Total Brain Irradiation for Metastatic Lesions in Breast Cancer Patients

Purpose: Brain metastasis (BM) has a significant negative impact on the survival of breast cancer patients. An intensive search is underway for a multi-modal approach to identify the most effective methods of treating such patients. Material and methods: The study included 40 patients with breast cancer who were diagnosed with BM on magnetic resonance imaging (MRI) of the brain. Total brain irradiation (TBI) up to 30 Gy (3 Gy) was used as the main treatment method. The median age was 48 (31–70) years. In 75 % of cases, a nonluminal subtype of breast cancer was found, in 57.5 % of cases–T2 breast cancer, in 70 % of cases–N0-1. Results: The median survival after TBI was 12 months, 6-month survival rate was 70 %, and 12 – month survival rate was 47.5 %. The risk of death was significantly increased (HR=3.309; 95 % CI: 1,184 – 9,250, p=0.023) in patients whose time interval from the manifestation of 1 relapse to BM was ≤24 months. In these patients, the survival was only 9.5 months and was significantly lower (p=0.0136) than in the patients with the same time interval was >24 months – 30 months. Conclusions: It was found that the effectiveness of total brain irradiation in patients with breast cancer brain metastasis is the highest if the time interval from the moment of manifestation of first relapse to brain metastasis is more than 24 months.

MET-4 Clinical investigation of the cases recurred as dissemination after postoperative local irradiation for metastatic brain tumors

Last year, the authors examined the outcome of the patients with metastatic brain tumor (MBT)treated by whole-brain irradiation (WBRT)or local irradiation (LRT)after surgery. As a result, it was shown that the overall survival (OS) was same but the recurrence pattern was different. Furthermore, it was shown that there were some cases with disseminated recurrence in the LRT group. One year has passed, cases showing disseminated recurrence after LRT were examined. The subjects were 28 patients for whom LRT was selected as post-surgical irradiation since December 2017, with an average age of 66.2 years and a male-female ratio of 19: 9. Non-small cell lung cancer was the most in 17 cases. During the observation period, recurrence was observed in 12 cases, new outbreaks at other sites in 8 cases, disseminated recurrence in 4 cases, and no local recurrence. There was no clear difference in kinds of carcinoma and removal fashion between disseminated recurrence cases and other cases. Disseminated recurrence occurred between 3–10 months after surgery, 2 presented with headache, 1 with convulsions, 1 confirmed during follow-up of images, and all underwent WBRT. The lesions shrank after irradiation, but they were easy to re-grow, and the prognosis was poor. On the other hand, 10 cases died in 24 cases other than disseminated recurrence, but all cases died of primary cancer. Although LRT after surgery is non-inferior to WBRT in terms of OS and has the advantage of maintaining cognitive function, this study shows that there is a considerable risk of disseminated recurrence regardless of the removal fashion or kinds of carcinoma. It was also shown that prognosis after disseminated recurrence was poor. It is desirable to select postoperative irradiation after explaining the recurrence pattern, and when LRT is adopted, it is necessary to consider setting a short observation interval immediately after irradiation.

NCMP-01. NOVEL BIOMARKERS FOR RADIATION-INDUCED NEUROTOXICITY

BACKGROUND Brain radiotherapy is the main therapeutic modality for brain metastases (BM), but carries short and long term toxicities, termed radiation-induced neurotoxicity (RIN), and classified to acute, early-delayed and late-delayed RIN according to its time onset. Although diagnosis of RIN is crucial for patient management, there is an unmet need for sensitive biomarkers for RIN. Here we report on a novel non-invasive biomarker for detection and monitoring RIN. As radiotherapy is known to induce brain cells apoptosis as well as BBB disruption, we hypothesized that circulating cell free DNA fragments derived from dying brain cells will be elevated in the blood of patients with RIN. Using comparative methylome analysis we identified 13 genomic loci showing brain-specific DNA methylation patterns, including markers for neurons, oligodendrocytes, and astrocytes. We searched for these brain-derived cfDNA (bncfDNA) in plasma samples of patients following brain irradiation. METHODS We followed 24 patients treated by brain radiotherapy for BM by clinical and radiological examinations before, during and after treatment. In addition, we serially collected blood samples for DNA analysis, and correlated bncfDNA levels with clinical and radiological assessment. RESULTS Patient`s median age was 60 years. Most common primary tumor sites were breast (25%), lung (20.8%) and melanoma (12.5%). RIN was detected in 10 patients (62%). BncfDNA levels increased up to 292.4 fold in acute RIN, up to 138533.1 in early-delayed RIN, and up to 58.4 fold in late-delayed RIN. Resolution of RIN correlated with decrease in bncfDNA. Changes in bncfDNA levels were independent of tumor response and suggested to reflect both symptomatic and asymptomatic RIN. CONCLUSION Increase in bncfDNA levels characterizes RIN independent of tumor response. Thus, BncfDNA may serve as a novel biomarker for brain cells death incurred by radiotherapy. Further studies are required to explore the clinical utility of bncfDNA as a RIN biomarker.

Chemotherapy strategies for young children newly diagnosed with desmoplastic/extensive nodular medulloblastoma up to the era of molecular profiling – a comparative outcomes analysis of prospective multi-center European and North American trials.

Aims Survival has been poor in several multi-center/national trials since the 1980s, either delaying, avoiding or minimizing brain irradiation in young children with medulloblastoma. The introduction of German regimens supplementing “standard” chemotherapy with both intravenous high-dose (HD-MTX) and intraventricular (IVENT-MTX) methotrexate, and North American regimens incorporating marrow-ablative chemotherapy with autologous hematopoietic cell rescue (HDCx+AuHCR), have reported encouraging outcomes. We performed a comparative outcomes analysis of these differing strategies for young children with desmoplastic/extensive nodular medulloblastoma. Method Data from 12 trials reported between 2005 and 2020 for children <six-years-old with desmoplastic/extensive nodular medulloblastoma were reviewed; event-free (EFS) survival+/-standard errors were compared. Results The German HIT-SKK’92 and HIT-SKK’00 trials incorporating HD-MTX and IVENT-MTX reported 85+/-8% and 95+/-5% 5-10-year EFS respectively; a third trial (ACNS1221) incorporating HIT-SKK therapy but without IVENT-MTX reported only 49+/-10% EFS. Three trials (Head Start I and II combined and CCG-99703) employing induction chemotherapy without HD-MTX, followed by one or three HDCx+AuHCR cycles, reported 3-5-year EFS of 67+/-16% and 79+/-11%. Two trials employing HD-MTX-containing induction chemotherapy (Head Start III and ACNS0334), followed by one or three HDCx+AuHCR cycles, reported 3-5-year EFS of 89+/-6% and 100%, respectively. Finally, four trials utilizing neither IVENT-MTX nor HDCx+AuHCR (UK-CNS-9204, CCG-9921, COG-P9934 and SJYC07) reported 2-5 year EFS of 35+/-11%, 77+/-9%, 58+/-8% and 53+/-9% respectively. Conclusion A trend towards better EFS for young children with desmoplastic/extensive nodular medulloblastoma is observed in trials including eitherHD-MTX and IVENT-MTX or including HD-MTX-containing induction chemotherapy and HDCx+AuHCR. Trials excluding HD-MTX, IVENT-MTX and HDCx+AuHCR have poorer outcomes.

Individual 3D-printed fixation masks for radiotherapy: first clinical experiences

Purpose To show the feasibility of 3D-printed fixation masks for whole brain radiation therapy in a clinical setting and perform a first comparison to an established thermoplastic mask system. Methods Six patients were irradiated with whole brain radiotherapy using individually 3D-printed masks. Daily image guidance and position correction were performed prior to each irradiation fraction. The vectors of the daily position correction were compared to two collectives of patients, who were irradiated using the standard thermoplastic mask system (one cohort with head masks; one cohort with head and neck masks). Results The mean systematic errors in the experimental cohort ranged between 0.59 and 2.10 mm which is in a comparable range to the control groups (0.18 mm–0.68 mm and 0.34 mm–2.96 mm, respectively). The 3D-printed masks seem to be an alternative to the established thermoplastic mask systems. Nevertheless, further investigation will need to be performed. Conclusion The prevailing study showed a reliable and reproducible interfractional positioning accuracy using individually 3D-printed masks for whole brain irradiation in a clinical routine. Further investigations, especially concerning smaller target volumes or other areas of the body, need to be performed before using the system on a larger basis.