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Role of Local Ablative Therapy in Patients with Oligometastatic and Oligoprogressive Non–Small Cell Lung Cancer

Journal of Thoracic Oncology, Volume 12, Issue 2, February 2017, Pages 179 - 193

Abstract

Because of an improved understanding of lung cancer biology and improvement in systemic treatment, an oligometastatic state in which metastatic disease is present at a limited number of anatomic sites is being increasingly recognized. An oligoprogressive state, which is a similar but distinct entity, refers to disease progression at a limited number of anatomic sites, with continued response or stable disease at other sites of disease. Such an oligoprogressive state is best described in patients with NSCLC treated with molecular targeted therapy. Possible explanations for development of the oligoprogressive state include the presence of underlying clonal heterogeneity and extrinsic selection pressure due to the use of targeted therapy. Traditionally, local ablative therapy (LAT) has been limited to symptom palliation in patients with advanced NSCLC, but the presence of oligometastatic or oligoprogressive disease provides a unique opportunity to evaluate the role of LAT such as surgery, radiation therapy, radiofrequency ablation, or cryoablation. There is increasing evidence to support the clinical benefit of LAT in patients with NSCLC with limited metastatic disease and in selected individuals in whom resistance to targeted therapies develops. In the latter instance, adequate treatment of drug-resistant clones by LAT could potentially help in avoiding switching systemic therapy prematurely. This review focuses on the biology of oligometastatic and oligoprogressive NSCLC and describes the role of LAT in the treatment of these conditions.

Keywords: Local ablative therapy, NSCLC, Oligometastatic disease, Oligoprogressive disease, Molecular targeted therapy.

Introduction

Lung cancer remains the leading cause of cancer deaths among both men and women in the United States. In 2016, lung cancer will be diagnosed in an estimated 224,390 patients and 158,080 will die from the disease in the United States.1 The 5-year overall survival (OS) rate for lung cancer (16%) is lower than that for most other solid tumors and is particularly low for patients with distant metastatic disease (2%).2 NSCLC is the most common type of lung cancer, comprising 86% of all cases.3

Platinum-based chemotherapy regimens are the standard of care for patients with advanced NSCLC without oncogenic driver mutations, and they are associated with response rates of 20% to 30%.4, 5, and 6

The therapeutic landscape of NSCLC has changed considerably with the advent of molecular targeted therapy, which has resulted in substantial improvements in response rates and survival in patients with selected driver mutations. Randomized trials that compared erlotinib, an EGFR tyrosine kinase inhibitor (TKI), with standard chemotherapy as first-line treatment for patients with advanced EGFR mutation–positive NSCLC have demonstrated objective response rates of 58% to 83% for erlotinib compared with 15% to 36% for chemotherapy.5 and 6 In patients with locally advanced or metastatic anaplastic lymphoma receptor tyrosine kinase gene (ALK)-positive NSCLC, the objective response rates associated with first-line use of crizotinib, an anaplastic lymphoma kinase (ALK) inhibitor, and chemotherapy were 74% and 45%, respectively.7

Traditionally, metastatic disease has been regarded as incurable and the role of local therapy has been limited to palliation of symptoms.8 Because of our evolving understanding of cancer biology and improvement in systemic therapy, it is now recognized that the spectrum of metastatic disease differs among patients and there exists in some individuals a state of limited metastatic burden or disease progression that can potentially be treated definitively with local ablative therapy (LAT) such as surgery, radiation therapy (RT), radiofrequency ablation (RFA), or cryoablation. These unique situations are labeled oligometastatic and oligoprogressive disease, respectively. In this article, we review the role of LAT in the management of oligometastatic and oligoprogressive NSCLC.

Materials and Methods

To identify the medical literature that describes the use of LAT for treatment of NSCLC, we searched PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) by using the search terms oligometastatic or oligometastases or oligoprogressive or oligoprogression or local therapy or local ablative therapy and lung cancer or lung cancers. This search was limited to the English-language literature published within the last 10 years. A total of 158 papers were identified, and the papers most relevant to LAT as a treatment modality for oligometastatic or oligoprogressive NSCLC were selected. A manual search of references in selected papers was also performed.

Definitions, Biological, and Clinical Characteristics of Oligometastatic and Oligoprogressive Disease States

The term oligometastatic disease is generally recognized as a state of stage IV disease associated with limited spread of disease at the time of diagnosis. This condition may, in some situations, reflect a more indolent phenotype than that associated with more widespread disease at presentation, and it may be appropriate for more aggressive initial therapy. However, it may also simply reflect an early snapshot of the same aggressive phenotype in other cases, in which the benefit from a highly aggressive approach could be more limited. Methods for differentiating between these two scenarios have to date relied primarily on the number of sites of disease and their specific anatomic location. Biological signatures associated with disease more amenable to the addition of aggressive local therapy in the setting of stage IV disease remain under investigation.

The newer term oligoprogressive disease relates to patients with stage IV disease who are receiving active systemic therapy that is controlling most of the disease in the body but a small number of sites show disease progression. Such an “early stage” of progression in the presence of ongoing control at most sites of disease by systemic therapy, as with oligometastatic disease, has been considered appropriate for exploration of aggressive local therapies to the sites of progression added to ongoing systemic therapy.

Oligometastatic Disease

The concept of oligometastases was first introduced in 1995 by Hellman and Weichselbaum to describe an intermediate state between localized disease and widespread metastases.9 Clinical evidence that supports the notion of oligometastases can be found in the literature. Surgical resection of liver metastases from colorectal cancer was associated with a 5-year OS rate of 36% to 37%.10 and 11 Surgical resection of pulmonary metastases from osteosarcoma resulted in an OS rate of 37% in a subset of patients.12 Complete resection of metastatic lesions from renal cell carcinoma was associated with a 5-year OS rate of 45% to 62%.13 and 14 Similarly, using RT for the treatment of extracranial oligometastases (especially pulmonary and hepatic oligometastases) from several solid malignancies resulted in favorable local control and OS rates.15 Although it is acknowledged that there has been a paucity of prospective randomized trials, these data provide supportive evidence that there is a subset of patients with a limited number of metastases who may achieve long-term survival after aggressive local control.

Several retrospective analyses of patients with metastatic NSCLC indicate that at the time of diagnosis some patients have a limited number of metastases. In an analysis of 38 patients enrolled in a phase II trial of oxaliplatin and paclitaxel, 28 (74%) had metastatic lesions in one or two organs only and 19 (50%) had three or fewer metastatic sites.16 Moreover, when patients with a limited number of metastatic lesions progressed, two-thirds had stable or progressive disease in the initially involved sites alone, without development of new metastatic lesions. Another single-center retrospective study by Parikh et al. showed that 26% of patients with stage IV NSCLC had oligometastatic disease, defined as five or fewer distant metastatic sites at diagnosis as detected by positron emission tomography–computed tomography and/or magnetic resonance imaging.17 These observations, taken together with data from other solid tumors, suggest the presence of an oligometastatic state in NSCLC in which LAT can potentially be associated with clinical benefits.

Relatively little is known about the molecular basis of oligometastatic disease in NSCLC. Tumor samples from 63 patients with five or fewer metastatic lesions in the lung parenchyma at initial presentation who underwent resection with curative intent were analyzed by microRNA profiling.18 This study showed that microRNA signature patterns may be able to distinguish patients with low rates of progression from those with high rates of progression after resection of metastatic lesions. More studies are needed to identify molecular biomarkers of oligometastases that can aid in proper patient selection.

Oligoprogressive Disease

The term oligoprogression, which took its inspiration from the oligometastatic disease literature, was first used in the literature in 2012.19 The notion of oligoprogressive disease is best described in patients with tumors harboring actionable mutations who are treated with molecular targeted therapies. Despite impressive response rates, the duration of response is relatively short, with resistance to therapy generally emerging within a year of start of treatment as a result of various mechanisms. Not uncommonly, disease progression during molecular targeted therapy occurs at a limited number of anatomic sites. For instance, among 104 patients with EGFR-mutant NSCLC who experienced disease progression during treatment with erlotinib or gefitinib, 16% had isolated CNS progression and a solitary extracranial lesion, as a site of progression developed in 23%.20

Several theories have been offered to explain the occurrence of disease progression at a limited number of sites in the absence of progression at other sites in response to targeted therapy. Firstly, intratumor heterogeneity in relation to the primary driver mutation contributes to resistance to molecular targeted therapies. For example, intratumor heterogeneity in EGFR mutations is associated with resistance to EGFR TKIs. Intratumor heterogeneity of EGFR mutations was examined in a study of 21 patients who received gefitinib for postoperative recurrence.21 Six of 21 patients had heterogeneous tumors consisting of both EGFR mutation–positive and EGFR mutation–negative tumor cells. The median progression-free survival (PFS) and OS times after treatment with gefitinib were shorter in this patient group (7.5 months and 16.5 months for patients with intratumor heterogeneity compared with 18 months and 27 months for patients without intratumor heterogeneity, respectively), suggesting a role of intratumor heterogeneity in resistance to EGFR TKIs.

Second, intertumor heterogeneity is known to occur either before or in response to treatment.22 Studies in NSCLC have reported a wide range of discordance rates (12%–86%) of EGFR mutation status between primary tumors, locoregional lymph nodes, and metastatic lesions.23 and 24 In a study of 180 Asian patients whose tumors were sequenced to assess discordance in EGFR mutation status in paired samples of primary lung adenocarcinoma and regional/distant metastases, the overall discordance rate was 13.9% in different spatial groups, with the highest discordance rate (24.4%) observed in pairs consisting of multiple pulmonary nodules, followed by 14.3% in pairs composed of primary tumor and metastatic lymph nodes.25 Among 38 patients treated with EGFR TKIs, resistance to EGFR TKI therapy developed in 34 (89%); of patients with EGFR TKI resistance, 10 (29%) had intertumor heterogeneity. These data indicate that intertumor heterogeneity occurs in a significant fraction of patients with NSCLC at the time of disease progression during molecular targeted therapy.

Third, resistance to targeted therapy can arise as a result of one or more molecular abnormalities that coexist. In patients with EGFR-mutated NSCLC, known mechanisms of resistance include emergence of the EGFR T790M mutation (50%–60%), MET proto-oncogene, receptor tyrosine kinase gene (MET) amplification, overexpression of hepatocyte growth factor, mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA), epithelial to mesenchymal transition, and transformation to a small cell cancer phenotype.26, 27, and 28 In NSCLC with ALK rearrangements, a similar pattern of resistance is observed.29 Acquired resistance after treatment with an ALK TKI develops because of emergence of secondary ALK mutations, ALK copy number gain, and activation of bypass signaling through the KIT proto-oncogene receptor tyrosine kinase and EGFR signaling pathways.29

Treatment of Oligometastatic and Oligoprogressive Disease

Potential Benefits of LAT for Oligometastatic and Oligoprogressive Disease in NSCLC

There are several potential benefits of using LAT for advanced NSCLC with limited tumor burden. First, local progression is the predominant pattern of failure for patients with advanced NSCLC treated with first-line systemic therapy30; among patients seen at the University of Colorado between 2005 and 2008, the pattern of failure analysis demonstrated that the first site of extracranial progression was local-only in 64% of patients.31 Second, the Norton-Simon hypothesis suggests that the effect of systemic therapy is proportional to the rate of tumor growth at the time of treatment and that tumor growth follows a sigmoidal pattern.32 and 33 LAT may move the tumor growth curve back to a state of exponential growth and thereby augment the antitumor activity of systemic therapy.30 Third, local therapy may serve as a means of eliminating an evolutionary reservoir of resistant subclones34 and thus help extend the use of systemic therapy, especially targeted therapy.

Use of LAT for Oligometastatic Disease

Selected prospective and larger retrospective studies that assessed the use of LAT for oligometastatic NSCLC are summarized in Table 1.35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, and 46 Although most of these studies are retrospective, a few prospective trials have also been conducted. In spite of highly variable treatment outcomes, findings from these studies indicate that there exist a subset of patients with NSCLC and oligometastatic disease who appear to benefit from LAT.

Table 1

Selected Studies of Local Ablative Therapy for Oligometastatic NSCLC

 

Author (Publication Year) Definition of Oligometastases Study Design No. Patients Site(s) of Metastatic Disease Types of LAT Treatment Outcomes after LAT Additional Findings
Median PFS2 (mo)a Median OS (mo)
De Ruysscher et al. (2012)35 <5 synchronous metastases Prospective 39 Adrenal, bone, brain, liver, lung, lymph node, muscle, ovary, pleura Surgery, RT 12.1 13.5
Collen et al. (2014)36 ≤5 synchronous or metachronous metastases Prospective 26 Adrenal, bone, brain, liver, lung, lymph, muscle, pleura, thyroid RT 11.2 23.0
Endo et al. (2014)37 (1) Untreated clinical T1–2 N0–1 disease with single-organ metastasis or (2) Single-organ metachronous metastasis after complete resection of pT1–2N0-1 disease Prospective 34 Adrenal, brain, kidney, lung Surgery NR 54.5b 6 (18%) had a benign lesion or no metastasis
Patchell et al. (1990)38,a A single metastasis to the brain Randomized 48 (37 patients with NSCLC) Brain Surgery plus WBRT vs. WBRT only NR 10.0 vs. 3.8
(p < 0.01)
Patients in the surgery group maintained Karnofsky score much longer
Andrews et al. (2004)39,a 1–3 brain metastases Randomized 331 (211 patients with NSCLC) Brain Stereotactic radiosurgery plus WBRT vs. WBRT NR 6.5 vs. 4.9
(p = 0.04)c
A statistically significant improvement in performance status in the stereotactic radiosurgery group
Furak et al. (2005)40 Brain metastases Retrospective 65 Brain Surgery NR 19.3 (synchronous)
12.0 (metachronous)
5-y OS rate of 24% (synchronous) and 16% (metachronous)
Burt et al. (1992)41 Brain metastases Retrospective 185 Brain Surgery NR 14.0 5-y OS rate of 13%, 10-y OS rate of 7%
Porte et al. (2001)42 Solitary adrenal metastasis Retrospective 43 Adrenal Surgery 13.0 11.0 3 patients survived >5 y
Holy et al. (2011)43 Solitary adrenal metastasis Retrospective 13 Adrenal SBRT 12.0 23.0
Barone et al. (2015)44 Solitary adrenal metastasis Retrospective 18 Adrenal Surgery NR 31.0 5-y OS rate of 29.3%
De Rose et al. (2016)45
  • (1) Controlled primary tumor
  • (2) <5 metastatic lesions
  • (3) A maximum lesion size ≤5 cm
  • (4) Controlled/absence of extrathoracic disease
Retrospective 60 Lung SBRT 32.2d 32.1d 2-y local control rate of 88.9%, 2-y OS rate of 74.6%
Okubo et al. (2009)46 ≤4 recurrent pulmonary oligometastatic lesions Retrospective 42 Lung Surgery 23.7 40.0 5-y OS rate of 34.8%

a Studies with various advanced solid tumors.

b OS among those who had complete resection of both primary NSCLC and metastatic sites (n = 20).

c Outcomes among patients with a single metastasis (n = 186).

d Median PFS and OS from diagnosis of pulmonary oligometastases. SBRT was performed at a median time of 8.9 months after the appearance of pulmonary oligometastases.

LAT, local ablative therapy; PFS2, time from initial disease progression until second progression after LAT; OS, overall survival; RT, radiation therapy; NR, not reported; WBRT, whole brain radiation therapy; SBRT, stereotactic body radiation therapy.

De Ruysscher et al. carried out the first prospective study of LAT in oligometastatic NSCLC.35 Forty patients with stage IV NSCLC and fewer than five synchronous metastatic lesions amenable to LAT (surgery or RT) were enrolled in a phase II trial. Most patients (87%) had a single metastatic lesion and 37 (95%) received chemotherapy as part of their initial treatment. The median OS was 13.5 months, and the 1-year and 2-year OS rates were 56.4% and 23.3%, respectively. The median PFS was 12.1 months, with 1-year and 2-year PFS rates of 51.3% and 13.6%, respectively.

In another prospective study of oligometastatic NSCLC (defined as five or fewer metastatic lesions), 26 patients (19 with synchronous metastases and seven with metachronous metastases) were treated with stereotactic body radiation therapy (SBRT) to primary tumors and metastatic sites; 17 patients received SBRT after induction chemotherapy and nine patients were treated with SBRT as the mainstay of treatment.36 The median OS and PFS times were 23 months and 11.2 months, respectively. The 1-year OS and 1-year PFS rates were 67% and 45%, respectively.

The ability of LAT to change patterns of failure in patients with relapsed, oligometastatic NSCLC was examined in a prospective single-arm phase II study. Twenty-four patients with metastatic NSCLC and no more than six sites of extracranial disease who progressed after chemotherapy were treated concurrently with SBRT and erlotinib.47 Thirteen patients were tested for the presence of EGFR activating mutations; none of the results were positive. The median PFS and median OS times were 14.7 months and 20.4 months, respectively. Upon progression, only three of 47 measurable lesions recurred within the SBRT field. In the remaining cases, progression occurred as a result of the emergence of new lesions at distant sites.

Several clinicopathologic factors seem to influence outcomes after LAT. Tumor burden is an important factor that determines the clinical benefit of LAT. Hanagiri et al. reported results of 19 patients with NSCLC who underwent surgical resection for distant metastases.48 There was a difference in the 5-year OS rate between patients with a single metastasis and those with two or more metastases (50.3% versus 16.7%). Likewise, an excellent 5-year OS rate of 40% was reported in 20 patients who underwent complete resection of solitary synchronous metastasis from NSCLC in a prospective study.37 Ashworth et al. identified other prognostic factors by analyzing individual patient data of 757 patients with one to five sites of disease from NSCLC.49 In multivariate analysis, three factors—metachronous metastases (versus synchronous metastases), absence of nodal involvement, and adenocarcinoma histologic type—were prognostic for improved OS. These clinicopathologic factors can potentially guide selection and stratification of patients for clinical trials of LAT in oligometastatic NSCLC.

LAT for Oligometastatic NSCLC Depending on Organ of Involvement
Intracranial Oligometastases

LAT for brain metastases from NSCLC is a well-established form of treatment and considered the standard of care.50 In a randomized study of surgery for the treatment of single metastasis to the brain (77% of patients with NSCLC), patients treated with surgical resection plus whole brain radiation therapy (WBRT) had improved survival (40 weeks versus 15 weeks) and remained functionally independent longer than those who were treated with WBRT alone.38 Similarly, in a randomized study of 333 patients with one to three brain metastases (64% of patients with NSCLC), stereotactic radiosurgery (SRS) plus WBRT improved functional autonomy and OS for patients with a single unresectable brain metastasis when compared with WBRT alone.39

Retrospective case series of patients with NSCLC and isolated CNS disease have also shown that this subgroup of patients has a relatively good prognosis and may achieve long-term survival after LAT for the primary tumor and metastatic lesions.40, 41, and 51 Taken together, these findings support the role of LAT in the treatment of intracranial oligometastatic disease.50

Extracranial Oligometastases

Adrenal Gland

The adrenal gland is one of the most studied extrathoracic organs in patients with extracranial oligometastatic NSCLC. Surgical resection of a solitary adrenal metastasis has been associated with favorable outcomes. Forty-three patients with advanced NSCLC and a synchronous or metachronous solitary adrenal metastasis who underwent surgical resection had a median OS of 11 months. In this study, there were three long-term survivors who lived more than 5 years.42 In another study by Mercier et al., 23 patients with a solitary adrenal metastasis—six with synchronous metastasis and 17 with metachronous metastasis—had complete resection of the adrenal lesion.52 The median OS was 13.3 months, which was comparable to that in the previous study, and the 5-year OS rate was 23.3%. Of note, the median PFS was 12.5 months for patients with metachronous adrenal metastasis metastasis and 2 months for those with synchronous metastasis. An interval of more than 6 months between surgical resection of the primary tumor and diagnosis of adrenal metastasis was associated with improved survival. A smaller case series of 18 patients who underwent adrenalectomy for an isolated adrenal metastasis revealed a median OS of 31 months and a 5-year OS rate of 29.3%.44

It has been suggested that survival outcomes among patients with metachronous adrenal metastasis are better than those among patients with synchronous adrenal metastasis. In a pooled analysis of 10 publications on adrenalectomy, the median OS of patients who underwent adrenalectomy for a metachronous adrenal metastasis was 31 months, which is significantly longer than a median OS of 12 months among patients with a synchronous adrenal metastasis.53

SBRT is an alternative approach to surgical resection for the treatment of adrenal oligometastatic NSCLC. Holy et al. described the use of SBRT in 18 patients with adrenal metastasis from NSCLC.54 Thirteen patients had a solitary adrenal gland metastasis and five had multiple metastatic lesions including adrenal metastases. Patients with multiple metastases received SBRT to the adrenal gland for palliation of symptoms (e.g., back pain). The median PFS was 4.2 months for all 18 patients, but 13 patients with a single adrenal metastasis had a longer PFS of 12 months. Similarly, five patients with multiple metastatic lesions died within 6 months after SBRT, but the median OS for patients with a solitary adrenal metastasis was 23 months and the local control rate was 77%. SBRT was well tolerated, with the most common adverse effect being grade 1 nausea. Adrenal or renal insufficiency was not observed after treatment.

In sum, the aforementioned data suggest that surgical resection or SBRT improves survival in patients with a solitary adrenal metastasis.

Lung

Most prospective trials that have evaluated the efficacy of RT for oligometastatic disease in the lung have included various primary tumor types. In a phase I/II trial of 38 patients treated with SBRT for one to three sites of disease in the lungs, colorectal cancer (23.7%) was the most common primary tumor, followed by sarcoma (18.4%), renal cell carcinoma (18.4%), and lung cancer (13.2%).55 This study demonstrated excellent local control rates of 100% and 96% at 1 and 2 years after SBRT, respectively. The median overall and distant PFS times were both 8.4 months. The median OS was 19 months and the 2-year survival rate was 39%. Three of 38 patients (8%) had grade 3 toxicity, and there was no grade 4 toxicity related to the treatment.

The patient populations in published studies that have focused on pulmonary oligometastases from NSCLC are heterogeneous, which makes comparisons between studies challenging. Also, most studies did not have a control group, and thus, drawing definitive conclusions on the efficacy of LAT is difficult. A study that reported treatment outcomes of SBRT in 22 patients with pulmonary oligometastatic NSCLC (defined as four or fewer synchronous or metachronous lung metastases and no other active sites of distant metastasis) revealed 1-year and 2-year OS rates of 86% and 49%, respectively.56 The median OS was 24 months. Local control was achieved in 93% of patients at 1 year and 64% at 2 years. Pennathur et al. reported their experience with 100 patients with “limited” recurrent NSCLC (no further definition provided) who were treated with SBRT.57 The median OS was 23 months (95% confidence interval: 19–41), 30-day mortality was 0%, and toxicity associated with SBRT was minimal. In multivariate analyses, presence of large tumors, radiation applied to a second or subsequent recurrence, and male sex were associated with worse prognosis after SBRT. In a study by De Rose et al., 60 patients with pulmonary oligometastases from NSCLC were treated with SBRT if they had a controlled primary tumor, had fewer than five sites of disease (synchronous or metachronous) with metastases not exceeding 5 cm, had controlled or absent extrathoracic disease, and were not eligible for chemotherapy.45 The local control rate at 2 years was 88.9% and the OS rates at 1 and 2 years were 94.5 and 74.6%, respectively, with a median OS of 32 months.

Surgery also has a role in the treatment of pulmonary oligometastases from NSCLC. In 42 patients with NSCLC and with disease recurrence presenting as metachronous pulmonary metastases, surgical resection of recurrent tumors resulted in a median OS of 40 months and a 5-year OS rate of 34.8%.46

Despite the limitations of data on the role of LAT for patients with NSCLC with pulmonary oligometastatic disease, the available evidence suggests that LAT has potential benefits in carefully selected patients, with median OS ranging between 2 and 3 years.

Other Organs

Isolated liver metastases from NSCLC are uncommon and there is a paucity of studies of sufficient size that have investigated the role of LAT in this population. A multi-institutional prospective trial of SBRT for the treatment of liver metastases from advanced cancers shows that SBRT is safe and feasible.55 In this trial, 47 patients with 63 lesions were treated with SBRT. Patients were eligible if they had one to three hepatic lesions measuring up to 6 cm, and patients with lung cancer comprised 21% of the study population. Local control rates were 95% and 92% at 1 and 2 years, respectively. For lesions measuring 3 cm or less, the 2-year local control rate was 100%. The median OS was 20.5 months. SBRT was well tolerated; grade 3 soft-tissue toxicity developed in only one patient. Having lung cancer as the primary tumor type was associated with worse OS, but further details were not reported. Studies that have examined the role of surgery for the management of hepatic oligometastases from NSCLC are also limited. There are a few case reports and case series suggesting potential long-term survival after resection of hepatic oligometastases in patients with NSCLC,58 and 59 but no firm conclusions can be drawn from these data.

A systematic review by DeLuzio et al. reported treatment outcomes of 32 patients (from 27 case reports) who were treated surgically for oligometastatic NSCLC to the pancreas.60 Fifteen patients (47%) underwent curative intent procedures and had a median OS of 29 months. Patients who did not undergo interventions with curative intent had worse outcomes.

Limitations of the Available Data

Although the results of the aforementioned studies focusing on the role of local ablation for the treatment of oligometastatic NSCLC compare favorably with historical controls, there are several limitations, including lack of a control arm, selection bias, and heterogeneity in study populations resulting from the use of different definitions of oligometastases. Studies that used propensity score–matched analyses or matched subset analyses to compare treatment outcomes between LAT-treated patients and those not treated with LAT suggested an improvement in survival favoring LAT,61 and 62 but definitive conclusions on the efficacy of LAT for the treatment of extracranial oligometastatic NSCLC cannot be reached. Recently, Gomez et al.63 reported results of a randomized phase II study that evaluated the efficacy of local consolidative therapy for patients with oligometastatic NSCLC. Patients were eligible if they had three or fewer metastatic sites and there was no evidence of disease progression after front-line systemic therapy (four or more cycles of platinum-doublet chemotherapy or 3 or more months of targeted therapy for patients with actionable mutations). Patients were randomly assigned to systemic maintenance therapy with or without local consolidative therapy consisting of radiation therapy, surgery, or both. Although this study demonstrated a PFS benefit favoring local consolidative therapy (11.9 months versus 3.9 months), given the nature of LAT, OS is a more appropriate end point and randomized studies with OS as a primary objective are needed to fully appreciate the net benefit of LAT in oligometastatic NSCLC. Figure 1 displays a proposed treatment algorithm that uses LAT in the management of oligometastatic NSCLC. In Table 2, we have summarized ongoing prospective trials of LAT in oligometastatic NSCLC. Finally, more research is needed to evaluate the benefits of other interventions for local ablation, such as cryoablation and RFA to treat oligometastatic NSCLC.64

gr1

Figure 1

Proposed treatment algorithm for patients with oligometastatic NSCLC. LAT, local ablative therapy; RT, radiotherapy; SRS, stereotactic radiosurgery; WBRT, whole brain radiation therapy. *Subgroups of patients with oligometastatic NSCLC who may derive benefit from LAT are yet to be determined, and patients with oligometastatic disease should be enrolled in clinical trials whenever possible. **There are only a limited number of studies in the literature that assessed the role of LAT in these organ systems. ˆRole of surgery for hepatic and pancreatic oligometastases is unclear and based on minimal literature.

 

Table 2

Selected Ongoing Prospective Trials of LAT for Oligometastatic or Oligoprogressive NSCLC

 

Trial Patient Population Eligibility Criteria Study Design Treatment Primary Outcome
NCT02417662 Oligometastatic NSCLC ≤3 metastatic lesions; no EGFR mutations or ALK rearrangement Randomized phase III Chemotherapy vs. chemotherapy plus radical RT to primary tumor and SBRT and/or SRS to metastases OS
NCT02076477 Oligometastatic NSCLC ≤5 distant metastatic lesions Randomized phase III Concurrent chemoradiation (radiation to the primary tumor and metastatic lesions) followed by chemotherapy vs. chemotherapy followed by chemoradiation ORR
NCT01796288 Oligometastatic NSCLC Nonsquamous NSCLC with no disease progression for 3 mo after second-line erlotinib and ≤5 metastatic lesions Randomized phase II RT vs. no RT PFS
NCT01185639 Oligometastatic NSCLC ≤5 metastatic lesions amenable to SBRT after 4 cycles of first-line chemotherapy Single-arm phase II SBRT PFS
NCT02450591 Oligometastatic NSCLC with EGFR mutations Completion of 12 wk of TKI therapy Single-arm pilot study Surgery or RT Feasibility
NCT01941654 Oligometastatic NSCLC with EGFR mutations Completion of 12 wk of TKI therapy and ≤4 residual metabolically active lesions on PET-CT Single-arm phase II LAT PFS at 1 y
NCT02759835 Oligoprogressive NSCLC with EGFR mutations
  • - Treatment-naive patients with EGFR sensitizing mutations or germline T790M mutation (cohort 1)
  • - Progressive disease after first- or second-generation EGFR TKI and T790M mutation (cohort 2)
  • - Progressive disease after osimertinib and eligible for LAT (cohort 3)
Single-arm pilot study LAT (surgery, RT, RFA, or cryoablation) at the time of progression on osimertinib if ≤5 progressive anatomic lesions PFS2

LAT, local ablative therapy; ALK, anaplastic lymphoma receptor tyrosine kinase gene; RT, radiation therapy; SBRT, stereotactic body radiation therapy; SRS, stereotactic radiosurgery; OS, overall survival; ORR, objective response rate; PFS, progression-free survival; TKI, tyrosine kinase inhibitor; PET-CT, positron-emission tomography–computed tomography; RFA, radiofrequency ablation; PFS2, time from initial disease progression until second progression after LAT.

Use of LAT for Oligoprogressive Disease

In patients receiving molecular targeted TKI therapy, once the cause of acquired resistance is identified, systemic treatment options include continued use of the original TKI, use of next-generation TKIs if sensitizing mutations are present, use of other appropriate biologic therapies in combination with the ongoing use of the initial TKI to target bypass pathways that might be contributing to acquired resistance, and standard chemotherapy. Also, treatment with recently approved immune checkpoint inhibitor therapy is a feasible option, and its activity in defined molecular subtypes remains under investigation.65 Although a subset of patients might benefit from these approaches, further development of resistance and/or lack of tolerability eventually results in discontinuation of treatment. In this section, we review evidence supporting the use of LAT in patients with NSCLC with intracranial and extracranial oligoprogressive disease.

Intracranial Oligoprogression

Disease progression in the CNS is a frequent and serious problem in patients with NSCLC treated with EGFR or ALK TKIs. This phenomenon may be due in part to poor blood-brain barrier penetration of targeted agents and a predilection of EGFR-mutated or ALK-positive NSCLC for the CNS.66 and 67 In a study of 100 patients with advanced EGFR-mutant NSCLC treated with gefitinib or erlotinib (including 19 patients with brain metastases at the time of diagnosis), the 2-year cumulative risk of CNS progression was 19%.68 Another study of 232 patients treated with gefitinib or erlotinib showed that the site of first disease progression was the CNS in 37 patients (16%).69 Among patients with NSCLC with ALK rearrangements treated with crizotinib, isolated CNS metastases at the time of progression develop in 20% to 46%.67

A few retrospective studies have demonstrated that continuation of targeted therapy after LAT in patients with isolated CNS failure is feasible and potentially beneficial (Table 3).19, 70, 71, 72, and 73 In a study by Weickhardt et al., 10 patients whose disease first progressed in the CNS while they were receiving erlotinib or crizotinib were treated with LAT, specifically SRS or WBRT. Patients with fewer than four CNS metastases received SRS, and those with four or more CNS metastatic lesions were treated with WBRT.19 The subsequent median PFS (time from initial disease progression until second progression during the same targeted therapy [PFS2]) was 7.1 months. After LAT to the brain, two patients (20%) did not show any evidence of disease progression, progression in the brain again developed in three (30%), and five (50%) had extracranial progression. In a study of 17 non–molecularly selected patients with NSCLC in whom isolated CNS failure developed after clinical benefits from an EGFR TKI (defined as partial response or stable disease for longer than 6 months), continuation of EGFR TKI therapy after radiotherapy (SRS or WBRT depending on the number of CNS metastatic lesions) was associated with prolongation of extracranial PFS; the median overall PFS2 and extracranial PFS2 were 80 and 171 days, respectively. In a study of seven patients with ALK-positive NSCLC in whom isolated CNS metastases developed after treatment with crizotinib, continued crizotinib administration after SRS or WBRT resulted in a median PFS2 of 5.5 months.73

Table 3

Studies of Local Ablative Therapy for Extracranial and Intracranial Oligoprogressive NSCLC after Molecular Targeted Therapy

 

Author (Publication Year) Study Population Definition of Oligoprogressive Disease Site of Metastatic Disease Study Design No. Patients Types of LAT Treatment Outcomes after LAT
Median PFS2 (mo) Median OS (mo)
Weickhardt et al. (2012)19 EGFR-mutant or ALK-rearranged NSCLC with resistance to erlotinib or crizotinib ≤4 sites of progression Extracranial Retrospective 15 Surgery, RT 4.0 NR
Yu et al. (2013)70 EGFR-mutant NSCLC with resistance to erlotinib or gefitinib <5 sites of disease at the time of LATa Extracranial Retrospective 18 Surgery, RT, RFA 10.0 41.0
Gan et al. (2014)71 ALK-rearranged NSCLC with resistance to crizotinib ≤4 sites of progression Extracranial Retrospective 14 Surgery, RT 5.5 39.0
Shukuya et al. (2011)72 EGFR-mutant NSCLC with resistance to gefitinib Isolated CNS progression Intracranial Retrospective 17 SRS, WBRT 2.7 (overall)
5.7 (extracranial)
13.4
Weickhardt et al. (2012)19 EGFR-mutant or ALK-rearranged NSCLC with resistance to erlotinib or crizotinib Isolated CNS progression Intracranial Retrospective 10 SRS, WBRT 7.1 NR
Takeda et al. (2013)73 ALK-rearranged NSCLC with resistance to crizotinib Isolated CNS progression Intracranial Retrospective 7 SRS, WBRT 5.5 NR

a Except for one patient, all patients had fewer than five sites of disease.

LAT, local ablative therapy; PFS2, time from initial disease progression until second progression after continuation of the same targeted therapy after LAT; OS, overall survival; ALK, anaplastic lymphoma receptor tyrosine kinase gene; RT, radiation therapy; RFA, radiofrequency ablation; CNS, central nervous system; SRS, stereotactic radiosurgery; WBRT, whole brain radiation therapy; NR, not reported.

Extracranial Oligoprogression

In our literature search, we identified three studies that have specifically examined the role of LAT in patients with actionable mutations and extracranial oligoprogressive disease during treatment with a TKI (see Table 3). In a retrospective study of 184 patients with EGFR-mutated NSCLC, 18 were treated with one or more local therapies (excluding intracranial treatments) at the time of disease progression, with subsequent readministration of the EGFR TKI (erlotinib or gefitinib) that they were receiving before LAT.70 The most common site of metastatic disease was the lung, followed by lymph nodes, bone, and the brain in the LAT group, and all patients except one had oligometastatic disease, defined as fewer than five sites of disease at the time of disease progression. LAT consisted of metastasectomy (lobectomy, wedge resection, pneumonectomy, or adrenalectomy), RFA, or RT. Most local therapies were well tolerated, with 85% of patients resuming EGFR TKI therapy within 1 month of LAT. The median time to progression after LAT was 10 months (range 1–51 months), and the median time from LAT until a change in systemic therapy was 22 months (range 1–54 months). The median OS from LAT was 41 months (range 1 to >65 months).

Another single-center study examined the benefits of the combination of LAT and continued TKI therapy (crizotinib or erlotinib) in patients with extracranial oligoprogressive disease, defined as four or fewer sites of extracranial progression.19 In this study, 15 of 51 patients (29%) whose disease had progressed while they were receiving crizotinib or erlotinib had extracranial oligoprogression and were deemed eligible for LAT. The most common sites of disease progression were bone and lung, followed by lymph nodes and adrenal gland. Most patients received SBRT, with eight of 15 (53%) treated at a single site of progression. One patient underwent adrenalectomy. The median PFS2 was 4.0 months. After LAT, four patients (27%) did not have disease progression, three (20%) had disease progression in the brain, and the rest (53%) had extracranial disease progression. Grade 1 or 2 fatigue, nausea, and anorexia were the most common side effects related to SBRT. In a follow-up study, a mature analysis of ALK-positive patients with NSCLC treated with SBRT or hypofractionated RT for extracranial oligoprogressive disease was reported.71 A total of 14 patients whose disease progressed while they were receiving crizotinib were treated with stereotactic radiotherapy. The 6-month and 12-month local control rates were 100% and 86%, respectively. No acute or late grade 3 to 5 toxicities were observed. The median overall duration of crizotinib therapy in patients treated with LAT was 28 months, compared with 10 months in those not eligible for LAT. The median PFS2 was 5.5 months (range 1–27). Of note, the median PFS2 was longer at 7 months versus 2 months in patients who received LAT for one or two lesions versus for three or four lesions, respectively.

Most patients in the aforementioned studies were treated with surgery or radiation therapy. Although RFA and cryoablation have been used for the treatment of metastatic NSCLC,64 and 74 their role in the treatment of oligoprogressive NSCLC has not been as comprehensively studied and therefore needs to be explored further. Recently, a case report of a patient with ALK-positive NSCLC whose disease progressed during administration of both crizotinib and ceritinib and in whom a new hepatic metastatic lesion developed showed that RFA can be effectively used to treat oligoprogressive NSCLC.75

Limitations of Available Data

Despite evidence supporting the use of LAT for oligoprogressive NSCLC, the aforementioned studies need to be interpreted with caution. Patients included in these studies may represent a highly selected group of individuals with relatively indolent disease. These studies were retrospective and lacked a control arm. Another drawback was the lack of a uniform definition of oligoprogression. In spite of these limitations, these studies indicate that LAT such as surgery or RT is safe and feasible in patients with oligoprogression during treatment with EGFR or ALK TKIs. Additionally, if surgery or RFA is used for local ablation, there is an added benefit of obtaining tumor tissue, which is crucial to understanding the mechanism of acquired resistance.

Figure 2 shows a proposed algorithm that incorporates LAT into the management of oligoprogressive EGFR-mutant or ALK-positive NSCLC. To further validate this algorithm, prospective clinical trials with predefined parameters of oligoprogression in molecularly selected patients are necessary.

gr2

Figure 2

Proposed treatment algorithm for patients with oligoprogressive NSCLC with acquired resistance to molecular targeted therapy. TKI, tyrosine kinase inhibitor; LAT, local ablative therapy; RT, radiotherapy; RFA, radiofrequency ablation; CA, cryoablation; ALK, anaplastic lymphoma kinase. *Although the exact definition of oligoprogression eligible for LAT remains to be determined, progression at not more than four to six anatomic sites with continued response or stable disease at other sites of disease is considered as oligoprogression in most studies. The location of disease (e.g., central nervous system versus non–central nervous system sites) also determines the type local ablation technique that can be used.

 

Conclusions

The advent of molecular targeted therapies and immunotherapy have resulted in substantial improvements in response rates and survival among patients with advanced, unresectable NSCLC. However, development of acquired resistance is an inevitable outcome of treatment and continues to limit survival. A subset of patients with NSCLC experience development of metastases at a limited number of sites or demonstrate limited disease progression in response to treatment. Patients with these disease characteristics represent a unique subgroup of patients with NSCLC who can potentially benefit from aggressive local treatment followed by continuation of previously administered systemic therapy. However, the currently available data have significant limitations, especially in relation to extracranial oligometastatic and oligoprogressive disease, and larger randomized trials need to be conducted to further clarify the optimal role of LAT in these settings.

Acknowledgments

This research was supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health.

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Footnotes

Thoracic and Gastrointestinal Oncology Branch and Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Corresponding author. Address for correspondence: Arun Rajan, MD, Thoracic and GI Oncology Branch, National Institutes of Health/National Cancer Institute, Room 4-5330, Building 10, 10 Center Drive, Bethesda, MD 20892.

Disclosure: The authors declare no conflict of interest.

Commentary by Solange Peters

The oligometastatic disease theory was initially described in 1995 by Heilman and Weichselbaum. Their theory was based on a multistep progression of certain types of cancer, such as prostate, colorectal, and melanoma. This theory is supported by molecular evidence that cancer cells can biologically acquire the ability to invade and metastasize sequentially, suggesting different subcategories of metastatic disease. Early in the metastatic process, there could be limited progression of disease, the so-called oligometastases.

Since then, much work has been performed to investigate its existence in many solid tumors. This has led to subclassifications of stage IV cancer, first defined the stage IV "incurable" entity. Importantly, the new 8th IASLC TNM classification has recently described the stage Iva oligometastatic status, characterized by a better outcome than unselectd metastatic NSCLC patients.

Patients and tumor attributes remain very important, while they will predict for OS and PFS in patients with oligometastatic NSCLC. Many retrospective series and meta-analysis have been describing such situations. Unfortunately, there is little consistency in the treatment strategies used for these patients in the studies and across studies. Once again, patient selection is critical in determining the best treatment approach, and systemic therapy maintains a central role in the a multimodailty treatment.

This review describes the role of local approaches in this situation. Indeed, there is increasing evidence to support the clinical benefit local treatments in patients with NSCLC with limited metastatic disease and in selected individuals in whom resistance to targeted therapies develops. In the latter instance, adequate treatment of drug-resistant clones by local ablative treatment could potentially help in avoiding switching systemic therapy prematurely.