The use of SBRT in the management of oligometastatic gynecological cancer: report of promising results in terms of tolerability and clinical outcomes

The use of stereotactic radiotherapy (SBRT) for oligometastases is supported by several literature studies, but in the setting of gynecological malignancies, this scenario remains quite unexplored. This study reports a preliminary assessment of clinical outcomes in a cohort of 40 patients with oligometastatic gynecological neoplasms. Radiotherapy was delivered in 3–10 fractions with VMAT-IGRT technique. Toxicity was retrospectively collected according to CTCAE v4.0. Data were retrospectively collected and analyzed. Univariate and multivariate analyses were performed for assessing any potential predictive factor for clinical outcomes. A total of 63 oligometastases were treated from December 2014 to February 2021. Median age was 63 years (range 30–89). Most frequent primary tumors were ovarian cancer in 42.5% and endometrium cancer in 42.5%. With a median follow-up of 27 months (range 6–69), no local failures were observed, our progression-free survival rates were 43.6% and 23% at one and 2 years, respectively, while 1 and 2-year overall survival rates were both 70%. No acute or late G ≥ 2 adverse events were observed. In our experience, SBRT for oligometastatic gynecological malignancies resulted in promising results in terms of clinical outcomes, with excellent local control and no evidence of severe toxicity, highlighting the effectiveness of this therapeutic option. Prospective studies to further explore this approach in this setting are advocated.


Introduction
Gynecological malignancies are highly represented in general population. Endometrial is the most common among them (Cronin et al. 2018), with continuously rising incidence rates, also due to the increasing prevalence of obesity (Passarello et al. 2019); cervical cancer is one of the leading causes of death among women, while ovarian cancer is the seventh most common cancer worldwide and it is frequently diagnosed in advanced stage (Camara et al. 2021;Stewart et al. 2019).
In the last years, improvements in diagnostic imaging techniques, such as 18F-FDG-positron-emission tomography (PET)/computed tomography (CT) and magnetic resonance imaging (MRI), have led to a significant improvement in terms of tumor detection rate, increasing the number of patients characterized by a limited number of metastases.
This brings to a newly-defined subgroup of patients, so called oligometastatic, represented by an intermediate stage of disease between locally-advanced and widely-disseminated. In this scenario, local control may help improving systemic control and the SABR COMET study has clearly demonstrated that stereotactic body radiotherapy (SBRT) in addition to standard of care can improve overall survival in oligometastatic patients (Palma et al. 2019).
Oligometastatic disease (usually considered between 3 and 5 lesions) can be divided into three main categories: oligorecurrence, oligoprogression, and oligopersistence. Nowadays the best therapeutic strategies for the different kinds of oligometastatic disease remain undefined (Guckenberger et al. 2020).
The traditional and current management of patients with metastatic or recurrent cervical, endometrial and ovarian cancer is represented by systemic therapy, with addition of PARP inhibitors and bevacizumab to platinum-based chemotherapy (Kitagawa et al. 2015;Long et al. 2005;Buechel et al. 2019).
Currently, SBRT in the setting of metastatic gynecological patients has been rarely investigated in the literature, mainly consisting of retrospective series. Macchia et al. (2020) and Reschko et al. (2020) described SBRT as a well tolerated and efficient treatment in recurrent, persistent or oligometastatic gynecological cancers. Furthermore, also within a previously irradiated fiels, SBRT for isolated pelvic or intra-abdominal recurrences of gynecologic malignancies is feasible with an acceptable toxicity rate (Ling et al. 2019).
In the present study, we have retrospectively evaluated the outcomes of a cohort of 40 patients affected by gynecological malignancies who have received extracranial SBRT for oligometastatic cancer.

Methods
Written informed consent was obtained from all the patients. From December 2014 to February 2021, 40 patients with extracranial oligometastatic gynecological malignancies were treated at our Department, assuming as oligometastatic disease any presentation with up to five lesions amenable for a local treatment, with a maximum diameter ≤ 5 cm. Concurrent systemic therapy or previous pelvic radiotherapy were not exclusion criteria for the purpose of this study.
SBRT was proposed to all patients with a Karnofsky Performance Status ≥ 70 and a life expectancy of ≥ 6 months.
Treatment management was assessed basing on a multidisciplinary assessment. Table 1 collects patients' characteristics.

Radiotherapy procedures
A 1-2.5 mm slice thickness computed tomography (CT) was acquired for planning purposes. Immobilization for treatment simulation was performed either with an abdominal thermoplastic mask plus compression in the case of abdominal targets, or with 4-dimensional CT for thoracic targets. In the case of liver SBRT, contrast-enhanced CT-scans were acquired. In the case of pelvic targets, immobilization was performed in supine position by means of a knee-ankle device.
Regarding the target volume delineation process, the gross tumor volume (GTV) consisted of the radiologically evident disease; when available, contouring was performed with co-registered diagnostic imaging (PET or MRI). Clinical target volume (CTV) was considered equal to the GTV. The planning target volume (PTV) was created by adding an isotropic margin ranging from 5 to 7 mm, depending on tumor site and critical structures proximity. The dosimetric goal for treatment planning was to guarantee at least 95% of the prescribed dose to the 95% of the PTV. Dose constraints for organs at risk were derived from peer-reviewed literature (Sahgal et al. 2019;Moraes et al. 2020;Hanna et al. 2018;Pollom et al. 2017).
In all cases, SBRT was performed by means of image guided volumetric modulated arc therapy (IGRT-VMAT).

Statistical analysis
Descriptive statistics were collected for baseline patients' characteristics. Local control (LC), progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier method. Univariate and multivariate analyses were performed to assess any potential predictive factor for clinical outcomes. A p < 0.05 was assumed as statistically significant. Multivariate analysis was performed with a Coxregression analysis. All statistical analyses were carried out using Graphpad Prism v9.0.2 (Graphpad, San Diego, CA, USA).
Concurrent systemic therapy was administered in eight patients (20%), consisting of PARP inhibitors in 5 cases, anti-VEGF antibody in 2 cases and trastuzumab in one patient.
One and 2-years progression-free survival (PFS) rates for the entire population were respectively 43.6% and 23%. Neither univariate nor multivariate analysis found any significant correlation for this clinical outcome. (Tables 2, 3).
Sixteen patients developed a sequential oligometastatic disease, for which a further SBRT course was proposed, with a second progression-free survival (PFS2) of 13 months (range 2-27), although this did not lead to a survival advantage, when compared to patients who developed immediate polymetastatic spread (p = 0.47). In the remaining 24 patients, polymetastatic spread occurred in 47.5% of cases  Two and 3-years overall survival rates were both 70%, with only one patient who died by other causes (Fig. 1).

Toxicity
SBRT treatment was well tolerated and all patients completed the planned treatment without any interruption. No acute or late grade 2 or higher adverse events were observed.

Discussion
The role of SBRT in the management of oligometastatic cancer disease has been supported by several literature experiences, either as a potentially curative treatment option, and as a means to postpone the start of a new systemic therapy (Lehrer et al. 2021;Palma et al. 2020).
Nonetheless, in the specific setting of gynecological malignancies, it is hard to draw definitive conclusions, since this subpopulation is usually under-represented in these trials (Chalkidou et al. 2021). This is probably due to the natural history of gynecological cancer, such as ovarian or cervical cancer, in which the addition of systemic therapy takes place early, given the high propensity to metastatic spread. A recent review by Zhang et al. highlights the substantial feasibility of SBRT for oligometastatic gynecological cancer especially for lymphnodal metastases, even in the case of previous pelvic irradiation. On the contrary, a major risk of G ≥ 3 adverse events is reported in the case of pelvic side wall or central pelvic recurrences treated with SBRT (Zhang et al. 2020).
In the present series, we have recorded the outcomes of 63 lesions in 40 patients treated with SBRT for extracranial oligometastases from gynecological malignancies. No local failures were observed in our series, highlighting the effectiveness of the SBRT treatment. Unlike previous experiences, we have not recorded a survival advantage in those patients who developed a sequential oligometastatic progression, further treated with a second course of SBRT (Nicosia et al. 2020a, b).
This evidence may raise the issue of the real role of focal treatments in this setting, suggesting a different natural history of gynecological malignancies when compared to other scenarios, as also highlighted by the sub-optimal PFS rates of most of the published studies concerning gynecological oligometastases.
Iftode et al. collected data concerning a series of 44 metastatic lesions arising from ovarian cancer who received SBRT, collecting satisfactory outcomes in terms of LC and PFS, with negligible toxicity (Iftode et al. 2018).
Ning et al. in a previous report focused their attention on cervical cancer oligometastases, collecting promising results, in agreement with the abovementioned studies. Of note, this study included both SBRT and conventional fractionation treatments, making harder to draw definitive conclusions (Ning et al. 2018).
Reddy et al. documented excellent local control results in a series of 27 patients with oligometastatic uterine cancer, recording worse local control rates in the case of liver metastases (Reddy et al. 2020).
The favorable toxicity profile of our series supports this therapeutic approach, also when combined with conventional systemic therapies, that for gynecological malignancies still represent the standard of care. This is also confirmed by one of the largest series available in the literature, in which in a multicenter series published by Macchia et al., the authors collected a 2-year toxicityfree survival rate of 95.1%. Interestingly, keeping in mind that this study refers to ovarian cancer oligometastases, a statistically significant correlation was found for higher LC rates, when a BED > 70 Gy radiotherapy schedule is applied (Macchia et al. 2020).
Similarly to our experience, a recent study by Smile et al. included different primary gynecological cancers also highlighting excellent results in terms of both toxicity and clinical outcomes (Smile et al. 2021).
The present study has several limitations; first of all, we retrospectively collect data of a heterogeneous sample of patients including different primary histologies and both patients who received and received not systemic therapy. Nonetheless, we report one of the largest series with the longest follow-up currently available, and the results are promising and in agreement with other literature experiences supporting the role of SBRT, also in this relatively unexplored field of the oligometastatic disease.

Conclusions
This mono-institutional experience supports the use of SBRT in the management of the oligometastatic gynecological cancer, by collecting no relevant toxicity and promising results in terms of clinical outcomes. Prospective studies are needed to further evaluate this therapeutic option in this scenario.