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Abstract
Introduction Data supporting stereotactic body radiotherapy for oligometastatic patients are increasing; however, the outcomes for gynecological cancer patients have yet to be fully explored. Our aim is to analyze the clinical outcomes of stereotactic body radiotherapy in the treatment of patients with recurrent or oligometastatic ovarian cancer or cervical cancer.
Methods The clinical data of 29 patients (35 lesions) with oligometastatic cervical cancer (21 patients, 72%) and ovarian carcinoma (8 patients, 28%) who were treated with stereotactic body radiotherapy for metastatic sites were retrospectively evaluated. All patients had <5 metastases at diagnosis or during progression, and were treated with stereotactic body radiotherapy for oligometastatic disease. Patients with ≥5 metastases or with brain metastases and those who underwent re-irradiation for primary site were excluded. Age, progression time, mean biologically effective dose, and treatment response were compared for overall survival and progression-free survival.
Results A total of 29 patients were included in the study. De novo oligometastatic disease was observed in 7 patients (24%), and 22 patients (76%) had oligoprogression. The median follow-up was 15.3 months (range 1.9–95.2). The 1 and 2 year overall survival rates were 85% and 62%, respectively, and the 1 and 2 year progression-free survival rates were 27% and 18%, respectively. The 1 and 2 year local control rates for all patients were 84% and 84%, respectively. All disease progressions were observed at a median time of 7.7 months (range 1.0–16.0) after the completion of stereotactic body radiotherapy. Patients with a complete response after stereotactic body radiotherapy for oligometastasis had a significantly higher 2 year overall survival and progression-free survival compared with their counterparts. In multivariate analysis, early progression (≤12 months) and complete response after stereotactic body radiotherapy for oligometastasis were the significant prognostic factors for improved overall survival. However, no significant factor was found for progression-free survival in the multivariable analysis. No patients experienced grade 3 or higher acute or late toxicities.
Conclusions Patients with early detection of oligometastasis (≤12 months) and with complete response observed at the stereotactic body radiotherapy site had a better survival compared with their counterparts. Stereotactic body radiotherapy at the oligometastatic site resulted in excellent local control rates with minimal toxicity, and can potentially contribute to long-term survival.
- cervix uteri
- radiotherapy
- radiotherapy, image-guided
- radiotherapy, intensity-modulated
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HIGHLIGHTS
Patients with complete response after stereotactic body radiotherapy for oligometastasis had a significantly higher 2 year progression-free survival and overall survival compared with their counterparts.
Early progression (≤12 months) and complete response after stereotactic body radiotherapy for oligometastasis were significant prognostic factors for improved overall survival.
No patients experienced grade 3 or higher acute or late toxicities after stereotactic body radiotherapy.
Introduction
Gynecological tumors are the fourth leading cause of cancer death in women.1 Systemic chemotherapy is the standard of care for metastatic disease; however, patients with distant metastasis are not amenable to curative treatment, and they have significantly higher mortality rates.2 Although patients with metastatic disease have dismal outcomes, a subset of patients with limited metastasis or recurrence may have the potential for long-term disease control.3 This subgroup of patients may be candidates for more aggressive treatments, including ablative doses of radiation delivered to the metastatic site, to diminish the disease progression.
Stereotactic body radiotherapy is a highly conformal irradiation technique that delivers high radiation doses to the tumor and spares the surrounding healthy tissues.4 5 The clinical use of stereotactic body radiotherapy has been validated in multiple tumor types with oligometastases, with local control rates >80%.5–7 Furthermore local consolidative treatment to the oligometastatic site with stereotactic body radiotherapy may improve survival rates.8–10 The benefit of stereotactic body radiotherapy to treast oligometastasis may be due to reduction of the burden of treatment-resistant cells, potentiation of systemic therapy, and a decrease in the growth of distant micrometastatic disease.11 12 Although data supporting aggressive local treatment for oligometastatic patients are increasing, the outcomes for gynecological cancer patients have yet to be fully explored.
Promising results in the treatment of oligometastatic disease from different tumors, including gynecological cancer, have been reported, indicating the existence of a dose–response relationship for local tumor control independent of tumor histology according to classical radiobiological sensitivity ranking.13–17 Most of these studies evaluated the outcomes of stereotactic body radiotherapy in oligometastatic gynecological tumors with different tumor sites, whereas only a few studies focused on stereotactic body radiotherapy in patients with oligometastatic ovarian cancer18 19 and cervical cancer.16 To this end, in this multi-institutional study we sought to report the clinical outcomes of stereotactic body radiotherapy in the treatment of patients with distantly recurrent or oligometastatic ovarian cancer or cervical cancer.
Methods
Patient Selection
The clinical data of 29 patients with oligometastatic gynecological tumor who were treated with stereotactic body radiotherapy for metastatic sites between June 2014 and February 2019 were retrospectively analyzed. Patients either had oligometastasis at diagnosis, which was de novo oligometastatic disease (seven patients, 24%), or had oligoprogression (22 patients, 76%) after completion of primary treatment. Patients were included if they had biopsy-proven ovarian carcinoma or cervical cancer, had <5 metastases at diagnosis or during progression, and had received treatment with stereotactic body radiotherapy for oligometastatic disease. Two patients with different primary tumor sites other than ovary and cervix (one patient with endometrial carcinoma and one patient with vulvar carcinoma) were excluded. Patients with ≥5 metastases or with brain metastases were excluded. Also, those who underwent re-irradiation for the primary site were excluded. The first metastatic site was categorized according to organ involvement, and patients were considered to have multi-organ metastasis if more than one organ was involved. All cases were presented and discussed at a multi-disciplinary tumor board. This study was approved by the local ethical board.
Treatment Planning
Systemic therapy was not allowed during stereotactic body radiotherapy delivery, and systemic chemotherapy was temporarily discontinued for 5–7 days before and after stereotactic body radiotherapy sessions. Patients were positioned supine with arms above the head and immobilized using a BodyFIX bluebag with vacuum wrap (Elekta, Stockholm, Sweden). The gross tumor volume included macroscopic disease defined on contrast-enhanced planning computed tomography (CT). For better delineation of gross tumor volume, positron emission tomography-computed tomography (PET-CT) or magnetic resonance imaging (MRI) were fused with contrast enhanced CT. The planning target volume was generated for 7 mm in all directions for lung, liver, and adrenal gland metastases. For lymph node and bone metastases 3 mm margins were given in order to generate planning target volume. The dose constraints are summarized in Table 1.
Dose constraints for organs at risk
Treatment was delivered every other day. The dose was prescribed to 90% isodose line, and planning target volume coverage was aimed at >95% of the prescribed dose. The stereotactic body radiotherapy doses differed according to metastatic sites (Table 2). All treatment plans were performed for delivery with an Axesse linear accelerator (Elekta AB, Stockholm, Sweden) using volumetric modulated arc therapy (VMAT) plans consisting of double or triple 360° arcs. All patients were treated with image-guided radiotherapy using daily cone-beam CT in order to overcome setup inaccuracies. Response evaluation with PET-CT was performed according to the PERCIST v1.0 criteria20; for patients who underwent treatment response evaluation through MRI, RECIST v1.1 was used.21 Toxicity outcomes were recorded during treatment and at each follow-up using the Common Terminology Criteria for Adverse Events version 4.03.
Patient characteristics and treatment outcomes
Statistical Analysis
Statistical analyses were performed using Statistical Package for the Social Sciences 20.0 software (SPSS, Chicago, IL, USA). The local control, overall survival, and progression-free survival rates were calculated using Kaplan–Meier analyses. Overall survival was defined from the first day of stereotactic body radiotherapy until death or until the last follow-up visit, whereas progression-free survival was calculated as the time between the first day of stereotactic body radiotherapy and any disease progression or death. Age, time to progression, mean biologically effective dose (BED; assuming an 
ratio of 10), and treatment response were compared for overall survival and progression-free survival. All values of p<0.05 were considered statistically significant.
Results
Patient Characteristics
The patient and tumor characteristics of the entire cohort are summarized in Table 2. Twenty-two patients (76%) had a performance score of 0 and seven patients (24%) had a score of 1. The median age at diagnosis was 55 years (range 40–83). Twenty-one patients (72%) had cervical cancer and eight patients (28%) had ovarian carcinoma. A total of 35 lesions were treated with stereotactic body radiotherapy. Twenty-five patients (86%) had one lesion, three patients (10%) had two lesions, and one patient (4%) had four lesions treated with stereotactic body radiotherapy. The stereotactic body radiotherapy sites were as follows: 20 lymph nodes (57%), five liver metastases (14%), five bone metastases (14%), four lung metastases (11%), and one adrenal gland metastasis (4%). The initial treatments were definitive chemoradiotherapy in 14 patients (48%) and surgery in 15 patients (52%). Of the 15 patients treated with surgery, nine (31%) patients received adjuvant chemotherapy and six (21%) patients had postoperative chemoradiotherapy.
Following stereotactic body radiotherapy of the oligometastatic lesion, 27 patients (93%) received systemic therapy, whereas two patients (7%) did not receive systemic therapy following the radiotherapy. These two patients had single lung metastasis measuring 2.0 and 2.4 cm, respectively. In one of these two patients, systemic chemotherapy was not given due to advanced age (83 years), whereas the other patient received chemotherapy before oligoprogression; both patients refused to receive additional chemotherapy regimens. For those patients receiving systemic treatment after stereotactic body radiotherapy, 15 patients (55%) received carboplatin and paclitaxel, six patients (21%) received bevacizumab only, and five patients (17%) were treated with immunotherapy only.
Patient Outcomes
For stereotactic body radiotherapy performed in 10 patients (34%) to treat oligometastasis, the metabolic response was observed by PET-CT at a median time of 3.1 months (range 2.4–3.5) after completion of the radiotherapy. A complete response was seen in five patients with PET-CT, while the remaining five patients had no complete response at post-treatment PET-CT or MRI. Response evaluation was performed with CT and/or MRI in 19 patients (66%), and complete response was observed in eight patients, whereas 11 patients had no complete response.
After a median follow-up of 15.3 months (range 1.9–95.2), 19 patients (65%) had disease recurrence at a median time of 7.7 months (range 1.0–16.0) after completion of stereotactic body radiotherapy. Progression at the stereotactic body radiotherapy site was observed at a median time of 5.3 months (range 3.0–7.7) after completion of the radiotherapy. Median follow-up time in patients who were alive with or without evidence of disease was 13.7 months (range 2.7–34.5) and 14.9 months (range 5.4–31.6), respectively.
Survival
The 1 and 2 year overall survival rates were 85% and 62%, respectively, and the 1 and 2 year progression-free survival rates were 27% and 18%, respectively (Figure 1A and B). The 1 year local control rates for patients and treated lesions were 84% and 89%, respectively (Figure 1C). Local recurrence was observed at four lesions (11%) treated with stereotactic body radiotherapy. Patients with complete response after stereotactic body radiotherapy to treat oligometastasis had significantly higher 2 year overall survival and progression-free survival compared with patients without complete response to the radiotherapy. In the univariate analysis, complete response was the only significant prognostic factor for overall survival (Table 3). In the multivariate analysis, early progression (≤12 months) and complete response after stereotactic body radiotherapy to treat oligometastasis were the significant prognostic factors for improved overall survival (Table 4). However, no significant factor was found for progression-free survival in multivariable analysis.
Kaplan–Meier analyses showing (A) overall survival, (B) progression-free survival, and (C) local control.
Univariate analysis for overall survival and progression-free survival
Table 4 Multivariateanalysis for overall survival and progression-free survival
Toxicity
No patients experienced grade 3 or higher acute or late toxicities. Five patients (17%) had grade 2 toxicities, wherein three patients with para-aortic lymph node stereotactic body radiotherapy had nausea or diarrhea, and two patients with liver metastasis had dizziness, which completely diminished shortly after the end of the treatment. Only three patients (10%) had grade 1 toxicities. No additional toxicity was reported in the subsequent follow-up period.
Discussion
In this study, we demonstrated the effectiveness and safety of stereotactic body radiotherapy in the treatment of oligometastatic cervical and ovarian cancer patients. The 2 year overall survival, progression-free survival, and local control rates for the oligometastatic gynecological cancer patients treated with stereotactic body radiotherapy and with systemic agents were 62%, 18%, and 84%, respectively; none of the patients experienced a toxicity level of grade 3 or higher. Although excellent local control at the oligometastatic site treated with stereotactic body radiotherapy was achieved, 65% of the patients had disease progression observed at a median time of 7.7 months after completion of the radiotherapy. However, 84% of the patients had distant disease progression other than the treated local recurrence, and this condition necessitates an effective systemic treatment in order to improve treatment outcomes. Those patients with early detection of oligometastasis (≤12 months) and with complete response observed at the stereotactic body radiotherapy treated lesion had better survival compared with their counterparts.
The treatment of choice for metastatic gynecological cancer is systemic chemotherapy and/or targeted therapies with median overall survival of 6.1–17.5 months and 3.1–8.6 months, respectively.22 23 The results of these studies varied because the number and site of metastases, the treatment strategies, and study designs were different. With the discovery of oligometastatic disease, several efforts have been made to improve the outcomes for oligometastatic patients with various cancer types,5 24 25 including gynecological tumors.14–16 18 19 However, there is no consensus on the application of stereotactic body radiotherapy in oligometastatic patients with gynecological cancer; conflicting results were reported due to the wide range of stereotactic body radiotherapy doses and fractionations that were used for stereotactic body radiotherapy delivery in highly heterogeneous patient populations with various primary tumors and different oligometastatic sites Table 5.14 16 18 26–28 Our results for local control rate, overall survival rate, and toxicity were similar to the findings reported in the literature. However, compared with previous studies,14 15 26 27 the current study involved a patient population that was relatively homogenous, including only patients with ovarian and cervical cancer. A few studies evaluated the outcomes of stereotactic body radiotherapy to the oligometastatic site only in patients with cervical cancer16 28 and ovarian cancer.18 19 In previous studies, the oligometastatic sites were predominantly lymph nodes; by contrast, in our study, the rate of oligometastatic lymph nodes was relatively less, except for the study by Mesko et al.14
Published studies involving patients treated with stereotactic body radiotherapy for oligometastatic gynecological tumors
Recently, it has been demonstrated that oligometastasis is common in various cancer types, and the early detection of oligometastasis has increased, thanks to developments in imaging modalities, including PET-CT and MRI.29 Early detection of oligometastasis or de novo oligometastatic disease may lead to a better survival. The oligometastatic state has long been recognized as potentially curable but was considered to be a rare exception to the cancer metastasis paradigm. As newer methods of analyzing patients with metastatic disease develop, such as the analysis of circulating tumor cells or functional imaging modalities, the oligometastatic state should be identified even earlier. The metastases from tumors with limited capacities might be separated from those with much further disease spread. Therefore, ablative local treatments of patients with true oligometastasis may be sufficient. However, another type of oligometastasis is defined as remaining tumor deposits following successful eradication of all other apparent and occult cancer cells by systemic agents, which may require aggressive local and systemic treatments. In late onset metastasis, oncogenic mutations may potentially cause strong activation of oncogenic pathways that repress metastasis while promoting proliferation.30
In this study, we demonstrated that early detection of oligometastasis (≤12 months) or detection of oligometastasis at diagnosis led to better survival compared with the detection of late-onset metastasis. Previous studies have demonstrated that patients with various cancer types treated with local consolidative treatment in all metastatic sites and primary tumor followed by maintenance systemic therapy had a better prognosis compared with patients treated with systemic chemotherapy alone.9 31 However, data regarding the effect of stereotactic body radiotherapy on de novo oligometastatic sites and primary tumors in gynecological tumors are lacking. In this study, no significant difference in survival was observed between de novo oligometastatic patients and patients with oligoprogression, and this disparity may be due to the limited number of patients.
The treatment response to stereotactic body radiotherapy, either complete or partial, has been demonstrated to be a prognostic factor in oligometastatic gynecological tumors.15 Laliscia et al15 reported a decreased or absence of PET metabolic activity in 76% of 45 patients with oligometastatic gynecological cancer. In the current study, the treatment response at the oligometastatic site treated with stereotactic body radiotherapy was observed in 25 patients (86%), and complete response after stereotactic body radiotherapy was seen in 13 patients (45%). We demonstrated that patients with complete response after stereotactic body radiotherapy had significantly better survival compared with patients without complete response after stereotactic body radiotherapy of oligometastatic lesions; however, no significant effect of treatment response on disease progression was observed.
Our study is not without limitations because of its retrospective nature and associated selection bias. Our sample size was small, limiting our ability to clarify the differences in outcomes by treatment site and disease pathology. However, the number of patients and targets treated was comparable with that of similar studies. Additionally, patients received different systemic agents that may have directly affected their survival. The relatively short-term follow-up may also be a limitation, although our goal was to report early clinical outcomes. Given the typically short survival time of the patient population, a median follow-up of 15.3 months can still provide meaningful information. Despite these inherent limitations, this study is important because it analyzed only patients with cervical cancer or ovarian carcinoma, and the rates of non-nodal metastasis are relatively higher than those reported by previous studies.
The use of stereotactic body radiotherapy to treat patients with oligometastatic gynecological cancers is a feasible treatment approach. This technique leads to high local control rates with minimal toxicity; together with effective systemic management, it has the potential to contribute towards achieving long-term survival in some patients. Determining the optimal strategies for patient selection, dose, and treatment delivery are areas of ongoing study. The high rates of distant progression confirm the need for further research into the combinations of stereotactic body radiotherapy and systemic therapy.
References
Footnotes
Contributors All authors contributed to the manuscript equally.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request. De-identified participant data.