Oligometastatic disease - Clinical Tree

CLINICAL PEARLS

Stage IV NSCLC is a heterogeneous disease, reflected in reclassifications seen in the eighth edition of the TNM staging system. Oligometastatic disease, described as an isolated metastasis or limited metastases in a single or limited number of organs, is now classified separately from other stage IV manifestations. The most commonly used criteria are five or fewer total metastases in up to three separate organs.
Favorable prognostic factors include isolated metastasis, clinical node–negative disease (cN0), pathological primary tumor size ≤7 cm, and metachronous disease. In terms of location, patients with intrathoracic oligometastases fare the best, and among extrathoracic disease, brain rather than extracranial oligometastases are associated with longer median overall survival.
When feasible and in appropriately selected patients, local control of the primary tumor and metastases via surgery, radiotherapy, and/or other ablative modalities combined with systemic therapy appears to offer the most survival benefit. This is now concordant with National Comprehensive Cancer Network (NCCN) guidelines. ^,
The most common sites of oligometastatic disease are brain, contralateral lung, and adrenals. Many other sites of distant disease have been described. ^, NCCN guidelines recommend a complete metastatic workup with mediastinal staging, whole-body positron emission tomography/computed tomography scan, and brain magnetic resonance imaging. If these tests are negative for T4, N2 (TNM eighth edition) or widely disseminated disease, the guidelines recommend treating all sites of disease with local consolidative therapy. Sites of oligometastatic disease should be confirmed pathologically before beginning local therapy when possible.
Future studies will continue to evaluate the effectiveness of local control techniques to optimize survival for these patients. The optimal timing and type of systemic therapy also need further investigation. As technology and our understanding of NSCLC improve, our treatment approaches will also evolve.

Introduction

Non–small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality in the United States. Approximately half of all patients with NSCLC present with stage IV, or metastatic disease, and this portends a particularly poor 5% 5-year overall survival (OS) rate. ^, While the 5-year OS rate for stage IV disease is significantly lower than NSCLC’s 19% median 5-year OS rate, it has become increasingly clear that metastatic disease exhibits heterogeneous behavior, with studies suggesting that number of metastases, clinical nodal stage (cN), pathological primary tumor size (pT), and timing and location of metastatic disease may all affect survival rates. ^, ^,

Oligometastatic disease broadly refers to an isolated metastasis or limited metastases concentrated in a “single or limited number of organs” and may account for up to 50% of stage IV diagnoses. ^, Hellman and Weichselbaum coined this term in 1995 and further hypothesized that cancer exists on a biological spectrum with the oligometastatic state representing a more indolent intermediary between local and widely disseminated disease with a limited metastatic potential. ^, On the basis of this theory, they suggested that patients with oligometastatic disease may be “amenable to curative therapeutic strategy” in contrast to those with widely disseminated metastases. Although oligometastases lack a precise, universal definition, most researchers have focused their attention on patients with five or fewer metastases, with few studies expanding their criteria up to eight metastases. The number of sites involved also varies, with most studies including between one and three organs in the definition. Furthermore, modifiers, such as de novo oligometastases, induced oligometastases, oligorecurrence, and oligoprogression, have been added to help clarify different temporal patterns of disease ( Table 6.1 ). A simpler temporal modification scheme simply separates oligometastases into synchronous or metachronous disease. When one considers that within the different categories of oligometastatic disease there are also a number of prognostic factors and site-specific variability, the heterogeneity of oligometastatic disease becomes clear.

TABLE 6.1 ■

Oligometastatic Definitions

Term	Definition
Oligometastases	Single metastasis or limited metastases concentrated in a single or limited number of organs
De novo oligometastases	Few metastases at diagnosis
Induced oligometastases	Widely metastatic at diagnosis but become oligometastatic after systemic therapy
Oligorecurrence	Appearance of 1–5 metachronous metastases after the primary cancer has been controlled by initial definitive therapy; may account for 33%–50% of patients with recurrent disease
Oligoprogression	Disease progression only in limited sites in patients receiving systemic therapy

This realization was addressed in the eighth edition of the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system, which was released in 2017, and further subcategorized metastatic disease in an effort to reflect differences in survival trends seen with isolated metastasis or limited metastases ( Table 6.2 ). In the eighth edition, M1a disease has remained unchanged from the previous edition and represents separate tumor nodule(s) in a contralateral lobe, tumor with pleural or pericardial nodules, or malignant pleural or pericardial effusions. The former M1b disease, which included all extrathoracic metastatic disease, is now separated into M1b for a single extrathoracic metastasis in a single organ and M1c for multiple extrathoracic metastases in one or several organs. Importantly, median survival differs significantly among these new groups (22.5 months for M1a; 17.8 months for M1b; 13.6 months for M1c; P < 0.001). These revisions were based on the International Association for the Study of Lung Cancer’s 2016 proposal for TNM stage revisions. The International Association for the Study of Lung Cancer performed a sophisticated analysis that used both clinical and pathological training and validation sets to arrive at its revision recommendations. Importantly, the clinical training sets included a small number of potentially oligometastatic cases ( n = 17,477; M1a = 277; M1b = 207; M1c = 398), and the pathological training sets only included M0 cases. Since pathological M1 disease was excluded from the training and validation sets, the outcomes following surgical intervention for M1 disease were not accounted for in their survival analysis. Given the improved survival trends seen elsewhere in the literature after local consolidative treatment of oligometastatic disease, we anticipate that more patients will be available for survival analysis with pathological M1 disease when developing the TNM ninth edition.

TABLE 6.2 ■

Reclassifications of M Stage in the AJCC TNM 8th Edition

TNM	7th Edition	8th Edition	8th Edition Median OS Survival ( P < 0.001)
M1a	Separate tumor nodule(s) in a contralateral lobe, tumor with pleural or pericardial nodules, or malignant pleural or pericardial effusions	No change	22.5 months
M1b	All extrathoracic metastatic disease	Single extrathoracic metastasis in a single organ	17.8 months
M1c ^a	N/A	Multiple extrathoracic metastases in one or several organs	13.6 months

AJCC, American Joint Committee on Cancer; OS, overall survival; TNM, tumor, node, metastasis.

a New M classification in the 8th edition.

Treatment

The treatment of stage IV NSCLC historically has been limited to palliative chemotherapy given its poor prognosis, but drastic changes have been made to treatment algorithms in the past decade as researchers and providers have garnered a new understanding of this disease. Particularly, there is a growing body of evidence to suggest that stage IV NSCLC, once thought to be incurable, can be managed with local control (LC) of both the primary tumor and limited sites of metastatic disease for patients with oligometastatic disease. A review of the literature has identified instances of increased median survival, increased disease-free survival, and even cure when this strategy is employed. Currently, different combinations of surgery, radiation therapy, other ablative modalities, and systemic therapy are used to treat oligometastatic disease definitively. The most survival benefit appears to be derived when LC of the primary tumor and all sites of metastatic disease is combined with systemic therapy. ^,

Local control

Definitive intent treatment of local intrathoracic disease and all sites of oligometastatic disease has repeatedly produced favorable survival outcomes in the literature. Retrospective reviews of patients with metastatic NSCLC treated with first-line systemic therapy have shown a predominantly local recurrence pattern, suggesting that aggressive LC of these sites may lead to prolonged survival. Following this rationale, researchers began to focus on LC of oligometastatic disease, and definitive local treatment is now one of the only facets of oligometastatic disease management that has been tested with a multicenter, randomized controlled phase 2 study.

In a 2016 randomized controlled trial, Gomez and colleagues demonstrated superior survival outcomes in patients with oligometastatic disease who received local consolidative therapy (LCT) versus maintenance treatment or observation (MT/O) only. Their study enrolled 49 patients with pathologically confirmed stage IV NSCLC who had residual, limited metastatic disease after standard first-line systemic therapy and randomized them to receive either LCT or MT/O. Eligible patients for randomization had three or fewer metastases after standard first-line systemic therapy and did not show signs of progression after initial therapy. Any nodal disease counted as one site to account for the prognostic significance of this group. LCT was defined as intent to ablate all residual disease (primary tumor, lymph nodes, and metastatic sites) after first-line chemotherapy and included surgery, radiotherapy, or both. Maintenance therapy included approved cytotoxic systemic therapy, and observation included close surveillance only. Patients in the LCT group had a significantly longer progression-free survival (PFS) (11.93 months; 90% confidence interval [CI], 5.72–20.90 months) than patients in the MT/O group (3.9 months; 90% CI, 2.30–6.64 months) (hazard ratio [HR], 0.35; 90% CI, 0.18–0.66; log-rank [ P = 0.0054]). Additionally, the 1-year PFS was 48% (90% CI, 28.7%–65.7%) for the LCT group compared with 20% (90% CI, 7.1%–38.0%) in the MT/O group. At the time of data analysis of the 2016 trial, median survival time had not been reached in either group, allowing a follow-up analysis in 2019 to report longer-term OS results.

In Gomez and colleagues’ 2019 follow-up analysis PFS remained longer in the LCT group (median 14.2 months; 95% CI, 7.4–23.1 months) compared with the MT/O group (median 4.4 months; 95% CI, 2.2–8.3 months) ( P = 0.022), and importantly, patients receiving LCT also experienced an OS benefit. Patients in the LCT arm survived a median 41.2 months (95% CI, 18.9 months to not reached) compared with patients in the MT/O arm who survived a median 17.0 months (95% CI, 10.1–39.8 months) ( P = 0.017). The potential for unreached median OS is unprecedented for stage IV NSCLC. Similarly promising, other series have suggested that in the proper cohort, such as in patients with oligometastases and early-stage intrathoracic disease, definitive intent local therapy can offer survival comparable with stage II disease. ^,

Control of the primary tumor and all sites of oligometastatic disease appears to be associated with the largest survival advantage; however, studies have demonstrated benefits from definitive control of local intrathoracic disease independent of management of oligometastatic sites. Definitive control of the primary tumor and regional spread via surgery or radiotherapy is referred to as aggressive thoracic therapy (ATT). Li and colleagues performed a meta-analysis that reviewed 668 patients with synchronous oligometastatic NSCLC from 1999 to 2015. Two-hundred and twenty-seven patients received ATT by either surgery alone, radiotherapy alone, or surgery combined with radiotherapy. Receiving ATT in this review was associated with a 52% overall reduction in risk of death compared with not receiving ATT (HR 0.48; 95% CI, 0.39–0.60; P < 0.00001); furthermore, pooled 1-year, 2-year, 3-year, and 4-year survival rates were 74.9%, 52.1%, 23.0%, and 12.6%, respectively, for patients who received ATT versus 32.3%, 13.7%, 3.7%, and 2.0%, respectively, for those who did not receive ATT. Importantly, a survival benefit persisted across all intrathoracic disease stages after stratified analysis.

Whether treatment is surgical or radiotherapy based, emerging evidence continues to support ATT as a treatment pillar of oligometastatic NSCLC. Optimal results appear to be achieved when ATT is combined with definitive intent LC of all sites of oligometastatic disease. This is now guideline concordant care per the National Comprehensive Cancer Network’s (NCCN, version 7.2019). NCCN guidelines suggest that in patients with M1b and select M1c disease (AJCC TNM eighth edition), definitive intent treatment of the primary tumor and oligometastases should be considered when feasible if patients also have T1-3 and N0-1 disease. Given the apparent importance of LC, providers should be familiar with the different strategies available to achieve this important treatment goal.

Surgery

Historically, surgery has played a palliative and diagnostic role in stage IV NSCLC, but with the suggestion of an oligometastatic disease state, surgery now has a role for curative intent. Despite encouraging survival outcomes when surgery is incorporated into treatment regimens for advanced stage IV NSCLC, its use appears to be decreasing. This could reflect an underutilization of surgery to treat oligometastatic NSCLC. Supporting this, a study by Uhlig and colleagues demonstrated that despite superior survival outcomes following surgical resection plus systemic therapy for stage IV NSCLC, this treatment approach was the least used when compared with external beam radiotherapy (EBRT)/thermal ablation (TA) plus systemic therapy, and systemic therapy alone. The surgical cohort had a 72.9% 1-year OS, and superior survival outcomes persisted after multivariable analysis and adjusting for cofounders, such as preferential surgical resection in oligometastatic NSCLC (HR vs. EBRT/TA plus systemic therapy: 0.62; 95% CI, 0.57–0.67; P < 0.001; HR vs. systemic therapy alone: 0.59; 95% CI, 0.55–0.64; P < 0.001). Interestingly, the overall composition of Charlson-Deyo Comorbidity Indices was statistically different among groups ( P = 0.001) with the surgical cohort having the lowest proportion of patients with a Charlson-Deyo score of 0 (surgical resection plus systemic therapy = 59.0% vs. EBRT/TA plus systemic therapy = 62.3% vs. systemic therapy alone = 64.1%), and the highest proportion of patients with a Charlson-Deyo score of ≥3 (surgical resection plus systemic therapy = 3.4% vs. EBRT/TA plus systemic therapy = 2.7% vs. systemic therapy alone = 2.8%). Despite these results, surgical resection plus systemic therapy was only used in 835 of 34,887 (2.4%) patients, compared with 9539 (27.3%) patients who received EBRT/TA plus systemic therapy and 24,513 (70.3%) patients who received systemic therapy alone.

Surgical resection is an option for LC of both the primary tumor and oligometastases in most organs but may be especially important for treatment of the primary tumor. ^, Ashworth and colleagues performed a systematic review that revealed an association between surgical management of the primary tumor and improved PFS. Their review included 757 patients who underwent curative treatment of the primary lung cancer and oligometastases. The authors performed a recursive partitioning analysis (RPA) to stratify patients into low-, intermediate-, and high-risk groups based on variables that remained significant predictors of OS and PFS after multivariate analysis. Patients with nonsurgical management of their primary tumors had poorer PFS after local treatment of oligometastases compared with those with complete surgical resection of their primary tumors (HR 2.45; 95% CI, 1.38–4.37; P = 0.002). This review only found an association between surgical resection of the primary tumor and PFS, not OS, but a retrospective study by Hanagiri and colleagues reported an encouraging 30% 5-year OS rate among patients who had complete surgical resection of their primary tumor and LC of distant metastases.

Surgical resection is an appealing treatment approach for the primary tumor in oligometastatic disease; however, it requires a surgically fit candidate, and surgical resection of metastatic disease remains controversial. Multidisciplinary teams (MDTs) that include surgeons can help with surgical decision making. Patients whose physicians attended MDT weekly were more likely to receive curative intent surgical resection when appropriate (odds ratio [OR] 2.9; 95% CI, 1.3–6.8). Furthermore, another study suggested that when the primary tumor was surgically resected, involvement of an MDT versus no MDT involvement improved 1-year survival in propensity matched groups (OR 0.48; 95% CI, 0.25–0.92). When surgical treatment of oligometastatic NSCLC is not feasible, less invasive modalities of ablating primary and metastatic disease remain options.

Radiotherapy

Radiation therapy, delivered as conventionally fractionated external beam radiation (EBRT), is a staple of curative intent treatment for early-stage NSCLC. The past decade has seen technological advancements that now allow for the precise deliverance of high-dose radiation to a local target while sparing normal, surrounding tissue. This technology is known broadly as hypofractionated image-guided radiotherapy, with the terms stereotactic radiosurgery (SRS) used with intracranial targets and stereotactic body radiotherapy or stereotactic ablative radiotherapy (SBRT or SABR) used with extracranial targets.

SBRT was first used in NSCLC treatment as an alternative to surgical resection of early-stage cancers in patients with prohibitive comorbidities or inadequate pulmonary reserve. On the basis of promising results with SBRT treatment for primary NSCLC, providers began to apply the modality to pulmonary oligometastases. In a study by Ouyang and colleagues, 71 oligometastatic NSCLC patients with 86 pulmonary lesions were treated with SBRT. OS and PFS were significantly better for these patients than for historical controls receiving palliative intent therapy only. Furthermore, patients tolerated the procedure well with no Common Terminology Criteria for Adverse Events (CTCAE v4.0) grades 4 to 5 toxicity reported. SRS is now recommended as an alternative to surgery for upfront treatment of intracranial NSCLC oligometastases, and extracranially, SBRT delivered at a biologically effective dose is associated with tumor control rates in excess of 90%, which approaches surgical management for patients who are not surgical candidates. ^,

Radiotherapy, like surgical resection, has its limitations. Safe delivery requires accurate image-guided mapping, patient immobilization, and sophisticated motion analysis to account for respiratory variation. Advances in technology continue to mitigate many of radiotherapy’s limitations; however, effective local treatment has shifted the recurrence pattern from local disease to distant disease. Out-of-field metastatic progression in many patients provides a strong rationale for combining LC modalities with systemic therapy in patients who can tolerate it.

Briefly, ablative techniques using radiofrequency, microwave, cryotherapy, chemical, or irreversible electroporation technology to treat oligometastatic NSCLC is gaining interest but is limited to select institutions and patient populations and, therefore, remains investigative at this time.

Systemic therapy

Systemic therapy has been a cornerstone of treatment for reasonably fit patients with stage IV NSCLC, but its role in oligometastatic disease is not as clear. Systemic therapy options include standard cytotoxic chemotherapy, target-directed therapy, or immunotherapy with checkpoint inhibitors, but the timing of administration and precise regimens are still debatable.

Studies have suggested that it may be helpful to continue systemic therapy in the setting of induced oligometastases or oligoprogression, but the optimal timing of systemic therapy in the setting of synchronous oligometastatic disease has not been defined. The NCCN guidelines simply state to consider neoadjuvant systemic therapy and restaging to confirm nonprogression before definitive LC or, alternatively, to consider adjuvant systemic therapy if systemic therapy has not already been given. It is common clinical practice to address symptomatic intracranial oligometastases with upfront SRS or resection followed by systemic therapy and to address extracranial oligometastases with upfront systemic therapy followed by LC. This practice is supported by research that suggests improved PFS when systemic treatment is administered before LC of extracranial oligometastases.

Currently, randomized trials investigating systemic therapies have largely included patients with widely disseminated rather than only oligometastatic disease. However, improvements in systemic treatment based on these randomized trials have led to the observation of induced oligometastases and oligoprogression, both of which have heightened the need for LC in these patients. ^, An induced oligometastatic response to neoadjuvant systemic therapy for widely disseminated disease may allow for selection of patients who are likely to gain long-term benefit from aggressive local therapy. Studies have suggested that these patients may be less likely to develop new metastases and experience improved PFS after consolidation with aggressive local therapy to all sites of residual disease when it is limited in nature (typically ≤3 lesions). Likewise, oligoprogression of select metastases with the bulk of disease well controlled by systemic therapy may also select patients who would benefit from LC of progressing sites. In the past, progression of any sites of disease during systemic treatment was an indication to switch regimens; however, local treatment to a limited number of progressing sites has allowed continuation of largely effective systemic therapy with greater than 6 months of additional disease control. ^, In addition to the timing of systemic therapy, the type of therapy employed may also influence outcomes.

The selected regimen typically depends on the tumor’s histological and genotypic information. Historically, platinum-based doublet chemotherapy has been first-line systemic treatment for stage IV NSCLC. However, the discovery of onco-addicted NSCLC that features anaplastic lymphoma kinase gene rearrangements or epidermal growth factor receptor (EGFR) mutations has led to the development of therapies that target these specific drivers and appear to offer more benefit than chemotherapy when these alterations are present. Ouyang and colleagues reported a significantly longer median PFS in patients with ≤5 oligometastatic lesions (26.4 months; 95% CI, 7.4–52.4 months) and OS (34.8 months; 95% CI, 18.8–50.8 months) in stage IV NSCLC EGFR mutants when SBRT followed EGFR-Tyrosine Kinase Inhibitor (TKI) therapy compared with a median PFS (6.9 months; 95% CI, 5.8–8.0 months) and OS (15.5 months; 95% CI, 3.5–27.5 months) when SBRT followed chemotherapy. The best results may be seen when target-directed therapy is combined with LC. Retrospective data have shown that adding SBRT to EGFR-TKI therapy extended median PFS to 20.6 months from 8.11 months when patients with ≤5 oligometastatic lesions were treated with EGFR-TKI therapy alone. Researchers have continued to identify more genetic alterations in NSCLC, which has resulted in an unprecedented growth of targeted therapies and clinical trials. Because of the recent change to the staging system, which now makes oligometastatic disease patients easier to track in large datasets, our understanding of oligometastatic disease should become clearer over the next few years.

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