ANTICANCER RESEARCH 35: 3055-3060 (2015) Radiosurgery or Fractionated Stereotactic Radiotherapy plus Whole-brain Radioherapy in Brain Oligometastases: A Long-term Analysis MARIO BALDUCCI1, ROSA AUTORINO1, SILVIA CHIESA1, GIANCARLO MATTIUCCI1, ANGELO POMPUCCI2, LUIGI AZARIO3, GIUSEPPE ROBERTO D’AGOSTINO1, MILENA FERRO1, ALBA FIORENTINO1, SERGIO FERSINO1, CIRO MAZZARELLA1, CESARE COLOSIMO4, VINCENZO FRASCINO1, CARMELO ANILE2 and VINCENZO VALENTINI1 Departments of 1Radiation Oncology, 2Neurosurgery, 3Physics and 4Radiology, Catholic University of the Sacred Heart, Rome, Italy Abstract. Aim: To analyze the outcome of patients with number, size, location, the patient’s Karnofsky performance brain oligometastases treated by radiosurgery (SRS) or status (KPS), age, extent of systematic disease and primary fractionated stereotactic radiotherapy (FSRT) after whole- disease status (4, 5). brain radiotherapy (WBRT). Patients and Methods: Overall Patients with one or two brain metastases and with survival (OS) and local control (LC) were evaluated in favorable prognostic features have a relatively favorable patients (patients) with 1-2 brain metastases. Results: Forty- survival; thus, the treatment is frequently more aggressive seven patients were selected. They were submitted to WBRT than for patients with multiple brain metastases (5). (median dose=3,750 cGy) followed by SRS (17 patients; Radiosurgery (SRS) delivered as a single fraction to median dose=1,500 cGy) or FSRT (30 patients; median individual intracranial lesions has been the most common dose=2,000 cGy). Median follow-up was 102 months technique used to dose-escalate on lesions following whole (range=17-151); the median survival was 22 months for the brain radiotherapy (WBRT) and considered as safe SRS group and 16 months for the FSRT group. One-year and alternative to surgical resection in small lesions (6-8). The 5-year survival was 56% and 16%, respectively, in SRT and RTOG 9502 established radiosurgery dose recommendations 62.1% and 3%, respectively, in FSRT. Neither treatment of 15-24 Gy for individual lesions up to 4 cm (9). However, proved to significantly impact OS (p=0.4). The 1-year LC recent clinical trials have called this practice into question rates were 80% and 61.1% in the two groups, respectively due to increased neurotoxicity noted in some (10), but not (p=0.15). Conclusion: SRS or FSRT after WBRT could offer all (11) studies when compared to focal therapy alone. the same outcomes in patients with brain oligometasteses. Fractionated stereotactic radiotherapy (FSRT) is preferred Further investigation is warranted to confirm these data and when the target is too large or located near or within critical define the optimal stereotactic modality. brain structures, such as the brain stem, optic pathway or motor cortex (12, 13). Benefits of re-assortment and re- Brain metastases are the most common intracranial oxygenation may occur with a fractionated radiotherapy malignant neoplasms in adults and occur in 25% to 35% of course; therefore, FSRT may be more efficacious in the cancer patients (1). They cause significant mortality and treatment of brain metastases compared to single-fraction morbidity, including cognitive impairment at the time of radiosurgery (12). None randomized trial has compared presentation (2). Surgery and radiotherapy are the main radiosurgery to FSRT, but published data do not seem to treatment options (3). Prognostic indicators include the highlight any difference in terms of local control (LC) and overall survival (OS) (13). A variety of alternative radiotherapeutic approaches are now available. In particular, intensity modulated arc-based Correspondence to: Rosa Autorino, MD, Department of Radiation conformal radiation therapy combined with image-guided Oncology, Catholic University of the Sacred Heart, Largo A. radiation therapy (IGRT) system lends itself to synchronous Gemelli, 8, 00168 Rome, Italy. Tel: +39 0630155339, Fax: +39 0630155908, e-mail: [email protected] boost strategies so multiple targets can be easily treated to different total and per fraction dose, providing a potential Key Words: Brain oligometastases, fractionation, stereotactic alternative platform to conventional stereotactic frame radiotherapy, whole brain radiotherapy, RPA. systems for precision radiotherapy (14). 0250-7005/2015 $2.00+.40 3055 ANTICANCER RESEARCH 35: 3055-3060 (2015) Recently, we implemented a volumetric arc therapy Table I. Patients’ characteristics. (RapidArc) and before using this novel technique to treat brain metastasis we decided to analyze a historical group of Characteristics Total SRT FSRT t-Student’s test patients treated by stereotactic technique. (p-value) In this analysis, we evaluated safety and efficacy of SRS compared to FSRT after WBRT in patients with brain No. of patients 47 17 30 NR oligometastases. Age (years) 57 57 56 0.46 Primary tumor Lung cancer 32 14 18 Patients and Methods Breast cancer 10 1 9 0.19 Rectal cancer 1 0 1 Patients affected by brain metastases of any primary tumor and Others 4 2 2 treated in our Institution with SRS or FSRT were the subject of the No of brain metastases present study. Inclusion criteria were: no prior radiotherapy or 1 37 16 21 0.052 surgery to the brain, less than 3 brain metastases, diameter ≤3 cm, 21019 confirmed by magnetic resonance imaging (MRI), controlled RPA Class primary tumor, absent or controlled extracranial metastases, 1 36 12 24 0.46 recursive partitioning analysis (RPA) (6-7) class 1-2. 21156 Prior to stereotactic radiotherapy, all patients received WBRT, Whole brain dose (cGy/n˚fr) using a thermoplastic mask as an immobilization system; during the 3,000/10 12 3 9 stereotactic phase two different systems were used: a fixed system 3,750/15 32 12 20 0.39 4,000/20 3 2 1 (3D-line srl, supplier, address) for SRS and a non-invasive Boost metastases dose (cGy/n˚fr) stereotactic relocatable immobilization system (3D-line medical 1,500/1 14 14 0 NR system, supplier, address) for FSRT. Image fusion with MRI scan 2,000/1 3 3 0 was performed to contour brain lesions in stereotactic plan. WBRT 2,000/4 21 0 21 was administered by two opposite latero-lateral fields. SRS was 2,500/5 9 0 9 performed by 6-megavoltage photons from a linear accelerator using multiple non-coplanar converging arcs. Until 2006, a conic collimator was used, that was replaced by a dynamic micromultileaf collimator (3D-line medical system). Treatment planning was carried out with the Eclipse Treatment Planning System (Varian, patients to FSRT. The median dose of WBRT was address) for the WBRT phase and with TPS Ergo (3D-line medical system) for stereotactic treatment. 3,750 cGy (range=3,000-4,000) with a daily dose of 250 cGy The dose was prescribed to the isocenter with the 95% isodose (range=200-300). Radiosurgery was delivered with a median encompassing brain for whole brain and 80 % isodose dose of 1,500 cGy (range=1,500-2,000), while, for FSRT, the encompassing the entire gross tumor volume (GTV) for SRS. Dose- median dose was 2,000 cGy (range=2,000-2,500) with a daily limiting structures, such as the eyes, optic nerves, optic chiasm and dose of 500 cGy. Using these total doses and fractionations brainstem, were delineated according to Emami et al. and assuming for brain tumors an alfa/beta ratio of 10 Gy, the recommendations (15). resulting 2Gy-equivalent dose (EQ2) was 31.25 Gy for SRS All patients were evaluated with MRI one month after treatment and then quarterly. Toxicity was evaluated according to National and 25 Gy for FSRT, respectively. No statistical difference Cancer Institute Common Toxicity Criteria, v 2.0. was found in the two groups in terms of age, histology, Statistical analysis was performed by MedCalc (www.medcalc.be). number of brain metastasis and RPA class. The Student’s t-Test was used to verify the absence of The patients’ characteristics of the entire cohort and both statistically significant differences in the distributions of prognostic treatment groups are reported in Table I. factors between the two groups. The median planning target volume (PTV) was 1.82 ml LC rates and OS were calculated using the Kaplan-Meier method. for the SRS group and 2.45 ml for the FSRT group. Cox proportional hazards regression model was used to analyze the effect of covariates on survival. Toxicity. Grade >3 acute toxicities, such as headache, hearing Results problems, nausea and vomiting, did not occur in treated patients. With regards to chronic adverse effects, grade 3 We retrospectively evaluated files relative to 379 patients chronic toxicities (alopecia, headache, neurocognitive and submitted to whole-brain radiotherapy for brain metastases motor deficits, as well as visual/hearing impairment) from January, 1997 to March, 2010, in our Institution. Among occurred in 5% of the patients in SRS. Out of this group, one them, 47 patients were evaluable for analysis; 25 were male patient revealed radionecrosis, radiologically demonstrated and 22 female with a median age of 57 years (range=40-77). and appeared 6 months after the completion of radiotherapy. The median number of brain metastases was 1 (range=1-2). Survival. Median follow-up was 102 months (range=17-151) After WBRT, 17 patients were submitted to SRS and 30 in all patients. The median LC was 14 months for the entire 3056 Balducci et al: Whole-brain Radiotherapy in Brain Oligometastases: SRS vs. FSRT Figure 1. Local control. Figure 2. Overall survival. cohort. No statistically significant difference was found these therapeutic approaches represent, together with WBRT, among patients treated by SRT (18 months) with respect to the standard treatment of 1-3 brain metastases (18). those treated by FSRT (12 months) (p=0.15) (Figure 1). The Radiosurgery delivered as a single fraction to individual 1-year LC rates were 80.0% and 61.1% in SRS and FSRT, intracranial lesions has been established as a safe alternative respectively.