Elsevier

Lung Cancer

Volume 82, Issue 2, November 2013, Pages 197-203
Lung Cancer

Is there an oligometastatic state in non-small cell lung cancer? A systematic review of the literature

https://doi.org/10.1016/j.lungcan.2013.07.026Get rights and content

Abstract

Objectives

Long-term survival has been observed in patients with oligometastatic non-small cell lung cancer (NSCLC) treated with locally ablative therapies to all sites of metastatic disease. We performed a systematic review of the evidence for the oligometastatic state in NSCLC.

Materials and Methods

A systematic review of MEDLINE, EMBASE and conference abstracts was undertaken to identify survival outcomes and prognostic factors for NSCLC patients with 1–5 metastases treated with surgical metastatectomy, Stereotactic Ablative Radiotherapy (SABR), or Stereotactic Radiosurgery (SRS), according to PRISMA guidelines.

Results

Forty-nine studies reporting on 2176 patients met eligibility criteria. The majority of patients (82%) had a controlled primary tumor and 60% of studies included patients with brain metastases only. Overall survival (OS) outcomes were heterogeneous: 1 year OS: 15–100%, 2 year OS: 18–90% and 5 year OS: 8.3–86%. The median OS range was 5.9–52 months (overall median 14.8 months; for patients with controlled primary, 19 months). The median time to any progression was 4.5–23.7 months (overall median 12 months). Highly significant prognostic factors on multivariable analyses were: definitive treatment of the primary tumor, N-stage and disease-free interval of at least 6–12 months.

Conclusions

Survival outcomes for patients with oligometastatic NSCLC are highly variable, and half of patients progress within approximately 12 months; however, long-term survivors do exist. Definitive treatment of the primary lung tumor and low-burden thoracic tumors are strongly associated with improved long-term survival. The only randomized data to guide management of oligometastatic NSCLC pertains to patients with brain metastases. For other oligometastatic NSCLC patients, randomized trials are needed, and we propose that these prognostic factors be utilized to guide clinical decision making and design of clinical trials.

Introduction

The primary treatment for most patients with metastatic NSCLC is palliative chemotherapy, which results in median survivals of 8–11 months [1] and provides minimal chance of long-term survival. Despite these generally dismal outcomes, encouraging reports of long-term survival in select patients with low-volume metastatic NSCLC treated with curative intent have emerged in the recent literature [2]. The rationale for this approach is based on a theory of cancer spread proposed by Hellman and Weichselbaum. Along the spectrum of locally confined to widely metastatic cancer, there exists an intermediate “oligometastatic state” where metastases are limited in number and location [3]. It has been hypothesized that in select oligometastatic patients, locally ablative therapies given with the intent of eradicating all sites of known metastatic disease could result in long-term survival, or even cure [4].

Much of the evidence supporting the oligometastatic state exists within the surgical literature. The international registry of lung metastases reported the outcomes of 5206 patients with resected lung metastases from a variety of primary cancers and reported a 5 year survival of 36% [5]. Analogously, hepatic resection is considered a standard treatment option for metastatic colorectal cancer and can result in 10-year survival rates of 20–26%, and potential cure [6]. However, neither intervention is supported by level 1 evidence from randomized trials. Furthermore, some have suggested that the long-term survival outcomes observed in such studies may be more reflective of patient selection, rather than treatment effect [7].

There is an increasing body of literature describing the use of less invasive ablative techniques for the treatment of oligometastases, such as Stereotactic Radiosurgery (SRS) and Stereotactic Ablative Radiotherapy (SABR), a novel radiotherapy technique that utilizes highly conformal, ablative doses, usually delivered in 8 or fewer fractions. SABR is a standard treatment option for medically inoperable patients with early-stage NSCLC, yielding local control and survival rates superior to conventionally fractionated radiotherapy techniques and comparable to those achieved with surgical resection [8], [9], [10], [11], [12]. Emerging data on the use of SABR in patients with oligometastatic cancer report high rates of local control and, in select patients, long-term survival. A systematic review reporting on 334 patients with pulmonary oligometastases (from a variety of primary tumors) treated with SABR from 13 institutions reported a 2 year local control rate of 77.9% and a 2 year OS of 53.7% [13]. SABR has also been utilized for metastases of the liver [14], [15] and adrenal gland [16], with rates of local control and survival outcomes comparable to those reported for surgical metastatectomy. Several studies have described the use of SABR in patients with mixed metastatic sites from a variety of primary cancers, and report local control rates of 74–80% and 2 year OS of 39–56% [17], [18], [19].

Other pertinent findings from these studies provide insight into the natural history of oligometastatic disease, such as the observation that approximately 80% of patients will develop further metastases, 2–4 years after SABR [20]. Conversely, approximately 20% of patients may achieve long-term survival without developing additional metastases and appropriate selection of patients for aggressive treatment is of paramount importance.

There is uncertainty as to whether the oligometastatic state truly exists in NSCLC, since the outcomes for NSCLC have historically been significantly poorer than other cancers. Though multiple retrospective case series have reported long-term survival in oligometastatic NSCLC patients treated with curative intent, outcomes and patient populations are variable and there are no clearly defined parameters to identify which patients might benefit most from ablative treatment of oligometastases. We performed a systematic review of the evidence for the oligometastatic state in NSCLC, to describe outcomes and prognostic factors that identify patients who may benefit from aggressive strategies.

Section snippets

Literature search strategy

A systematic review of the literature was performed according to PRISMA systematic review guidelines (www.prisma-statement.org). The Medline and EMBASE databases were searched for relevant papers between 1985 and 2012 that met the study inclusion/exclusion criteria:

Inclusion and exclusion criteria

We identified reports containing the survival outcomes and prognostic factors of NSCLC patients with 1–5 synchronous or metachronous metastases with a “controlled” primary (with “local control” defined as concurrent or previous

Literature search results

The search identified 1897 potentially eligible articles (1880 MeSH only and 17 keyword only; Fig. 1). After applying the exclusion criteria, 135 publications remained potentially eligible. Twenty-one additionally pertinent papers were identified from a bibliography review of these papers and two abstracts were identified from the ASTRO 2012 conference proceedings, leading to a total of 158 potentially eligible articles. These articles underwent full data abstraction to ensure final eligibility

Discussion

Although there have been calls for aggressive treatment of oligometastatic NSCLC, [21] this systematic review has revealed that survival outcomes reported in the literature for patients with oligometastatic NSCLC treated with curative intent are extremely variable, with 5-year survivals ranging from very poor (<10%) to excellent (>80%). In most studies included herein, the patients were highly selected, most often with a controlled primary tumor, 1–3 metastases, most often located in the brain,

Conclusion

There is a paucity of randomized data to guide the management of patients with oligometastatic NSCLC. The preponderance of evidence suggests that the patient selection is a key determinant of long-term survival in patients with oligometastatic NSCLC. Although some highly selected patients do achieve long-term survival, most develop progression with the first-year post-treatment. Key determinants of long-term survival include definitive treatment of the primary tumor, a long disease-free

Conflict of Interest Statement

None declared.

Funding

This work was supported by a clinician-scientist grant from the Ontario Institute for Cancer Research, funded by the Government of Ontario.

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