Radiosurgery and fractionated stereotactic body radiotherapy for patients with lung oligometastases

Metastatic progression of cancer is linked to poor prognosis and is the leading cause of cancer-related deaths [1]. Few decades ago, the diagnosis of metastatic disease was related to lethal outcomes. This paradigm has changed after Hellman and Weichselbaum introduced the concept of oligometastases: the intermediate state between non-metastatic cancer and highly palliative disseminated metastatic disease [2]. Patients with an initially limited number of metastases or with progression of only few lesions after cytoreductive therapy might be potentially cured or reach long-term survival when treated with local ablation therapy for all lesions. The search for prognostic biomarkers for discrimination of potentially oligometastatic patients is still ongoing. In some small prospective studies circulating tumor cells as well as circulating tumor DNA in liquid biopsies were able to predict treatment outcomes and response to ablative therapy [3]. However, until prognostic biomarkers will be established for routine application, the selection of patients that could benefit from local ablative therapy rather than from palliation will be based on clinical features.

The lungs are one of the most common metastatic sites for various solid tumors [4, 5]. Stereotactic body radiotherapy (SBRT) and surgical resection are frequently used treatment options for patients with a limited number of pulmonary lesions. Although SBRT compared to surgery for lung metastases have not been studied in a prospective randomized trial, retrospective data suggest that both methods achieve equal results in terms of local control and overall survival [6, 7]. Single fraction radiosurgery (SFRS) is especially attractive as an outpatient procedure in terms of patients’ compliance, cost effectiveness and limited treatment time. However, up to now there is no recommendation when to administer SFRS over fractionated SBRT (fSBRT). The aim of this study was to analyze local control (LC) after SFRS and fSBRT in patients with lung oligometastases and identify prognostic clinical features for better survival outcomes.

This analysis represents a single-center experience in treating oligometastatic lung lesions with curative intended SFRS and fSBRT. The 1-, 2-year LC and OS rates for the entire cohort were 82, 70 and 84%, 71%, respectively. Our findings are comparable with the current findings in the literature (Table 7) [8‐16].

SBRT is an attractive non-invasive treatment option providing good therapy outcomes with minimum toxicity. The BED ≥100 Gy, smaller tumor size, shorter interval between diagnosis and treatment of metastases are favorable prognostic factors influencing local control of lung metastases after SBRT [9, 17‐19]. The existing data on fractionation schedules as well as dosage of SBRT for lung metastases is limited by retrospective nature or non-randomized prospective study design. Therefore, no standardized treatment regimens are yet available. The primary results of TROG 13.01 SAFRON II Phase II trial which compares SFRS to fSBRT for lung metastases are expected soon [20].

According to our data, small lung metastases (median PTV ≤ 9.9 cm³, median diameter 12 mm) might safely be treated with SFRS applying 24–26 Gy (median D_max of 53 Gy and a median BED_max of 81 Gy) with excellent 1- and 2-year LC rates of 89 and 83%, implying that BED < 100 Gy using SFRS might be sufficient for durable control in small lung lesions. This observation, however, contradicts the findings of other studies, where BED < 100 Gy was found to be a negative prognostic factor for LC. Ricco et al. analyzed whether different lung metastases volumes and BED were associated with treatment outcomes [17]. In this study, lesions after SBRT with BED ≥100 Gy reached better LC rates. Moreover, in the group with BED ≥100 Gy smaller metastases (volume < 11 cm³) were linked to improved LC and OS rates. The median number of fractions employed was 3 (range: 1–8), how many lesions were treated with SFRS remains unclear. Other trials rarely report on the significance of BED and fractionation regimens in terms of treatment outcome for metastases according to their size [9, 12]. Nevertheless, the existing data on size-adapted SFRS for lung metastases as well as primary lung tumors is promising with 1 year LC rates varying from 89.1–93.4% [15, 21‐23]. However, diverse measurement units or target volumes describing metastases size (e.g. diameter, GTV, PTV) found in the literature make it difficult to categorize lesions or to identify the optimal dose. Randomized, prospective studies are needed to determine which fractionation schedule is the most suitable for lung metastases according to the size in terms of therapy outcomes, toxicity and patient’s compliance.

In the current study, 1- and 2-year LC rates for metastases from CRC compared with non-CRC were significantly worse. Recently, Jingu et al. investigated the impact of primary tumor histology on LC rates after SBRT for lung metastases in a metanalysis and systematic review. Analysis of 1920 patients (619 with CRC, 1301 non-CRC) showed that LC was significantly inferior in the CRC group (p < 0.00001). In addition, the dose escalation (BED > 130 Gy) was associated with decreased local recurrences [24]. Furthermore, Ahmed and colleagues concluded that lung metastases from rectal carcinoma are related with increased radio-resistance, and therefore are more likely to relapse after SBRT. The authors recommend dose escalation with BED > 100 Gy for radio-resistant tumors in order to improve treatment outcomes [25]. In the present study, the median BED for relapsed metastases from rectal cancer was 87.5 Gy (range: 56–124.8), suggesting that an insufficient dose for this histology may be responsible for lower LC rates in patients with CRC. Therefore, SBRT with BED < 100 Gy should be used with caution in patients with lung oligometastases from rectal cancer.

We found time to the first metastasis ≥12 months, KPS > 70% and N0 to be independent favorable prognostic factors for OS. Metachronous metastases with longer metastasis free interval are associated with indolent tumor histology and thus are frequently linked to better outcomes, with the favoring time to metastasis diagnose varying from ≥2 months to ≥75 months depending on the primary tumor type [26‐28]. Furthermore, in agreement with our results good performance score before initiation of the SBRT was linked to better survival in various studies [29, 30]. Absence of lymph node involvement was addressed as a prognostic factor mostly in series on oligometastatic lung cancer [27, 31]. Unlike our finding, no prognostic value of N classification was reported in studies with cohorts of heterogenous primary tumor type, therefore this finding must be interpreted carefully. Despite the small sample size, we identified two commonly reported prognostic factors that might be useful for selecting oligometastatic patients for curative SBRT.

The major limitation of this study is its retrospective design with inhomogeneous primary tumor types and the limited number of patients. Therefore, neither a subgroup analysis based on metastasis histology nor an analysis of the effects of dose escalation was performed. Treatment planning calculations with Ray-Tracing, Pencil Beam or Monte Carlo dose algorithms for lung might produce differences in dose distribution for target and organs at risk. However, there was no difference detected in the treatment outcomes in metastases planed with different treatment algorithms. Since multiple metastases in the same patient were treated with different fractionation, finding the prognostic value of SFRS vs. fSBRT for survival outcomes was not feasible.

KPS > 70%, longer time to first metastasis and absence of locoregional lymph node metastases were found to be positive predictive factors for OS in patients with lung oligometastases after SBRT. Long-term LC and low toxicity rates were achieved after short SBRT schedules.