Microwave ablation for non-small cell lung cancer with synchronous solitary extracranial metastasis

Abstract

Aims

Local therapy including surgery or radiotherapy has been reported for the treatment of non-small cell lung cancer (NSCLC) with synchronous solitary metastasis, while studies with other local ablative treatment are rare. Here, we summarized our single-center experience of microwave ablation (MWA) for both primary and metastatic lesions in NSCLC patients with synchronous solitary extracranial metastases.

Patients and methods

We retrospectively screened our institute database from January 2014 to Jun 2019. NSCLC patients with synchronous extracranial solitary metastasis with primary and metastatic lesions that were treated with MWA were identified and analyzed.

Results

Of the 1472 stage IV NSCLC patients found, 38 were diagnosed with synchronous extracranial solitary metastasis and 29 of them received MWA for primary and metastatic lesions. The most common distant metastases were contralateral lung metastases (14 cases), followed by bone (6), liver (4), adrenal gland (3) and pleura metastases (1). Median OS and PFS was 21.5 and 12.5 months, respectively. Patients with N0 had significantly longer PFS (median 18.5 vs. 8.0 months) and OS (median 42.7 vs. 19.0 months). In addition, systemic therapy was showed to be a prognostic factor for better PFS (12.9 vs. 7.5 months). Clinical pathological factors including age, histology, T stage, PS score, and metastasis locations are not significantly associated with survival.

Conclusions

MWA may serve as an alternative treatment for NSCLCs with synchronous solitary extracranial metastases.

Introduction

Clinically, only a small portion of non-small cell lung cancers (NSCLCs) are diagnosed at an early stage, while over 60% patients present with locally advanced or metastatic disease (stage III or IV) at initial diagnosis, at which point surgical resection may not be considered (Siegel et al. 2019; Travis et al. 2015). Despite the progress in anticancer therapy including targeted agents or newly developed checkpoint inhibitor, prognosis for metastatic NSCLC remains to be improved.

Stage IV NSCLC is a heterogeneous disease. Multiple preclinical and clinical data increasingly supported the concept that patients with oligometastases present a distinct population from widely spread metastatic disease (Hellman and Weichselbaum 1995; Wong et al. 2016; Lussier et al. 2011; Weichselbaum and Hellman 2011). Based on the 8th edition of the TNM classification of lung cancer, the M1a category includes cases of pleural or pericardial effusions, contralateral or bilateral lung/pleural nodules, or a combination of these parameters. Solitary metastasis in a single distant organ has been newly classified as M1b, while multiple lesions in single or multiple organs should be reclassified in a new M1c category. Both M1a and M1b have been classified in IVa stage while widespread metastasis is categorized as IVb disease, suggesting that patients presenting with synchronous solitary metastasis may present a distinct population. For these patients, life expectancy and prognosis may be better and aggressive local ablative therapy can be beneficial. Several studies suggested that selected patients who present with synchronous solitary metastases may have long-term survival if receiving surgical resection or radiotherapy for both primary and metastatic lesions (Tonnies et al. 2014; Salah et al. 2012; Ambrogi et al. 2001; Toffart et al. 2018).

In previously published literatures, local therapy for patients with solitary metastases mainly consists of surgery, chemoradiotherapy or multi-modality treatment, while studies concerning other local ablative treatment have been rarely reported. Image-guided thermal ablation techniques including radiofrequency ablation (RFA), microwave ablation (MWA), and cryoablation have been widely applied for NSCLC with oligometastatic disease, especially for those that are not surgical candidates (Vogl et al. 2017; Baere et al. 2016; Ni et al. 2019; Solbiati 2018; Ye et al. 2018; Hertzanu and Ye 2019; Wei et al. 2019). Thermal ablation showed good safety, efficacy, and local disease control while preserving lung parenchyma. Studies have showed advantages of MWA in contrast to other thermal ablation techniques in large tumors, in locations adjacent to vessels and in fully perfused areas (Palussiere et al. 2017). Our recently published results indicated that local MWA consolidative therapy with concurrent TKIs resulted in better local control and survival than TKIs monotherapy in EGFR-mutant advanced NSCLCs with extracranial oligometastases (Ni et al. 2020). The present report was initiated to summarize our single-center experience of MWA to primary and metastatic lesions for NSCLC patients with synchronous solitary extracranial metastases.

Methods

Patients

This is a retrospective single-center study. We analyzed the database of patients who underwent NSCLC and were treated with MWA between January 2014 and Jun 2019 at the Shandong Provincial Hospital affiliated to Shandong First Medical University. Of those, 29 NSCLC patients with synchronous extracranial solitary metastasis who received MWA for both primary and metastatic lesions were retrospectively identified. The study was approved by the ethics committee of Shandong Provincial Hospital affiliated to Shandong First Medical University and written informed consent to use the clinical data for research was obtained from each participant before the medical intervention started. Patients were evaluated with physical examination, systemic examination of either contrast-enhanced computed tomography (CT) of the chest and abdomen, bone scans, or positron emission tomography/computed tomography (PET–CT), brain CT or magnetic resonance imaging (MRI). Patients who met the following criteria were enrolled: (1) pathologically or cytologically confirmed NSCLC; (2) stage IV disease according to the 7th edition of the American Joint Committee on Cancer staging system, with synchronous solitary metastatic disease; (3) primary NSCLC and metastases technically completely microwave ablated; (4) no further metastatic lesions were detected (solitary metastasis); (5) ≥ 18 years old, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) score ≤ 2.

The exclusion criteria included: (1) patients who did not undergo a systemic examination prior to enrolling in this study; (2) diagnosed with synchronous brain metastasis at baseline; (3) newly diagnosed distant metastasis within 1 month after ablation therapy. Patients’ selection steps are shown in Fig. 1.

Fig. 1.

Flow chart of patients’ treatments

Treatment procedures

All patients had been discussed in a multidisciplinary tumor board, where a consensus was reached that MWA treatment to all known sites of disease was clinically reasonable and feasible. To limit potential bias, including selection bias, patients were included based on the ‘intention-to-treat’ decision of the multidisciplinary tumor board. Detailed ablation procedures were as we previously described. Generally, needle biopsy and MWA of primary tumors was performed first and the metastasis was then ablated. The interval between primary tumor and metastasis treatment allowed the administration of induction chemotherapy, adjuvant chemotherapy or TKIs and was less than 1 months in all cases. One month after ablation, contrast-enhanced computed tomography (CT) and/or magnetic resonance (MR) imaging was performed to determine the local response (complete or incomplete ablation) based on criteria as we previously described (Ye et al. 2018). Patients received contrast-enhanced CT or MR scan every 1–2 months after ablation to assess their response to treatment and to identify adverse events.

Data processing and statistical analysis

All patients were analyzed for baseline characteristics, tumor and treatment characteristics, ablation completeness, ablation complications and 30-day mortality. Primary endpoints were overall survival (OS) and progression-free survival (PFS). OS was calculated from the first day of ablation treatment until the last date of follow-up or death. PFS was calculated from first day of treatment until any relapse, local or distant, or death (whichever occurred first). Kaplan–Meier curve and log-rank test were used for survival analyses. Cox proportional hazards model was used to calculate the hazard ratio (HR) and corresponding 95% confidence intervals (CI). P values were two-sided and considered significant if < 0.05. Statistical analysis was performed using SPSS for Windows Version 17.0 (IBM, Chicago, IL).

Results

Patient characteristics

Based on the inclusion and exclusion criteria, 29 NSCLC patients with synchronous solitary extracranial metastases who received MWA for both primary and metastatic lesions were included in the present study (patients’ characteristics shown in Table 1). Adenocarcinoma was the predominant histologic type (18, 62.1%). All adenocarcinomas were detected for EGFR gene mutations and TKIs were admitted as first-line therapy whenever applicable. In all patients, 24 (82.8%) received post-ablation systemic therapy, of which 6 patients received EGFR-TKIs.

Table 1.

Baseline patient characteristics

Variables	Numbers (%)
Age
Median (IQR)	68 (58–78)
Sex
Male	9 (31.0)
Female	20 (69.0)
ECOG performance status
0–1	21 (72.4)
2	8 (27.6%)
Histology
Adenocarcinoma	15 (51.7)
Squamous cell carcinoma	12 (41.4)
NSCLC, undefined	2 (6.9)
T stage
T1	14 (48.3)
T2	13 (44.8)
T3	2 (6.9)
Nodal status
N0	10 (34.5)
N1	10 (34.5)
N2/N3	9 (31.0)
Metastasis location
Contralateral lung	14 (48.3)
Bone	6 (20.7)
Liver	4 (13.8)
Adrenal gland	3 (10.3)
Pleura	1 (3.4)

The clinical N involvement was N0 in 10 patients (34.5%), N1 in 10 patients (34.5%), N2 in 6 patients (21%) and N3 in 3 patients (10%). The most common distant metastases were contralateral lung metastases (14 cases), followed by bone (6), liver (4), adrenal gland (3) and pleura metastases (1). The site of the bone metastasis was rib in two patients, vertebra in four patients.

Outcomes and prognostic factors

Median OS of all patients was 21.5 months (IQR 12.5–25.1 months) and PFS was 12.5 months (IQR 7.0–16.0 months) (Fig. 2). Patients with N0 had significantly longer PFS (median 18.5 vs. 8.0 months, HR 0.27, 95% CI 0.11–0.65, P < 0.01) (Fig. 3a) and OS (median 42.7 vs. 19.0 months, HR 0.20, 95% CI 0.06–0.66, P < 0.01) (Fig. 3b). In addition, systemic therapy was showed to be a prognostic factor for better PFS (12.9 vs. 7.5 months, HR 0.18, 95% CI 0.03–0.95, P = 0.04) (Fig. 4a), and nearly retained significance for OS (24.5 vs. 18.2 months, HR 0.14, 95% CI 0.02–1.01, P = 0.052) (Fig. 4b). Multivariable Cox regression analysis confirmed that negative nodal involvement was associated with better PFS and OS. Other clinical pathological factors including age, histology, T stage, PS score, and metastasis locations are not significantly associated with patients’ survival (Table 2).

Fig. 2.

Progression-free survival (a) and overall survival (b) of all patients

Fig. 3.

Kaplan–Meier analysis of PFS (a) and OS (b) by nodal involvement. Patients with N0 had significantly longer PFS (median 18.5 vs. 8.0 months, HR 0.27, 95% CI 0.11–0.65, P < 0.01) and OS (median 42.7 vs. 19.0 months, HR 0.20, 95% CI 0.06–0.66, P < 0.01)

Fig. 4.

Kaplan–Meier analysis of PFS (a) and OS (b) by systemic treatment. Patients with systemic treatment have better PFS (12.9 vs. 7.5 months, HR 0.18, 95% CI 0.03–0.95, P = 0.04) and relatively long OS (24.5 vs. 18.2 months, HR 0.14, 95% CI 0.02–1.01, P = 0.052)

Table 2.

Results of Cox regression analyses

Variables	Multivariable Cox regression analysis for PFS and OS
	PFS			OS
	HR	95% CI	P	HR	95% CI	P
Gender (male vs. female)	1.87	0.39–4.37	0.37	2.58	1.78–3.55	0.76
Age (< 65 vs. ≥ 65)	0.89	0.80–0.99	0.45	0.99	0.84–1.20	0.98
ECOG score (0–1 vs. 2)	0.91	0.31–2.65	0.86	0.39	0.11–1.36	0.14
Histology (adenocarcinoma vs. others)	2.25	0.76–6.70	0.15	0.94	0.27–3.2	0.92
T stage (T1 vs. T2/T3)	1.59	0.67–3.76	0.29	2.32	0.85–6.36	0.10
Nodal status (N2/N3 vs. N0/N1)	3.57	1.89–6.73	< 0.01	3.36	1.51–7.45	< 0.01
Metastasis location (lung vs. other sites)	2.54	0.64–4.58	0.53	1.65	0.67–3.47	0.34

Treatment complications

Generally, most MWA complications were mild and well tolerated. There was no perioperative mortality during ablation procedures or within 30 days after MWA. Twenty patients (69%) suffered mild or moderate pain after ablation, but no severe post-ablation pain occurred. Post-ablation pneumothorax image findings were observed in 10 (23.1%) lung ablation sessions, while 4 (40%) of them received chest tube drainage. Self-limited, post-ablation syndrome including fever (below 38.5 °C), fatigue, general malaise, nausea, and vomiting, etc., occurred in 11/58 (19%) of ablation sessions. Hypertensive crises occurred in one adrenal gland MWA procedure (33.3%) and were managed by anesthesiology with phentolamine and sodium nitroprusside.

Discussion

NSCLC patients with distant metastases were classified as having stage IV disease and a poor prognosis. However, there is growing evidence supporting the benefits of aggressive local therapy to primary and metastatic lesions for patients with synchronous oligometastasis. More restricted than the definition of oligometastasis, we enrolled patients with synchronous solitary extracranial metastasis. The present study was conducted to describe criteria for selecting patients who would benefit from MWA treatment to primary tumor and synchronous metastases.

Several retrospective series concerning surgery for synchronous solitary metastasis reported a median survival ranging between 13.5 and 41 months (Tonnies et al. 2014; Collaud et al. 2012; Mordant et al. 2012; Hanagiri et al. 2012). In a recently published study with 1592 advanced stage NSCLC patients, 109 (7%) had a synchronous solitary metastasis (M1 disease), of which 90 (83%) received local therapy including surgery or radiotherapy of curative intent at the primary and metastatic sites. Local therapy for both sites was associated with long-term survival (Toffart et al. 2018). However, most series reporting on patients with synchronous solitary metastases have focused on brain metastases. Moreover, local therapy applied in these studies mainly included surgical resection or radiotherapy.

The most common synchronous distant metastatic sites in NSCLC patients are the brain, bone, liver and adrenal gland (Quint et al. 1996). Brain was reported as the most frequent (60%) solitary metastatic site (Mordant et al. 2012; Downey et al. 2002; Luketich et al. 1995; Nieder et al. 2019), while studies concerning solitary extracranial metastasis are scarce. Luketich et al. initially identified 14 NSCLC patients who received local treatment of their primary lesions followed by solitary extracranial metastases resection. An overall 10-year survival of 86% was observed in these patients (Luketich et al. 1995). Ambrogi et al. conducted a small sample retrospective study and enrolled nine NSCLC patients with synchronous solitary extracranial metastasis: adrenal gland (n = 5), cutaneous (n = 2), axillary lymph node (n = 1) and kidney (n = 1). Resection of both primary tumor and solitary metastases was associated with a 5-year survival rate of 55.6% (Ambrogi et al. 2001). In a systemic review of 51 articles including 62 cases with solitary metastasis (other than adrenal gland or brain) who received combined primary cancer treatment and metastasis resection, the 5-year survival rate reached 50% for the entire cohort (Salah et al. 2012). The long-term survival of patients who underwent simultaneous resection or radiotherapy of primary and metastatic tumors stimulated our interest in the role of MWA therapy for this situation, especially for those who are not amenable for surgical resection. MWA has several advantages compared to RFA, achieving higher temperatures, larger ablation zones, less intraprocedural pain, as well as reduced susceptibility to the heat sink effect (Pusceddu et al. 2019). Our previous published results indicated that MWA as local consolidative therapy leads to better disease control and survival in EGFR-mutant advanced NSCLC patients with extracranial oligometastasis (Ni et al. 2020). In the present study, all patients received MWA for their primary and metastatic lesions and had a median PFS of 12.5 months and OS of 21.5 months. This encouraging result is consistent and comparable with previously series in surgery or radiotherapy, which expands the clinical practice of MWA for stage IV NSCLCs.

According to our results, clinical nodal involvement (N0 versus N+) was a prognostic factor of survival. Indeed, patients with clinical N0 stage had a median survival of 42.7 months compared to 19 months for lymph node positive patients (P < 0.01). These findings were in accordance with multiple studies on surgical or radiation treatment (Salah et al. 2012; Ambrogi et al. 2001; Collaud et al. 2012; Downey et al. 2002). The second factor of good prognosis is related to the addition of systemic chemotherapy/TKIs. Multiple retrospective studies commonly supported that prognosis might be ameliorated by systemic therapy (Hanagiri et al. 2012; Griffioen et al. 2013; Congedo et al. 2012). As local MWA cannot be applied for hilar or mediastinal lymph node metastases, combination with thoracic radiotherapy or aggressive systemic therapy should be considered in these patients subgroup.

Our study still has some limitations. First, this is a single-center retrospective study with small sample size. Second, patients with brain metastasis were excluded in this study. Therefore, further investigation of combined primary pulmonary MWA and brain radiotherapy for NSCLCs with solitary brain metastasis may be interesting and necessary. Moreover, without a control group with solitary metastasis who did not receive aggressive MWA therapy, it is difficult to ascertain whether MWA actually improves survival.

In conclusion, aggressive MWA therapy of primary and metastatic lesions in selected NSCLC patients with synchronous extracranial solitary metastasis can result in long-term survival. Intra-thoracic positive nodal involvement appears as a significant clinical factor in predicting survival and patients with additional systemic therapy have better survival than those without. Prospective clinical trials, ideally randomized, should evaluate the role of MWA therapy in NSCLCs with synchronous extracranial solitary metastases.

Compliance with ethical standards

Conflict of interest

The authors report no conflicts of interest.