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Radiosurgery Or Hypofractionated Stereotactic Radiotherapy for Brain Metastases from Radioresistant Primaries (Melanoma and Rena

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Radiosurgery Or Hypofractionated Stereotactic Radiotherapy for Brain Metastases from Radioresistant Primaries (Melanoma and Rena Lesueur et al. Radiation Oncology (2018) 13:138 https://doi.org/10.1186/s13014-018-1083-1 RESEARCH Open Access Radiosurgery or hypofractionated stereotactic radiotherapy for brain metastases from radioresistant primaries (melanoma and renal cancer) Paul Lesueur1,2,7* , Justine Lequesne3, Victor Barraux4, William Kao1, Julien Geffrelot1, Jean-Michel Grellard3, Jean-Louis Habrand1,7, Evelyne Emery5,7, Brigitte Marie6, Juliette Thariat1,7 and Dinu Stefan1 Abstract Background: Until 50% of patients with renal cancer or melanoma, develop brain metastases during the course of their disease. Stereotactic radiotherapy has become a standard of care for patients with a limited number of brain metastases. Given the radioresistant nature of melanoma and renal cancer, optimization of the fractionation of stereotactic radiotherapy is needed. The purpose of this retrospective study was to elucidate if hypofractionated stereotactic radiotherapy (HFSRT) impacts local control of brain metastases from radioresistant tumors such as melanoma and renal cancer, in comparison with radiosurgery (SRS). Methods: Between 2012 and 2016, 193 metastases, smaller than 3 cm, from patients suffering from radioresistant primaries (melanoma and renal cancer) were treated with HFSRT or SRS. The primary outcome was local progression free survival (LPFS) at 6, 12 and 18 months. Overall survival (OS) and cerebral progression free survival (CPFS) were secondary outcomes, and were evaluated per patient. Objective response rate and radionecrosis incidence were also reported. The statistical analysis included a supplementary propensity score analysis to deal with bias induced by non-randomized data. Results: After a median follow-up of 7.4 months, LPFS rates at 6, 12 and 18 months for the whole population were 83, 74 and 70%, respectively. With respect to fractionation, LPFS rates at 6, 12 and 18 months were 89, 79 and 73% for the SRS group and 80, 72 and 68% for the HFSRT group. The fractionation schedule was not statistically associated with LPFS (HR = 1.39, CI95% [0.65–2.96], p = 0.38). Time from planning MRI to first irradiation session longer than 14 days was associated with a poorer local control rate. Over this time, LPFS at 12 months was reduced from 86 to 70% (p = 0.009). Radionecrosis occurred in 7.1% for HFSRT treated metastases to 9.6% to SRS treated metastases, without any difference according to fractionation (p = 0.55). The median OS was 9.6 months. Six, 12 and 18 months CPFS rates were 54, 24 and 17%, respectively. Conclusion: Fractionation does not decrease LPFS. Even for small radioresistant brain metastases (< 3 cm), HFSRT, with 3 or 6 fractions, leads to an excellent local control rate of 72% at 1 year with a rate of 7.1% of radionecrosis. HFSRT is a safe and efficient alternative treatment to SRS. Keywords: Stereotactic radiotherapy, Brain metastases, Radioresistant, Melanoma, Fractionation, Renal Cancer * Correspondence: [email protected] 1Radiotherapy department, Centre François Baclesse, Caen, France 2Laboratoire d’accueil et de recherche avec les ions accélérés, CEA-CIMAP, Caen, France Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Lesueur et al. Radiation Oncology (2018) 13:138 Page 2 of 10 Background metastases and follow-up MRI to assess the response to About 10 and 50% of patients with renal cancer [1]or treatment and intracranial control. Patients who had melanoma [2], develop brain metastases during the received upfront WBRT before SRS or HFSRT were course of their disease respectively. Multimodality treat- excluded. Patients with performans status (PS) superior ment including neurosurgery, radiotherapy, systemic to 2 were not included. The different metastases from a treatments, and best supportive care with respect to dis- same patient could be treated with SRS or HFSRT. ease burden, patient preference and performance status Patients could have several stereotactic irradiation ses- is usual. Stereotactic radiotherapy has become a stand- sions during the course of their disease. ard of care for patients with a limited number of brain metastases [3, 4]. This is so regardless a histology-based Hypofractionated stereotactic radiotherapy and approach despite different spread patterns and different radiosurgery treatments response to the various treatment modalities. On the Brain metastases were treated using a Cyberknife system basis of such results, in our institution, we treat patients (Accuray Inc. ®, Sunnyvale®, California). Patients were having up to 10 brain metastases from melanoma or positioned supine on the 6D robotic couch and immobi- renal cancer with stereotactic radiotherapy. Given the lized with a commercial stereotactic mask fixation sys- radioresistant nature of melanoma and renal cancer, tem. Tracking was performed with the Cyberknife 6D optimization of the fractionation of stereotactic radio- skull system®. All the patients benefited from a 1 mm therapy is needed. Following the linear quadratic model thick slice CT scan (CT, Philips®, BigBore®) and a 1 mm [5], and considering an α/β ratio about 2.5 [6, 7], then slice gadolinium-enhanced cerebral MRI (Siemens®). GTV biological effective dose is much higher with SRS was delineated on axial T1-weighted gadolinium-enhanced (>18Gy) than with HFSRT. Thus, it was expected that MRI. CTV was a zero-margin expansion from GTV and brain metastases of radioresistant primary tumors PTV was defined as an isocentric 2 mm expansion from treated with HSFRT would show poorer local control GTV. Doses were prescribed to the 80% isodose line to than these treated with SRS. Indeed, a retrospective achieve a minimum 95% target coverage of the prescribed study with a small sample concluded that fractionated dose. All the metastases treated with a fractionation differ- stereotactic radiotherapy was less effective in radioresis- ent from 1, 3 or 6 were also excluded from the analysis. tant tumors and recommended that radioresistant The radiotherapist determined fractionation and the deliv- tumors should be treated in a single fraction if possible ered dose after consideration of PTV final volume and [8, 9]. The linear quadratic model has been suggested to proximity of critical structures such as optic chiasma, optic be incorrect for large dose fractions, because it does not nerves, cavernous sinus, or brain stem for example. Radio- take into account additional biological effects resulting surgery was favored if metastases measured less than 1 cm from high dose on endothelial cells and tumor immun- diameter and far from an organ at risk. Consequently me- ity. Thus, local control could be not strictly correlated to tastases size and localization were the two variables used to calculated biological effective dose. build the propension score (cf Statistical analysis). Brain In this retrospective study we aimed to examine if metastases were irradiated on alternate days, every other hypofractionated stereotactic radiotherapy impacts local day. When patients presented several metastases to irradi- control of brain metastases from radioresistant tumors ate, then, they were not irradiated the same day, but the such as melanoma and renal cancer. day after. Salvaged treatments were also evaluated when asses- Methods sing outcomes. If SRS or HFSRT failed, patients could Patients receive WBRT or neurosurgery. In case of distant cere- Between May 2012 and December 2016, we screened all bral relapse, another session of stereotactic radiotherapy patients who had received a stereotactic radiotherapy for or WBRT could be proposed, at the discretion of the brain metastases from melanoma or renal cancer in our radiotherapist. institution (Centre François Baclesse, Caen, France). This study was approved by the French ethic commit- Follow-up and outcomes tees: CEREES and CNIL. An information letter was sent Patients were clinically examined one month after treat- to patients still alive at time of data collection. Histology ment, and then every two months. At each medical con- was confirmed by pathologic analysis, with biopsy from sultation a gadolinium-enhanced MRI was performed. primitive site or from metastases. Patients should have Duration of follow-up was calculated as time from first had at least a pre and post treatment MRI evaluation. fraction of HFSRT or SRS to last MRI evaluation. The Metastases bigger than 14140mm3 (corresponding to a primary outcome was local progression-free survival sphere of 3 cm diameter) were excluded. MRI was (LPFS: Patient alive without in-field local recurrence). systematically performed, to make diagnosis of brain For lesions larger than 1 cm, an increase of enhanced Lesueur et al. Radiation Oncology (2018) 13:138 Page 3 of 10 tumor volume superior to 20% was considered as a local between both groups. Cox model and log-rank test were ap- progression and a decrease superior to 30% as a partial plied to original and to the matched samples to evaluate
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