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

Abstract

Summary Background Retrospective evidence indicates that disease progression after first-line chemotherapy for metastatic non-small cell lung cancer (NSCLC) occurs most often at sites of disease known to exist at baseline. However, the potential benefit of aggressive local consolidative therapy (LCT) on progression-free survival (PFS) for patients with oligometastatic NSCLC is unknown. Methods We conducted a multicenter randomized study (NCT01725165; currently ongoing but not recruiting participants) to assess the effect of LCT on progression-free survival ((PFS). Eligible patients hadwere (1) histologic confirmation of (2) stage IV NSCLC, (3) ≤3 disease sites after systemic therapy, and (4) no disease progression before randomization. Front line therapy was ≥4 cycles of platinum doublet therapy or ≥3 months of inhibitors of epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) for patients with EGFR mutations or ALK rearrangements. Patients were randomized to either LCT ([chemo]radiation or resection of all lesions) +/− maintenance therapy versus maintenance therapy/observation only. Maintenance therapy was recommended based on a list of approved regimens, and observation was defined as close surveillance without cytotoxic therapy. Randomization was not masked and was balanced dynamically on five factors: number of metastases, response to initial therapy, central nervous system metastases, intrathoracic nodal status, and EGFR/ALK status. The primary endpoint was PFS, powered to detect an increase from 4 months to 7 months (hazard ratio [HR}=0.57) using intent-to-treat analysis. The plan was to study 94 randomized patients, with an interim analysis at 44 events. PFS, overall survival (OS), and time to develop a new lesion were compared between arms with log-rank tests. Results The study was terminated early after treatment of 49 patients (25 LCT, 24 control), when at a median follow-up time for PFS of 18.7 months, the median PFS time in the LCT group was 11.9 months (90% confidence interval [CI] 5.72 ,20.90) versus 3.9 months (90% CI 2.30, 6.64) in the maintenance group (HR=0.35, 90% CI 0.18,0.66, log rank p=0.005). Toxicity was similar between groups, with no grade 4–5 events. Grade 3 or higher adverse events in the maintenance therapy arm were fatigue (n=1) and anemia (n=1). In the LCT arm, Grade 3 events were: esophagitis (n=2), anemia (n=1), pneumothorax (n=1), and abdominal pain (n=1). Overall survival data are immature, with only 14 deaths recorded. Interpretation LCT +/− maintenance therapy for patients with ≤3 metastases from NSCLC that did not progress after initial systemic therapy improved PFS relative to maintenance therapy alone. These findings imply that aggressive local therapy should be further explored in phase III trials as a standard treatment option in this clinical scenario.

Should aggressive thoracic therapy be performed in patients with synchronous oligometastatic non-small cell lung cancer? A meta-analysis

“…Recently, a phase 2 randomized study found that local consolidative therapy with or without maintenance therapy for patients with three or fewer metastases from NSCLC that did not progress after initial systemic therapy improved progression-free survival compared with maintenance therapy alone (41). This study support our findings at some degree, however, we focus aggressive therapy particularly to the primary tumor and patients without treatment before.…”

A Model to Predict the Use of Surgical Resection for Advanced-Stage Non-Small Cell Lung Cancer Patients

“…However, the inclusion of surgical intervention into the treatment strategy for advanced-stage NSCLC has been reproducibly associated with improvements in survival [3][4][5][6][7][8]. Using data from population-based and institutional databases, we and others have demonstrated significantly longer cancer-specific and overall survival in advanced NSCLC patients treated with surgical intervention (alone or in combination) compared with nonsurgical modalities, including chemoradiotherapy, chemotherapy alone, radiotherapy alone, and no treatment (p < 0.001) [3][4][5][6].…”

“…Survival for advanced-stage NSCLC is only 4%, and outcomes are generally governed by response to systemic therapy [1]. Yet, the inclusion of surgical therapy into multimodality treatment regimens has been reproducibly associated with improved outcomes [3][4][5][6][7][8]15]. A recurrent criticism of these studies is that the observation of improved survival with surgical intervention is attributable to selection bias for patients with favorable characteristics (fewer comorbidities, lower-volume disease) rather the surgical treatment.…”

A new race against lung cancer

“…Recently, in a randomized multicenter phase II clinical trial the issue regarding a right way to manage these patients is correctly answered (9).…”