EP-1126: Whole brain radiotherapy of breast cancer brain metastases: intracranial progression and prognosis

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3

German Cancer Consortium (DKTK) German Cancer Research Center (DKFZ) Heidelberg, Germany, Purpose or Objective Imaging of positron emission tomography (PET) combined with MRI was conducted prior to re-irradiation for 7 highgrade glioma patients. MRI-based treatment planning of three independent raters was compared with biological tumor volumes (BTVs) automatically generated from PETMRI data in this prospective phase I clinical trial (NCT01579253). Material and Methods MRI-based treatment plans for 7 high-grade glioma patients with PET-MR imaging preceding re-irradiation were created by three independent raters including all contrast-enhancing regions. Inter-rater reliability was evaluated by the intraclass correlation coefficient (ICC). BTVs with a threshold of 1.6 and a union of these BTVs with the consensus MRI-based GTVs were compared to the consensus GTVs only. OTP-Masterplan® was used for treatment planning. Dice coefficients and conformity indices were used for comparing the consensus GTVs and BTVs and for the union of consensus GTV plus BTV with the original planning target volume (PTV). Results PET-MR imaging conducted prior to re-irradiation of 7 high-grade glioma patients (2 WHO grade III, 5 WHO grade IV) was used for this planning study with three independent raters. Median follow-up from initial diagnosis was 52 months and median post-recurrence survival 13 months. Median age at the beginning of reirradiation was 54 years and median KPS 80. Median postrecurrence progression-free survival from the beginning of re-irradiation was 8 months. Six patients received bevacizumab concomitantly to re-irradiation and 1 patient temozolomide. Median GTV volume ranged from 35 to 40.5 cc, median consensus GTV volume of all three raters was 41.8 cc, median BTV 36.6 cc and the union of consensus GTV and BTV in median 59.3 cc. The ICC between the raters was on average measures 0.96, 0.96 and 0.97. The dice coefficient between the consensus GTV and the BTV was in median 0.61 and the conformity index 0.44. The dice coefficient between the union of consensus GTV and BTV with a margin of 8 mm and the original PTV was median 0.84 and the conformity index in median 0.73. Conclusion PET-MRI derived BTVs may help to adjust the margin at treatment planning of recurrent high-grade glioma reirradiation and reduce inter-rater variability. The most prominent advantage of this imaging modality is the „onestop-shop' including two coregistered imaging modalities of high quality. EP-1125 Concomitant temozolomide therapy improves survival outcome of patients with multifocal glioblastoma M. Syed1, J. Liermann1, T. Sprave1, V. Verma2, J. Rieber1, S.B. Harrabi1, N. Bougatf3, D. Bernhardt1, A. Mohr1, S. Rieken1, J. Debus1, S. Adeberg1 1 Universitaetsklinik Heidelberg, Department of Radiation Oncology, Heidelberg, Germany 2 University of Nebraska Medical Center, Department of Radiation Oncology, Omaha, USA 3 University Hospital Heidelberg, Heidelberg Ion-Beam Therapy Center HIT, Heidelberg, Germany Purpose or Objective Concomitant temozolomide (TMZ) therapy has been established as first line treatment of malignant gliomas after several studies had shown better survival outcomes. These studies have largely been performed with patients with unifocal lesions. Our study aims to investigate the role of temozolomide therapy in multifocal glioblastoma

(GBM) along with radiotherapy by comparing differences in survival rates of patients with unifocal GBM (uGBM) and multifocal GBM (mGBM). Material and Methods We retrospectively analyzed 265 patients with primary GBM undergoing radiation therapy at the Department of Radiation Oncology, Heidelberg University Hospital between 2004 and 2013. Of these, 202 (76%) were uGBMs and 63 (24%) were mGBMs. 133 (65%) with uGBM and 43 (68%) with mGBM received concomitant treatment with TMZ. First, progression-free survival (PFS) and overall survival (OS) between groups were compared using the Kaplan-Meier method. Second, univariate and multivariate Cox proportional hazards regression was applied to discern prognostic factors including TMZ with PFS and OS in the cohorts. Results Hundred ninety-five patients (73%) experienced tumor progression on follow-up MRI scans performed after radiation therapy. Patients with mGBM experienced significantly worse OS of 11.5 months (range 1.6 - 25 months) as compared to patients with uGBM with an OS of 14.8 months (range 1 – 55.9 months) (p=0.032), with similar patient characteristics in both Groups. There were no significant differences in PFS between the respective groups (6.5 versus 6.6 months, p=0.750). Concomitant TMZ therapy was associated with significantly better OS in mGBM (8.3 vs 14.2 months, p = 0.006) and uGBM (11.7 vs 17.0 months, p<0.001). Univariate and multivariate analyses for OS revealed a negative prognostic effect for multifocal disease (p<0.001) and a positive prognostic effect for concomitant TMZ treatment in mGBM (p=0.008) and uGBM (p < 0.001). Conclusion Patients with mGBM generally experienced significantly worse overall survival than patients with uGBM after radiation therapy. Concomitant TMZ treatment improved OS of patients with mGBM and uGBM by approximately five months. EP-1126 Whole brain radiotherapy of breast cancer brain metastases: intracranial progression and prognosis. D. Ou1, L. Cao1, C. Xu1, J. Chen1 1 Ruijin Hospital- Shanghai Jiaotong University School of Medicine, Radiation Oncology, Shanghai, China Purpose or Objective Despite the increasing systemic treatment for breast cancer (BC), CNS metastases represent one of most aggressive conditions of metastatic disease. The prognosis became very diverse with regard to molecular subtypes of the primary disease. The current study aims to assess the survival benefit and pattern of intracranial progress of BC patients with brain metastasis (BM) after whole-brain radiotherapy (WBRT). Material and Methods A total of 79 consecutive BCBM, who were diagnosed and treated with WBRT between Jan 2010 and Mar 2016 were studied. All of them were diagnosed with primary invasive ductal carcinoma. Molecular subtypes were defined in 77 patients, as following: Luminal A-like (n=14), Luminal Blike (n=26), HER-2 positive non-luminal (n=13) and Triple Negative (TN) (n=24). Results The median patient age at the diagnosis of BM was 49 years (range 22–77 years) and the median KPS at BM was 80. The median time to BM (TTBM) was 36 months (range 0-232 months). Sixty-five patients received upfront WBRT and 14 received WBRT subsequent to SBRT. Systemic treatment were administered to 50 patients after WBRT, including endocrine therapy in 10 patients, chemotherapy in 42 patients, anti-HER2 therapy in 14 patients.

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The time to BM in patients with HER-2 positive was shorter than Luminal-A like (20.5 vs. 89.0months，p <0.001). Median overall survival (OS) after BM was significantly associated with Breast-GPA 0-1, 1.5-2, 2.5-3 and 3.5-4 were 4.3, 14.0, 14.8 and18.2 months, respectively (p =0.012, fig A). Univariate analysis found that KPS at the diagnosis of BM, infra-tentorial metastases, total doses and systemic therapy after WBRT were significantly associated with OS after BM (p< 0.05). The multivariate analysis showed infra-tentorial metastases, total doses and systemic therapy after WBRT were independent prognostic factors for OS after BM(p <0.05). The median OS was significantly improved in HER-2 + patients receiving anti-HER2 therapy after WBRT (25.4 vs. 5.6 months, p = 0.040). Also, the median OS was significantly improved in GPA 1.0-2.0 patients who received upfront WBRT (14 vs. 7.9 months, p = 0.012). The proportion of occurrence of intracranial progress for hormone receptor (HR) negative patients was higher than HR positive (51.4 % vs. 27.5 %, p = 0.018). Conclusion The breast cancer molecular subtype is an important prognostic factor in BCBM. The patients with infratentorial metastases, radiation dose of less than 40Gy or no systemic treatment after WBRT are associated with worse OS. Patients with HR negative disease were more likely to develop intracranial progress. Those with less favorable prognosis according to Breast-GPA may benefit from the upfront WBRT. EP-1127 Dose to hippocampus in brain metastases radiosurgery: need for an hippocampal sparing approach S. Scoccianti1, D. Greto1, S. Calusi2, L. Poggesi1, C. Arilli2, M. Casati2, A. Compagnucci2, C. Becherini1, G.A. Carta1, I. Desideri1, M. Baki1, L. Visani1, G. Simontacchi1, P. Bonomo1, L. Bordi3, P. Bono3, S. Pallotta2, L. Livi1 1 Azienda Ospedaliera Universitaria Careggi, Radiotherapy Unit, Florence, Italy 2 Azienda Ospedaliera Universitaria Careggi, Medical Physics Unit, Florence, Italy 3 Azienda Ospedaliera Universitaria Careggi, Neurosurgery Unit, Florence, Italy Purpose or Objective In recent years, on the basis of experimental and clinical evidence, some authors have suggested that neural stem cells in the gyrus dentatus of the hippocampus may be implicated as the main site of treatment-related cognitive deficits. Learning and memory impairment may be proportional to the volume of irradiated tissue in this location. Gondi et al (IJROBP 2013) suggested using very low dose constraints for the bilateral hippocampi volume (BHp) when patients are treated in conventional fractionation [dose to 40% of the BHp volume (DBHp40%)<7.3 Gy]. To date, dose constraints for hippocampus to be used in a single session are unknown. As far as they will be established, minimizing the dose is the only choice we can make. The aim of this study was to evaluate the dose received by hippocampus during Gammaknife Radiosurgery (GKRS) treatment for multiple brain metastases (BM) and to evaluate whether an Hippocampal Sparing approach could be useful. Material and Methods From 2013 to July 2015, 148 patients with BM were treated using GKRS. 20 plans of patients with ≥ 5 brain metastases were selected. In the 'real” plans for these patients, no attempt was made to spare the hippocampus. The plans were reviewed and, after contouring of BHp according to RTOG atlas, dose volume histograms for BHp were generated. Data regarding maximum, mean and DBHp40% were collected. Brain volume receiving 12 Gy (V12brain) was registered. All plans were replanned

('theoretical plans”) in order to minimize dose to BHp while maintaining equal target coverage. Results Median BHp was 3,95 cc. V12brain was <10cc in all plans. Distance from the hippocampus of each single lesion was the most important factor related to BHp dose. When this distance is >2 cm DBHp40% is negligible (<1.5 Gy). The size of lesions also affected the dose to BHp. Number of lesions do not have an impact on the BHp dose. Dosimetric parameters both for 'real” and 'theoretical” plans are listed in table 1. We observed a significant reduction of dose to BHp in optimized plans (i.e. 33% reduction in average DBHp40%). Real Plan (Gy) Theoretical Plan (Gy) Max D BHp 5,57 (0,1-24,3) 3,12 (0,1-18,2) Min D BHp

0,6 (0-2,3)

Mean D BHp 1,5 (0-5) DBHp40%

0,41 (0-1,3) 0,99 (0-3,4)

1,53 (0,03-5,1) 1,02 (0,03-3,7)

Conclusion Dose to BHp may be quite high during radiosurgery for brain metastases, especially in patients with lesions within 2 cm from the hippocampus. Since the hippocampus has been shown to be very radiosensitive also during a conventionally fractionated treatment, it is reasonable avoiding high single dose to this structure during a radiosurgical treatment. Thus, hippocampus needs to be included among the organs at risk during the planning process of radiosurgery, in order to be spared and to further minimize the risk of treatment-related neurocognitive impairment. Currently, in our institution, we are prospectively evaluating the neurocognitive impairment in patients treated with radiosurgery in order to find a relationship between dose and neurocognitive deficits. EP-1128 Stereotactic radiotherapy or whole brain with simultaneous integrated boost in brain metastases? F. Beghella Bartoli1, S. Chiesa1, C. Mazzarella1, S. Luzi1, R. Autorino1, S. Bracci1, F. Miccichè1, G.C. Mattiucci1, C. Masciocchi1, M. Massaccesi1, V. Valentini1, M. Balducci1 1 Policlinico A.Gemelli, Radiation oncology departmentGemelli ART, Roma, Italy Purpose or Objective Brain metastasis (BMs) are frequently observed during oncological history. Treatment options include surgery, whole-brain radiotherapy (WBRT), stereotactic radiotherapy (SRT) or some combination of these. Despite multimodal treatment, prognosis remains severe. In this analysis we compared the SRT with WBRT plus simultaneous integrated boost (WBRT-SIB) in oligometastatic brain patients. Material and Methods From our database we selected oligometastatic patients affected by less than 3 brain metastases, with a primary tumor control, who underwent to SRT or WBRT-SIB. The SRT group received 850 cGy/die for 3 fractions, while the WBRT-SIB group received 300 cGy/die to the whole brain with a simultaneous integrated boost of 500 cGy/die to the BMs for 10 fractions. The two groups were matched for the following potential prognostic factors: age, gender, tumor type, number of brain metastasis and recursive partitioning analysis class (RPA). Local control (LC), overall survival (OS) and toxicity were evaluated. Results From 538 patients submitted consecutively to radiotherapy for brain metastases, 45 patients were eligible for this analysis. The groups were comparable in terms of sex, age, number of metastasis and RPA class. Median age was 63 years (range 38 – 87), 27 male and 18