The Treatment of Patients with Oligometastatic Lung Cancer

(From L to R) Prof. Anne-Marie C. Dingemans & Dr. Lizza E.L. Hendriks

By Anne-Marie C. Dingemans, MD, PhD,
and Lizza E.L. Hendriks, MD, PhD

Patients with stage IV NSCLC are generally viewed as having incurable disease; however, for years, patients presenting with a solitary brain or adrenal metastasis have been treated with local ablative treatment (LAT) with curative intent, and multiple series have shown long-term overall survival (OS) in some of these patients. The concept of a clinically significant state of oligometastases was first described in 1995,1 proposing that oligometastatic cancer has a different biology, and that these patients, therefore, could benefit from LAT.

Long-term benefit of LAT in patients with up to three or five metastatic sites has been observed in several, mainly retrospective, series.2 In 2012, De Ruysscher et al.3 published the first prospective clinical trial in patients with NSCLC with synchronous oligometastases. In this single-arm phase II study, 40 patients with stage IV NSCLC and fewer than five metastases, amenable for LAT (radiotherapy or surgery), were enrolled. The 2- and 3-year survival rates were 23.3% and 17.5%, respectively, showing that some patients with oligometastatic NSCLC could benefit long-term from LAT. Although patients with up to four metastases were eligible, only 13% had more than one metastasis. In addition, 95% also received systemic chemotherapy. The study was unable to define predictive patient or tumor characteristics.

In recent years, the concept of oligometastatic treatment has evolved. Growing interest has been pushed by the increasing number of available treatment strategies, as well as the widespread introduction of minimally invasive surgery and stereotactic radiotherapy. Several guidelines have described oligometastatic NSCLC as a separate entity. For example, the European Society for Medical Oncology guideline states that patients with one to three synchronous metastases might have longterm disease-free survival when treated with systemic treatment and LAT.4 In addition, in the last edition of the TNM (8th) staging system, patients with solitary metastasis (M1b) were identified as a separate prognostic group with a superior OS compared to patients with more widespread metastases (M1c).5 However, data on the staging of these patients were lacking, and selection bias might have occurred, as some hospitals entered only a few patients.6

Impressive Data but No Change to Daily Practice
After years of retrospective data and single-arm trials reporting on oligometastatic NSCLC, the first randomized phase II trial was presented by Daniel Gomez, MD, at the 2016 American Society of Clinical Oncology Annual Meeting. Progression-free survival (PFS), the primary endpoint, was shown to be significantly superior when patients with oligometastatic NSCLC were treated with LAT compared to follow-up or maintenance therapy after treatment with at least four cycles of platinum-containing chemotherapy or 3 months of an EGFR TKI (EGFR mutation) or crizotinib (ALK rearrangement). Oligometastatic disease was defined as no progression after this systemic treatment; a maximum of three remaining metastases were allowed with lymph nodes counting as one site. After random assignment of 49 of the planned 94 patients, the independent safety monitoring board recommended closing the study because of substantial efficacy improvement. The median PFS was 11.9 and 3.9 months in the LAT and the control group, respectively (HR 0.35, 95% CI [0.18, 0.66], p = 0.0054).7 Since then, oligometastatic NSCLC has become a prominent topic at cancer conferences. One wonders whether additional evidence is needed, or whether this randomized phase II trial with PFS as the primary endpoint will change daily clinical practice.

In the meantime, another randomized phase II study was recently published, assigning patients with EGFR/ALK negative NSCLC and up to six extracranial cancer sites (including primary) with no evidence of disease progression after four to six cycles of chemotherapy to either maintenance chemotherapy alone or to chemotherapy with LAT (radiotherapy) to all tumor sites.8 The primary outcome was PFS. An unplanned interim analysis prompted by publication of the Gomez trial led investigators to stop this study. Twenty nine of the 36 planned patients, including 11 previously treated for brain metastases, were randomly assigned to a study arm, The median PFS was 9.7 months in the radiotherapy arm and 3.5 months in the control group (HR 0.30, 95% CI [0.11, 0.82]; p = 0.01). The phase III part of this study is ongoing (NCT03137771), and OS is the primary outcome measure.

In addition to both randomized trials, data from a single-arm phase II study of pembrolizumab in oligometastatic NSCLC were presented at the 2017 IASLC World Conference on Lung Cancer by Joshua Bauml and colleagues at the University of Pennsylvania.9 The treatment sequence was reversed compared to the previously described trials: 45 patients with up to four metastases and no progression after LAT to all known sites were treated with up to a year of pembrolizumab. The 1-year PFS was 68%.

Although the PFS difference is impressive in both randomized phase II studies, some concerns must be registered before implementing this strategy in daily practice. Most importantly, the total number of patients enrolled in the two trials combined is very limited (78, including eight patients with EGFR mutation/ALK rearrangement), and the majority had only one metastatic site. Knowing that assessment of local progression might be challenging in patients treated with radiotherapy, especially stereotactic ablative radiotherapy, OS data are needed to draw firm conclusions. Because patients were randomly assigned after first-line treatment, baseline characteristics were not known, and selection bias might have occurred. The question as to whether an induced oligometastatic state (after induction treatment) is the same as de novo presentation with oligometastatic disease at NSCLC diagnosis must be addressed. The hypothesis is that patients with true oligometastatic disease at presentation have less metastatic capacity; this might be different from those with more overt metastasis at diagnosis but with a few remaining after induction treatment.10

Ongoing Trials: Standardizing Definitions and Staging
A search on ClinicalTrials.gov showed that ongoing clinical trials all use different definitions of oligometastatic NSCLC and that they all require different staging procedures. In one of the ongoing studies, the SARON trial (NCT02417662), patients with oligometastatic NSCLC (defined as up to three metastases with mandatory FDGPET and brain imaging) are registered before treatment initiation and are randomly assigned in the absence of disease progression after two chemotherapy cycles to two additional cycles of chemotherapy with or without radical radiotherapy to all tumor sites. The number of metastases and mediastinal lymph nodes are stratification factors. The primary outcome measure is OS. This trial, if it completes enrollment, may give the final answer as to whether local ablative treatment will improve OS in patients with oligometastatic NSCLC. In addition, OLIGO-CARE, a joint project of the European Organisation for Research and Treatment of Cancer (EORTC) and the European Society for Radiotherapy and Oncology (ESTRO), has been initiated. OLIGO-CARE is a pragmatic observational basket study to evaluate radical radiotherapy for patients with oligometastatic cancer.

In conclusion, oligometastatic NSCLC will continue to be an important topic of discussion at upcoming international cancer conferences. Most trials focus on radical radiotherapy as the LAT modality, but optimally, trials should also include surgery as an option. However, despite initial promising results, important issues need to be addressed. To speak the same language, a uniform definition of oligometastatic NSCLC is needed. This definition might change as new insights emerge. The EORTC lung cancer group has started an initiative to develop a consensus definition of oligometastatic disease for synchronous NSCLC. In addition, to be treated appropriately, these patients must be accurately staged (i.e., FDG-PET and brain MRI/CT), as has been proposed by the EORTC imaging group.11 But most importantly, future trials must address predictive factors because a selection tool is needed to identify those patients who are more likely to have long-term benefit from LAT. ✦

About the Authors: Prof. Dingemans is a pulmonologist in the Department of Pulmonology and GROW, School for Oncology and Development Biology, Maastricht University Medical Center, The Netherlands. Dr. Hendriks is a pulmonologist in the Department of Pulmonology and GROW, School for Oncology and Development Biology, Maastricht University Medical Center, The Netherlands.

References:
1. Hellman S and Weichselbaum RR. Oligometastases. J Clin Oncol. 1995;13(1):8-10.

2. Ashworth A, et al. Is there an oligometastatic state in non-small cell lung cancer? A systematic review of the literature. Lung Cancer. 2013;82(2):197-203.

3. De Ruysscher D, et al. Radical treatment of nonsmall-cell lung cancer patients with synchronous oligometastases: long-term results of a prospective phase II trial (Nct01282450). J Thorac Oncol. 2012;7(10):1547-1555.

4. Novello S, et al. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27(suppl 5):v1-v27.

5. Eberhardt WE, et al. The IASLC Lung Cancer Staging Project: Proposals for the Revision of the M Descriptors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer. J Thorac Oncol. 2015;10(11):1515-1522.

6. Hendriks LE, Dingemans AM, and De Ruysscher D. Proposals for the M-descriptors of the Eight TNM Classification for Non-Small Cell Lung Cancer: Are More Data Needed? J Thorac Oncol. 2016;11(3):e42-43.

7. Gomez DR, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol. 2016; 17(12):1672-1682.

8. Iyengar P, et al. Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial. JAMA Oncol. 2018;4(1):e173501.

9. Bauml J, et al. OA 17.08 Phase II Study of Pembrolizumab for Oligometastatic Non- Small Cell Lung Cancer (NSCLC) Following Completion of Locally Ablative Therapy (LAT). J Thorac Oncol. 12(11):S1794-S1795.

10. Weichselbaum RR and Hellman S. Oligometastases revisited. Nat Rev Clin Oncol. 2011;8(6):378-382.

11. deSouza NM, et al. Strategies and technical challenges for imaging oligometastatic disease: Recommendations from the European Organisation for Research and Treatment of Cancer imaging group. Eur J Cancer. 2018;91:153-163.