The SABR-COMET trial, which enrolled patients with oligometastatic disease from any primary site, demonstrated an OS benefit with the addition of SBRT to palliative standard-of-care treatments, and is discussed in detail elsewhere. (See "Stereotactic body radiation therapy for lung tumors", section on 'Lung metastases'.)

Other modalities — Various image-guided ablation techniques and combination treatment strategies are being developed to provide definitive therapy to localized tumor deposits. Although these approaches do not have a well-established role in the treatment of oligometastases, they may be useful in selected situations where the appropriate expertise is available. (See "Image-guided ablation of lung tumors".)

Radiofrequency ablation – Radiofrequency ablation (RFA) is an ablative technique that delivers high-frequency microwaves via a probe inserted into the tumor to thermally destroy tissue. RFA has been used for primary lung cancers [40-46] and pulmonary metastases [40-46]. The principles, results, and toxicity of RFA are discussed elsewhere. (See "Image-guided ablation of lung tumors", section on 'Radiofrequency ablation'.)

Cryoablation – Cryoablation is a technique that destroys tissue via extreme cold and freezing. A series of patients treated with multisite cryoablation for oligometastatic NSCLC has been reported with high treated tumor control rates and promising survival [47]. However, confirmatory studies are needed to validate these early findings. (See "Image-guided ablation of lung tumors", section on 'Cryoablation'.)

Combination approaches – For patients with widespread or more limited NSCLC, combining immunotherapy with SBRT in an effort to potentiate the immune response is an active area of investigation with promising results in preliminary studies [48-50], though further data are needed prior to incorporating this strategy into routine clinical practice.

PROGNOSTIC FEATURES

Number of metastases — In retrospective studies, the survival of patients with oligometastatic NSCLC is more favorable than in those with more numerous metastases (>5). However, this more favorable prognosis is irrespective of whether local therapy specifically directed toward the metastases is administered [7,9]. These observations may introduce a selection bias in retrospective studies. For this reason, an assessment of the value of local therapy requires prospective study.

As examples of available data, an analysis of 423 patients presenting with stage IV NSCLC from 2009 to 2012 found that the median survival was longer for patients with oligometastatic NSCLC (≤5 distant metastases) compared with patients with more extensive disease (17 versus 14 months; hazard ratio [HR] 0.73, 95% CI 0.53-1.01) [7]. Similarly, in another study, median survival in 370 patients with early-stage NSCLC who developed oligometastases was significantly longer than in those who developed diffuse metastases (12.4 versus 6.1 months; HR 0.53, 95% CI 0.41-0.69) [6].

Other factors that may influence outcomes — Although published studies generally use specific criteria (eg, solitary, ≤3, ≤5 metastases) to define oligometastatic disease, other factors also likely influence outcome of oligometastatic disease.

The following are suggested to be poor prognostic features, as suggested by observational evidence:

Synchronous rather than metachronous lesions [18]

More nodal involvement [7,18,51]

Squamous cell histology [52]

Poor performance status [52]

Presence of brain metastases [18]

Lack of epidermal growth factor receptor (EGFR) mutation [7]

Metastases to more than one organ [7,53]

Shorter interval from initial diagnosis to metastatic development [53]

Older age [53]

Specific microRNA signatures [54]

Extrapulmonary metastases [55]

Metabolic tumor volume and total lesion glycolysis, on positron emission tomography [56]

Prospective, randomized data are needed to confirm these as prognostic features and to determine whether any of them predict outcome to local treatments in oligometastatic disease.

SPECIAL CONSIDERATIONS FOR SPECIFIC SITES OF OLIGOMETASTASES

Brain metastases — Brain metastases from NSCLC are common. Limited brain metastases can be managed aggressively with resection. The use and benefit of specific therapy directed toward brain metastases has coincided with improved neurosurgical and radiosurgical techniques. Alternatively, ablative doses of radiation therapy (RT) delivered via stereotactic radiosurgery can be considered. (See "Overview of the treatment of brain metastases" and "Brain metastases in non-small cell lung cancer".)

Adrenal metastases — The adrenal gland is a common site of metastatic spread of NSCLC. Both surgery and stereotactic body RT (SBRT) can be used to target adrenal metastases. However, the diagnosis should not be based exclusively on imaging findings. Histologic confirmation of metastatic involvement with NSCLC is critical; in one study, 4 of 14 suspected adrenal tumors proved to be cortical adenomas [57].

Several single- and multi-institution retrospective series report favorable outcomes after adrenalectomy for adrenal oligometastasis from NSCLC [57-62], particularly if ipsilateral to their primary tumor [58]. Overall survival (OS) rates of >10 to 30 percent after three to five years have been reported [57-61,63]. In two single-institution studies [59,64] and in a pooled analysis of 10 studies [63], those with metachronous (versus synchronous relative to the primary NSCLC) adrenal metastases survived longer, while synchronous versus metachronous adrenal metastases were not prognostic in a multi-institutional French study [60]. In a separate observational study of 20 patients with isolated adrenal metastases from NSCLC who underwent surgical resection, the five-year survival rate for those with metastases ipsilateral to their primary tumor was 83 percent, versus 0 percent among those with contralateral metastases [58].

Data have also suggested that SBRT may be effective for those with oligometastatic disease only to the adrenal glands [65]. In a meta-analysis of 39 observational studies including 1006 patients with adrenal metastases, two-thirds of whom had a lung cancer primary, SBRT was associated with one- and two-year OS rates of 66 and 42 percent, respectively.

A review based upon three studies addressed the question of whether adrenalectomy is superior to definitive chemoradiation in the setting of a solitary adrenal metastasis [66]. Patients who either underwent or did not undergo adrenalectomy were compared in these three studies. From the analysis of three studies, adrenalectomy with regional nodal clearance for adrenal metastases was advocated for patients with "otherwise early-stage" NSCLC; R0 resection, long disease-free interval, and no other evident metastases were favorable prognostic factors. In one of the studies analyzed, among 37 patients with isolated adrenal metastases, the five-year survival was 34 percent in the adrenalectomy group versus 0 percent in the nonoperative group [58].

Lung metastases — Both surgery and SBRT are important options for patients with lung metastases. (See "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques" and "Stereotactic body radiation therapy for lung tumors".)

For patients undergoing surgery, sublobar resections are generally preferred over a more extensive resection (lobectomy, pneumonectomy), given the likelihood of new lung metastases developing over time and relatively limited pulmonary reserve after multiple resections.

In a Japanese study of 66 patients with pulmonary metastases from NSCLC (mostly adenocarcinoma), 18 had synchronous lesions in the same lobe, 16 had synchronous lesions in different lobes, and 42 had metachronous lesions [67]. Their respective five-year survivals after resection were 80, 31, and 35 percent; significant adverse risk factors included nodal metastases, increased age, and shorter interval from prior resection.

Hepatic metastases — Hepatic resections may be appropriate for select patients with oligometastatic disease in the liver, particularly those of good performance status, with a limited disease burden that is slowly progressive and resistant to other treatment modalities. There are many studies describing outcomes of patients treated with SBRT for hepatic metastases, albeit not specific to NSCLC histologies. Studies describing the outcome after partial hepatectomy for NSCLC metastases are limited to case reports and small case series [68-71]. The techniques and indications for resecting liver metastases have been developed primarily in patients with colorectal cancer. (See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy".)

Other metastatic locations — In a systematic review of patients with NSCLC undergoing definitive therapy for primary lung cancer and resection of solitary metastases to sites other than brain and adrenal, 62 patients were identified and analyzed [51]. The most common sites included bone (21 percent), liver (15 percent), kidney (11 percent), and spleen (10 percent). There are only extremely limited data for resection of bone [72] or skin [73] metastases.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and management of lung cancer".)

SUMMARY AND RECOMMENDATIONS

The oligometastatic state – The oligometastatic state in patients with non-small cell lung cancer (NSCLC) is defined by a limited number of metastases in a limited number of organ site(s). These patients may have a more indolent biology than those with more widespread metastases. There is variable opinion on the number and/or bulk of disease that constitutes oligometastases, although most studies have used three to five as a cut-off. (See 'The oligometastatic state' above.)

Presentation – Patients who present with limited metastases at the time of initial cancer diagnosis are said to have "de novo oligometastases" or "synchronous oligometastases." Oligorecurrence (or metachronous oligometastases) occurs in patients who have undergone curative-intent treatment to locoregional disease that remains controlled in the setting of new metastatic disease. (See 'Presentation' above.)

Selection of patients for local treatments – For patients with NSCLC who have a good performance status and one to three metastases, we suggest local therapy with systemic therapy rather than systemic therapy alone (Grade 2B). In such instances, we treat all sites of malignancy with surgical or ablative therapies. However, treatment decisions regarding local therapies should be made in a multidisciplinary setting, and in some cases, systemic therapy alone may be preferable (eg, for those with shorter disease-free intervals). (See 'Selection of patients for local treatments' above and 'Treatment of both primary and metastatic sites' above.)

Incorporation of systemic therapy with local therapies

The optimal timing of ablative treatment with systemic therapy is not known. We typically suggest that systemic therapy be administered prior to local therapies rather than the opposite sequence (Grade 2C), and typically advise a course of at least three months of systemic therapy, although we recognize that practice varies. The benefit of systemic therapy initially is that it may allow metastatic disease to "declare itself" as truly oligometastatic versus more widely metastatic disease, for which local therapies would likely not have been of benefit. Alternatively, ablative therapy while deferring systemic therapy until patients develop radiographically evident widespread metastatic progression can be considered, particularly in the setting of oligorecurrence or oligoprogression (as opposed to treatment-naïve disease). (See 'Incorporation of systemic therapy with local therapies' above.)

The choice of systemic therapy is influenced by molecular studies and is the same as the existing standard of care for stage IV disease. (See "Overview of the initial treatment of advanced non-small cell lung cancer", section on 'Initial systemic therapy' and "Subsequent line therapy in non-small cell lung cancer lacking a driver mutation" and "Initial systemic therapy for advanced non-small cell lung cancer lacking a driver mutation".)

-For patients with oligometastatic recurrence or progression while on targeted therapy, we temporarily hold systemic therapy perioperatively or during radiation therapy (RT) in an effort to reduce adverse effects. Upon completion of local therapy, a second-line agent would be chosen in many cases after local treatment, although if the site of treated oligometastatic disease was intracranial only, it would be appropriate to continue the original targeted agent. (See "Brain metastases in non-small cell lung cancer", section on 'Brain metastases upon progression on TKI'.)

Choice of local therapy technique – Although either surgery and/or RT may be used as local treatment options for oligometastatic NSCLC, from a practical perspective, nonoperative interventions are often preferred, given the comorbid conditions typical for patients with NSCLC that limit their ability to tolerate an operative intervention. (See 'Choice of technique' above.)

Prognostic features – Greater number of metastatic sites is associated with worsened prognosis. Other factors that likely influence prognosis include extent of lymph node involvement, histology, and presence of intracranial disease. (See 'Prognostic features' above.)

Special considerations for brain metastases – Limited brain metastases can be managed aggressively with resection. Alternatively, ablative doses of RT delivered via stereotactic radiosurgery can be considered. (See "Overview of the treatment of brain metastases" and "Brain metastases in non-small cell lung cancer".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Howard (Jack) West, MD, who contributed to earlier versions of this topic review.

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Topic 97507 Version 31.0

References

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