|Year : 2019 | Volume
| Issue : 2 | Page : 151-156
Fractionated stereotactic radiosurgery for locally recurrent brain metastases after failed stereotactic radiosurgery
Ferrat Dincoglan, Omer Sager, Selcuk Demiral, Hakan Gamsiz, Bora Uysal, Elif Onal, Ayca Ekmen, Bahar Dirican, Murat Beyzadeoglu
Department of Radiation Oncology, University of Health Sciences, Gulhane Medical Faculty, Ankara, Turkey
|Date of Web Publication||2-May-2019|
Department of Radiation Oncology, University of Health Sciences, Gulhane Medical Faculty, Ankara
Source of Support: None, Conflict of Interest: None
AIMS AND BACKGROUND: There is scant data on the utility of repeated radiosurgery for management of locally recurrent brain metastases after upfront stereotactic radiosurgery (SRS). Most studies have used single-fraction SRS for repeated radiosurgery, and the use of fractionated stereotactic radiosurgery (f-SRS) in this setting has been poorly addressed. In this study, we assessed the utility of f-SRS for the management of locally recurrent brain metastases after failed upfront single-fraction SRS and report our single-center experience.
METHODS AND STUDY DESIGN: A total of 30 patients receiving f-SRS for locally recurrent brain metastases after upfront single-fraction SRS at our department between September 2011 and September 2017 were retrospectively evaluated for local control (LC), toxicity, and overall survival outcomes.
RESULTS: Median age and Karnofsky performance status were 57 (range: 38–78 years) and 80 (range: 70–100) at repeated radiosurgery (SRS2). The median time interval between the two radiosurgery applications was 13.5 months (range: 3.7–49 months). LC after SRS2 was 83.3%. Radionecrosis developed in 4 of the 30 lesions after SRS2, and total rate of radionecrosis was 13.3%. Statistical analysis revealed that the volume of planning target volume (PTV) at SRS2 was significantly associated with radionecrosis (P = 0.014). The volume of PTV was >13 cm3 at SRS2 in all patients with radionecrosis.
CONCLUSION: A repeated course of radiosurgery in the form of f-SRS may be a viable therapeutic option for the management of locally recurrent brain metastases after failed upfront SRS with high LC rates and an acceptable toxicity profile despite the need for further supporting evidence.
Keywords: Brain metastasis, fractionated stereotactic radiosurgery (f-SRS), recurrence
|How to cite this article:|
Dincoglan F, Sager O, Demiral S, Gamsiz H, Uysal B, Onal E, Ekmen A, Dirican B, Beyzadeoglu M. Fractionated stereotactic radiosurgery for locally recurrent brain metastases after failed stereotactic radiosurgery. Indian J Cancer 2019;56:151-6
|How to cite this URL:|
Dincoglan F, Sager O, Demiral S, Gamsiz H, Uysal B, Onal E, Ekmen A, Dirican B, Beyzadeoglu M. Fractionated stereotactic radiosurgery for locally recurrent brain metastases after failed stereotactic radiosurgery. Indian J Cancer [serial online] 2019 [cited 2019 Jul 15];56:151-6. Available from: http://www.indianjcancer.com/text.asp?2019/56/2/151/257566
| » Introduction|| |
Approximately 10–30% of all patients with cancer suffer from brain metastases during the course of their disease as a major cause of morbidity and mortality. Brain metastases have an increasing frequency due to improved control of extracranial disease in cancer patients, thanks to more effective therapies. Stereotactic radiosurgery (SRS) has emerged as a viable treatment modality for management of brain metastases with an improved toxicity profile compared to traditional whole brain irradiation (WBI). In this context, deferring WBI and using SRS as a frontline treatment for patients with a limited number of brain metastases has gained widespread popularity with the primary advantage of improved cognitive functionality., However, the risk of developing new brain metastases at 1 year is about 40–70% when WBI is deferred., Therapeutic options in this setting include WBI, SRS, and surgery. Management of new metastatic lesions using SRS and continuing with deferral of WBI has been suggested in several studies.,,,
Nevertheless, there is scant data on the management of locally recurrent brain metastases after SRS. In the absence of randomized evidence to assist in decision-making for treatment, management options in this setting include surgery, WBI, systemic therapies, repeated SRS or radiotherapy, and supportive care., Vast majority of radiosurgery series in the literature have focused on results of SRS for management of newly developed metastatic lesions after primary treatment. Outcomes of repeated SRS to the locally recurrent brain metastases after upfront SRS have been poorly addressed in the literature with most series using single-fraction radiosurgery for repeated SRS.,,,, Fractionated stereotactic radiosurgery (f-SRS) may be considered as a viable therapeutic option in the management of locally recurrent brain metastases developing after failed upfront SRS to minimize adverse radiation effects of single-fraction SRS including radiation necrosis, permanent impairment of neurological functions, and steroid-refractory edema.
In this context, we assess the safety and efficacy of f-SRS for locally recurrent brain metastases initially managed with upfront single-fraction SRS in this study and report our experience with three different dose–fractionation schedules including 3 × 7, 5 × 5, and 5 × 6 Gy.
| » Methods|| |
A total of 30 patients receiving f-SRS for locally recurrent brain metastases after upfront single-fraction SRS at our department between September 2011 and September 2017 were retrospectively evaluated for local control (LC), toxicity, and survival outcomes. All patients had local recurrence or progression at the initially irradiated region and were decided to receive repeated radiosurgery with f-SRS after thorough multidisciplinary assessment, including lesion size, location, and initial radiosurgery dose. Informed consent of all patients were obtained before treatment and the study was performed in compliance with the Declaration of Helsinki principles.
Patient immobilization was secured by the use of a thermoplastic mask (Novastereo; Novater, Milano, Italy) fixed to the stereotactic head frame and mouth bite (Civco, USA). All patients underwent computed tomography (CT) simulation at CT simulator (GE Lightspeed RT; GE Healthcare, Chalfont St. Giles, UK) to acquire planning images with 1.25-mm slice thickness which were transferred to the contouring workstation (SimMD; GE, UK). All patients also had gadolinium-enhanced magnetic resonance imaging (MRI) to be used for target and critical organ delineation. Contouring of gross tumor volume (GTV), planning target volume (PTV), and organs at risk (OARs) was based on the fused CT and MR images. GTV was delineated as the contrast-enhancing lesion, excluding the surrounding edema. PTV was generated by 1 mm isotropical expansion of the GTV. After completion of contouring procedures, structure sets including the GTV, PTV, and OARs were sent to the radiosurgery planning system (ERGO++ planning system, Elekta). Frameless radiosurgery treatment planning was performed using the volumetric modulated arc treatment technique with 6-MV photons and 3- or 5-mm dynamic multileaf collimators. High-precision, image-guided volumetric modulated arc therapy was delivered using a linear accelerator (LINAC) with 6-MV photons using the frameless technique. f-SRS dose and fractionation was based on lesion size, location, and association with critical neurovascular structures. While patients with PTV <14 cm3 (corresponding to a sphere of 3 cm in diameter) received 3 × 7 Gy f-SRS, dose–fractionation scheme was determined as 5 × 5 or 5 × 6 Gy for larger PTVs to minimize the risk of late adverse effects. A dose was prescribed to the 85–95% isodose line encompassing the PTV. Setup verification was performed by matching of reference planning CT images with the kV-CBCT images using the XVI software (X-ray volumetric imaging [XVI] version 4.0, Elekta, UK) with bony anatomy registration. Patients received f-SRS on alternating days with intravenous steroid injection after each treatment fraction.
Follow-up of patients was based on thorough neurological assessment and neuroimaging with gadolinium-enhanced MRI. Follow-up visits were scheduled at 2-month intervals for the first year and 4–6-month intervals thereafter. Patients were instructed to inform their treating physician about any neurological worsening irrespective of the follow-up schedule. Radiation Therapy Oncology Group (RTOG) toxicity criteria were used for the assessment of acute and late adverse effects. Treatment response was evaluated using the Response Assessment in Neuro-Oncology Brain Metastases criteria. Complete response was defined as complete resolution of the target lesion on MRI. Partial response was defined as ≥30% decrease of the target lesion in the sum of the longest distance relative to baseline. Stable disease was defined as <30% decrease relative to baseline but <20% increase in the sum of the longest distance relative to nadir. Progressive disease (PD) was defined as ≥20% increase in the sum of the longest distance relative to nadir. For the purpose of comparing our results with other studies, we regarded any progression in lesion size as PD. Distant failure (DF) was defined as the appearance of a new lesion outside of the irradiated region or occurrence of leptomeningeal disease. Differentiation of tumor progression and radionecrosis was based on histopathological verification or assessment of imaging characteristics on perfusion MR, diffusion MR, and MR spectroscopy images by an experienced neuroradiologist. Decreased N-acetyl-aspartate-to-creatine ratio, increased choline-to-N-acetyl-aspartate and choline-to-creatine ratios on MR spectroscopy imaging, restricted diffusion, and elevated cerebral blood volume on diffusion and perfusion MRI were regarded as predictive of recurrent tumor versus radiation necrosis. Diffusion and perfusion MRI along with MR spectroscopy were used for the assessment of radionecrosis and recurrent tumor. Any contrast-enhanced lesion located within the irradiated volume on T1-weighted gadolinium-enhanced MRI was deemed to be suggestive of radiation necrosis or progression. For differentiation, a cerebral blood volume ratio >2.0 at dynamic susceptibility-weighted perfusion MRI along with more than one increased contrast enhancement on consecutive MRI assessments and corresponding elevated choline-to-N-acetyl-aspartate and choline-to-creatine ratios on MR spectroscopy imaging were presumed to be recurrent tumor. No response to steroid management was also considered as a sign of the recurrent tumor. Increased T1 contrast enhancement within the previously irradiated region including a central hypointensity accompanied by peripheral edema which remained stable or regressed on consecutive follow-up MRI assessment despite additional therapy was considered as radionecrosis, also without any findings suggestive of recurrent tumor on MR spectroscopy and diffusion and perfusion MRI.
Primary end points of the study were LC, overall survival (OS), and risk of radionecrosis. LC, OS, and risk of radionecrosis were estimated using the Kaplan–Meier method and were calculated from the time of repeated radiosurgical treatment. Variables including age, gender, KPS at SRS1 and SRS2, tumor localization, PTVs at SRS1 (upfront SRS) and SRS2 (repeated f-SRS), time interval between two radiosurgery applications, dose for SRS1 and SRS2 and BED10 values, histopathological subtype, and Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) scores were assessed by statistical analysis using IBM-SPSS version 21 (IBM Corp., Armonk, NY, USA). Log-rank and Cox regression tests were used for univariate and multivariate analyses with the P value set at <0.05 for statistical significance.
| » Results|| |
Between September 2011 and September 2017, 30 locally recurrent brain metastases of 30 patients were treated using a repeated course of radiosurgery using dose–fractionation schedules of 3 × 7, 5 × 5, and 5 × 6 Gy. Median follow-up duration after SRS2 was 22 months (range: 10–45 months). Patient and tumor characteristics are summarized in [Table 1]. Sixteen patients (53.3%) were female and 14 patients (46.7%) were male. Primary cancer was non-small cell lung cancer in 11 patients (36.7%), breast cancer in 9 patients (30%), melanoma in 4 patients (13.3%), renal cell cancer in 3 patients (10%), soft tissue sarcoma in 1 patient (3.3%), and colorectal cancer in 2 patients (6.7%). Out of the total 30 lesions, 9 lesions (30%) were located at the frontal lobe, 8 lesions (26.7%) were located at the temporal lobe, 7 lesions (23.3%) were located at the parietal lobe, 4 lesions (13.3%) were located at the occipital lobe, and 2 lesions (6.7%) were located at the cerebellum.
Upfront radiosurgery was performed in a single fraction for all patients. Median age and KPS was 55.5 (range: 37–76 years) and 90 (range: 70–100), respectively, at initial radiosurgery (SRS1) with the majority of patients (73.3%) having a KPS of 90–100. DS-GPA scores were 0–1 in 2 patients (6.6%), 1.5–2.5 in 6 patients (20%), 3 in 11 patients (36.7%), and 3.5–4 in 11 patients (36.7%) at SRS1. Median dose and BED10 values at SRS1 were 18 Gy (range: 16–24 Gy) and 50.4 Gy (41.6–81.6 Gy), respectively. Median volume of PTV was 8.85 cm3 (range: 0.1–21.6 cm3) at SRS1.
The dose for SRS2 was 3 × 7 Gy for lesions <14 cm3 and 5 × 5 or 5 × 6 Gy for lesions ≥14 cm3. Median age and KPS was 57 (range: 38–78 years) and 80 (range: 70–100), respectively, at repeated radiosurgery (SRS2) with 53.3% of patients having a KPS of 90–100. DS-GPA scores were 0–1 in 7 patients (23.3%), 1.5–2.5 in 13 patients (43.4%), 3 in 8 patients (26.7%), 3.5 in 1 patient (3.3%), and 4 in 1 (3.3%) patient at SRS2. Median dose and BED10 values at SRS2 were 21 Gy (range: 21–30 Gy) and 35.7 Gy (range: 35.7–48 Gy), respectively. Median volume of PTV was 14.3 cm3 (range: 1.6–35.6 cm3) at SRS 2. Median time interval between the two radiosurgery applications was 13.5 months (range: 3.7–49 months).
After SRS2, recurrence was detected in 5 of the 30 lesions (16.7%). Thus, overall LC after SRS2 was 83.3%. Out of the total five local failures, one (20%) was verified by histopathological assessment and other four local failures (80%) were detected by neuroimaging. All four patients who were not amenable to surgery received salvage WBI. LC with three and five fraction SRSs are shown on [Figure 1]a and [Figure 1]b, respectively.
|Figure 1: (a) Probability of local control for 3 × 7 Gy and (b) probability of local control for 5 × 5 and 5 × 6 Gy|
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Statistical analysis revealed no association of LC with age, gender, histopathological subtype, dose–fractionation schedule, BED10, KPS and DS-GPA scores, and median time interval between SRS1 and SRS2 (P > 0.05). The only parameter associated with LC after SRS2 was the volume of PTV (P < 0.001). All lesions with local failure after SRS2 had a volume >20 cm3 with a median volume of 29.9 cm3 (range: 22.7–35.6 cm3). Median OS was 23 months. OS at 12, 18, and 24 months was 76%, 60.8%, and 34.9%, respectively [Figure 2].
Radionecrosis developed in 4 of the 30 lesions after SRS2, and total rate of radionecrosis was 13.3%. All cases of radionecrosis responded to steroid treatment with no patients undergoing surgical intervention. Statistical analysis revealed that the volume of PTV at SRS2 was significantly associated with radionecrosis (P = 0.014). Median PTV volume in patients developing radionecrosis after SRS2 was 22.7 cm3 (range: 13.2–30.1 cm3). The volume of PTV was >13 cm3 at SRS2 in all patients with radionecrosis. While time interval between the two radiosurgical applications was not statistically significant for the development of radionecrosis, a trend was found on statistical analysis (P = 0.062). The time interval between the two radiosurgical applications was <10 months in all patients with radionecrosis.
Only one patient (3.3%) suffered from RTOG grade 3 neurological toxicity (visual loss) which responded to steroids and hyperbaric oxygen treatment. DF was detected in 16 patients (53.3%) and treated with SRS. Leptomeningeal disease in one patient (3.3%) was treated with WBI.
| » Discussion|| |
Optimal management of locally recurrent brain metastases after failed upfront SRS is yet to be defined with no available study in the current literature having high level of evidence to dictate treatment decisions. Earlier detection and more effective systemic therapies have led to longer survival of patients with brain metastases which emphasize the importance of salvage treatment. While surgery and WBI are included in the therapeutic options, both of them have limitations and disadvantages. Majority of the metastatic lesions are unresectable and located at an eloquent brain region which typically limits the utility of surgery due to the risk of excessive toxicity. Moreover, LC rates are not satisfactory with surgery as the sole salvage treatment., On the other hand, the use of WBI is limited due to risk of impaired neurocognitive functions and quality-of-life concerns., Given the relatively higher radiation doses at upfront radiosurgery, many patients with radioresistant recurrent metastatic lesions may not benefit from traditional WBI as salvage treatment. Results with chemotherapy have also been typically unsatisfactory. At this very challenging situation with poor outcomes of conventional treatments, encouraging results have been reported in studies using repeated radiosurgery.,,, In the study by Yamanaka et al., 41 patients with a total of 193 metastatic brain lesions were treated due to the appearance of new lesions or tumor regrowth. Out of the four patients receiving repeated radiosurgery for tumor regrowth in the study, three patients developed recurrence and one patient suffered from radiation necrosis. More recent studies with higher number of patients shed light on the utility of radiosurgery.,, In the study by Rana et al., 32 brain metastases of 28 patients were treated with repeated radiosurgery. Overall LC was reported to be 84.4% while 1- and 2-year LC rates were 88.3% (95% CI, 76.7–100%) and 80.3% (95% CI, 63.5–100%), respectively. Median OS was 22 months, and median local failure-free survival was 13.6 months. The rate of radionecrosis was 18.8%, and the median interval between the two SRS applications was 9.7 months. In the study by Koffer et al., 24 brain metastases of 22 patients were treated using repeated radiosurgery. Actuarial LC rates at 6 and 12 months were 94.1% and 61.1%, respectively. Four patients (16.7%) developed radiation necrosis. OS at 12 months was 37.5% and the median interval between the two radiosurgery procedures was 13.4 months. In the study by Mckay et al., 46 brain metastases of 32 patients were treated with repeated radiosurgery. LC was 79% (95% CI, 67–94%) at 1 year. Symptomatic radiation necrosis developed in 11 of the 46 treated lesions (24%). Most predictive factor for the development of radiation necrosis was found to be the volume of a lesion receiving 40 Gy (V40 Gy) on dosimetric data analysis (P = 0.003). Overall, studies of single-fraction repeated SRS reported similar results and concluded that the procedure was safe and feasible. Rates of radiation necrosis in the studies by Rana et al., Koffer et al., and Mckay et al. ranged between 16% and 24%.,, In our retrospective study of stereotactic reirradiation of locally recurrent brain metastases using f-SRS, LC was 83.3% after SRS2, and total rate of radionecrosis was 13.3%. We found higher PTV volumes and shorter intervals between the two radiosurgery applications to be associated with higher risk of radionecrosis. While the sample size and follow-up duration in our study may be limited to draw firm conclusions, our results with f-SRS appear to be consistent with the literature.
Radiation-induced brain necrosis is the most important late adverse effect of SRS, significantly deteriorating quality of life of the affected patients. Rates of radiation necrosis have been reported to be 2–32% in the literature.,,,,, Studies using upfront SRS delivered in 3–5 fractions have reported lower rates of radionecrosis in the range of 5–12%; nevertheless, the risk of radionecrosis is expected to be significantly higher in the setting of repeated radiosurgery directed at the initially irradiated lesions. Considering the advantage of fractionated regimens for avoiding late adverse effects of radiosurgery, fractionated radiosurgery regimens have been an active area of investigation for reirradiation of brain metastases initially treated with SRS. Very few studies have reported results of f-SRS as a repeated SRS procedure after failed upfront SRS of brain metastases. In the study by Minniti et al., 47 brain metastases of 43 patients were treated using dose–fractionation schemes of 3 × 7 and 3 × 8 Gy. Reported rates of 1- and 2-year LC were 70% and 60%, respectively. At a follow-up time of 19 months, 1- and 2-year survival rates were 37% and 20% after repeated f-SRS. Nine patients (19%) developed radiation necrosis and the rate of RTOG grades 3–4 neurological complication due to radionecrosis was 14%. In our study, radionecrosis rate was 13.3%, and one patient developed grade 3 complication as a result of radionecrosis. Lower rate of radionecrosis in our study may be explained by more fractionated radiosurgery schedules and treatment delivery on alternating days.
Improving the toxicity profile of radiation delivery is a pertinent goal of contemporary cancer management. In this context, it is critical to determine the optimal dose–fractionation schedule for f-SRS. However, there is a paucity of data regarding the optimal radiosurgery dose and fractionation for stereotactic reirradiation of brain metastases, and dose selection is based mostly on retrospective data and institutional experiences. Radiosurgery dose–fractionation schedules in our study are consistent with the limited number of studies using f-SRS for reirradiation of brain metastases., Nevertheless, radiation necrosis occurred in four patients (13.3%) in our study receiving 5 × 5 Gy (one patient) and 5 × 6 Gy (three patients). No patients in the 3 × 7 Gy group experienced radionecrosis in our study, which may partly be explained by the smaller PTV volumes in these patients. Despite the limited sample size in our study, using 3 × 7 Gy for stereotactic reirradiation of recurrent brain metastases may be preferred in the setting of smaller PTVs (<13 cm3) which clearly warrants further investigation. The occurrence of radionecrosis mostly in the 5 × 6 Gy group may partly be explained with the high PTV volumes and BED10 values in our limited number of patients. Our sample size is limited to draw firm conclusions on optimal dose and fractionation for stereotactic reirradiation, and further studies are needed to shed light on this issue. Nevertheless, radiosurgery dose–fractionation was individually determined for our patient cohort based on several factors including PTV volume, initial radiosurgery dose, time interval from initial SRS treatment, lesion location, and association with critical neurovascular structures. Multidisciplinary approach and decision-making should be considered for optimal management of these patients.
We acknowledge the limitations of our retrospective study including the small number of patients and heterogeneity in patient and treatment characteristics. Nevertheless, our study is one of the very few studies addressing the utility of f-SRS for locally recurrent brain metastases initially managed with upfront single-fraction SRS and adds to the literature by demonstrating encouraging results with f-SRS as a viable therapeutic option with an acceptable toxicity profile.
In conclusion, f-SRS offers a feasible therapeutic option for management of locally recurrent brain metastases initially managed with upfront single-fraction SRS. Risk of radionecrosis may be lower with f-SRS compared to single-fraction radiosurgery in this setting despite the need for further supporting evidence.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]