External Validation of the Graded Prognostic Assessment in Patients with Brain Metastases from Small Cell Lung Cancer

Background: Recently, graded prognostic assessment (GPA) for small cell lung cancer (SCLC) patients with brain metastases has been developed. This includes age, performance status, number of brain metastases and presence of extracranial metastases. The aim of the present study was to validate this four-tiered prognostic score in a European cohort of patients. Methods: The retrospective validation study included 180 patients from two centers in Germany and Norway. Results: Median survival from radiological diagnosis of brain metastases was 7 months. The GPA point sum as continuous variable (0–4 points) was significantly associated with survival (p < 0.001). However, no significant survival difference was observed between patients in the two strata with better survival (3.5–4 and 2.5–3 points, respectively). Long-term survival in the poor prognosis group (0–1 points) was better than expected. Conclusion: This study supports the prognostic impact of all four parameters contributing to the GPA. The original way of grouping the parameters and breaking the final strata did not give optimal results in this cohort. Therefore, additional validation databases from different countries should be created and evaluated

Hippocampus-Avoidance Whole-Brain Radiation Therapy Is Efficient in the Long-Term Preservation of Hippocampal Volume

Background and Purpose: With improved life expectancy, preventing neurocognitive decline after cerebral radiotherapy is gaining more importance. Hippocampal damage has been considered the main culprit for cognitive deficits following conventional whole-brain radiation therapy (WBRT). Here, we aimed to determine to which extent hippocampus-avoidance WBRT (HA-WBRT) can prevent hippocampal atrophy compared to conventional WBRT. Methods and Materials: Thirty-five HA-WBRT and 48 WBRT patients were retrospectively selected, comprising a total of 544 contrast-enhanced T1-weighted magnetic resonance imaging studies, longitudinally acquired within 24 months before and 48 months after radiotherapy. HA-WBRT patients were treated analogously to the ongoing HIPPORAD-trial (DRKS00004598) protocol with 30 Gy in 12 fractions and dose to 98% of the hippocampus ≤ 9 Gy and to 2% ≤ 17 Gy. WBRT was mainly performed with 35 Gy in 14 fractions or 30 Gy in 10 fractions. Anatomical images were segmented and the hippocampal volume was quantified using the Computational Anatomy Toolbox (CAT), including neuroradiological expert review of the segmentations. Results: After statistically controlling for confounding variables such as age, gender, and total intracranial volume, hippocampal atrophy was found after both WBRT and HA-WBRT (p Conclusion: HA-WBRT is a therapeutic option for patients with multiple brain metastases, which can effectively and durably minimize hippocampal atrophy compared to conventional WBRT

Comparison of intraoperative radiotherapy as a boost vs. simultaneously integrated boosts after breast-conserving therapy for breast cancer

BackgroundCurrently, there are no data from randomized trials on the use of intraoperative radiotherapy (IORT) as a tumor bed boost in women at high risk of local recurrence. The aim of this retrospective analysis was to compare the toxicity and oncological outcome of IORT or simultaneous integrated boost (SIB) with conventional external beam radiotherapy (WBI) after breast conserving surgery (BCS).MethodsBetween 2009 and 2019, patients were treated with a single dose of 20 Gy IORT with 50 kV photons, followed by WBI 50 Gy in 25 or 40.05 in 15 fractions or WBI 50 Gy with SIB up to 58.80–61.60 Gy in 25–28 fractions. Toxicity was compared after propensity score matching. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan–Meier method.ResultsA 1:1 propensity-score matching resulted in an IORT + WBI and SIB + WBI cohort of 60 patients, respectively. The median follow-up for IORT + WBI was 43.5 vs. 32 months in the SIB + WBI cohort. Most women had a pT1c tumor: IORT group 33 (55%) vs. 31 (51.7%) SIB group (p = 0.972). The luminal-B immunophenotype was most frequently diagnosed in the IORT group 43 (71.6%) vs. 35 (58.3%) in the SIB group (p = 0.283). The most reported acute adverse event in both groups was radiodermatitis. In the IORT cohort, radiodermatitis was grade 1: 23 (38.3%), grade 2: 26 (43.3%), and grade 3: 6 (10%) vs. SIB cohort grade 1: 3 (5.1%), grade 2: 21 (35%), and grade 3: 7 (11.6%) without a meaningful difference (p = 0.309). Fatigue occurred more frequently in the IORT group (grade 1: 21.7% vs. 6.7%; p = 0.041). In addition, intramammary lymphedema grade 1 occurred significantly more often in the IORT group (11.7% vs. 1.7%; p = 0.026). Both groups showed comparable late toxicity. The 3- and 5-year local control (LC) rates were each 98% in the SIB group vs. 98% and 93% in the IORT group (LS: log rank p = 0.717).ConclusionTumor bed boost using IORT and SIB techniques after BCS shows excellent local control and comparable late toxicity, while IORT application exhibits a moderate increase in acute toxicity. These data should be validated by the expected publication of the prospective randomized TARGIT-B study

External Validation of the Graded Prognostic Assessment in Patients with Brain Metastases from Small Cell Lung Cancer

Background: Recently, graded prognostic assessment (GPA) for small cell lung cancer (SCLC) patients with brain metastases has been developed. This includes age, performance status, number of brain metastases and presence of extracranial metastases. The aim of the present study was to validate this four-tiered prognostic score in a European cohort of patients. Methods: The retrospective validation study included 180 patients from two centers in Germany and Norway. Results: Median survival from radiological diagnosis of brain metastases was 7 months. The GPA point sum as continuous variable (0&ndash;4 points) was significantly associated with survival (p &lt; 0.001). However, no significant survival difference was observed between patients in the two strata with better survival (3.5&ndash;4 and 2.5&ndash;3 points, respectively). Long-term survival in the poor prognosis group (0&ndash;1 points) was better than expected. Conclusion: This study supports the prognostic impact of all four parameters contributing to the GPA. The original way of grouping the parameters and breaking the final strata did not give optimal results in this cohort. Therefore, additional validation databases from different countries should be created and evaluated

PRO: Do We Still Need Whole-Brain Irradiation for Brain Metastases?

(1) Background: In recent decades, the use of whole-brain radiation therapy (WBRT) in the treatment of brain metastases has significantly decreased, with clinicians fearing adverse neurocognitive events and data showing limited efficacy regarding local tumor control and overall survival. The present study thus aimed to reassess the role that WBRT holds in the treatment of brain metastases. (2) Methods: This review summarizes the available evidence from 1990 until today supporting the use of WBRT, as well as new developments in WBRT and their clinical implications. (3) Results: While one to four brain metastases should be exclusively treated with radiosurgery, WBRT does remain an option for patients with multiple metastases. In particular, hippocampus-avoidance WBRT, WBRT with dose escalation to the metastases, and their combination have shown promising results and offer valid alternatives to local stereotactic radiotherapy. Ongoing and published prospective trials on the efficacy and toxicity of these new methods are presented. (4) Conclusions: Unlike conventional WBRT, which has limited indications, modern WBRT techniques continue to have a significant role to play in the treatment of multiple brain metastases. In which situations radiosurgery or WBRT should be the first option should be investigated in further studies. Until then, the therapeutic decision must be made individually depending on the oncological context

Long-term survival results after treatment for oligometastatic brain disease

AimThe aim of this study was to characterize the survival results of patients with up to four brain metastases after intense local therapy (primary surgery or stereotactic radiotherapy) if extracranial metastases were absent or limited to one site, e.g. the lungs.BackgroundOligometastatic disease has repeatedly been reported to convey a favorable prognosis.Material and methodsThis retrospective study included 198 German and Norwegian patients treated with individualized approaches, always including brain radiotherapy. Information about age, extracranial spread, number of brain metastases, performance status and other variables was collected. Uni- and multivariate tests were performed.ResultsMedian survival was 16.5 months (single brain metastasis) and 9.8 months (2–4, comparable survival for 2, 3 and 4), respectively (p = 0.001). After 5 years, 15 and 2% of the patients were still alive. In patients alive after 2 years, added median survival was 23 months and the probability of being alive 5 years after treatment was 26%. In multivariate analysis, extracranial metastases were not significantly associated with survival, while primary tumor control was.ConclusionLong-term survival beyond 5 years is possible in a minority of patients with oligometastatic brain disease, in particular those with a single brain metastasis. The presence of extracranial metastases to one site should not be regarded a barrier towards maximum brain-directed therapy

Validation of the graded prognostic assessment for gastrointestinal cancers with brain metastases (GI-GPA)

Purpose - The purpose of this study was to validate a new prognostic model (GI-GPA) originally derived from a multi-center database (USA, Canada, Japan). Patients and Methods - This retrospective study included 92 German and Norwegian patients treated with individualized approaches, always including brain radiotherapy. Information about age, extracranial spread, number of brain metastases, performance status and other variables was collected. The GI-GPA score was calculated as described by Sperduto et al. Results - Median survival was 4 months. The corresponding figures for the 4 different prognostic strata were 2.3, 4.4, 9.4 and 12.7 months, respectively (p = 0.0001). Patients whose management included surgical resection had longer median survival than those who were treated with other approaches (median 11.9 versus 3.0 months, p = 0.002). Comparable results were seen for additional systemic therapy (median 8.5 versus 3.5 months, p = 0.01). Conclusion - These results confirm the validity of the GI-GPA in an independent dataset from a different geographical region, despite the fact that overall survival was shorter in all prognostic strata, compared to Sperduto et al. Potential explanations include differences in molecular tumor characteristics and treatment selection, both brain metastases-directed and extracranially. Long-term survival beyond 5 years is possible in a small minority of patients

Long-term survival results after treatment for oligometastatic brain disease

Aim - The aim of this study was to characterize the survival results of patients with up to four brain metastases after intense local therapy (primary surgery or stereotactic radiotherapy) if extracranial metastases were absent or limited to one site, e.g. the lungs. Background - Oligometastatic disease has repeatedly been reported to convey a favorable prognosis. Material and methods - This retrospective study included 198 German and Norwegian patients treated with individualized approaches, always including brain radiotherapy. Information about age, extracranial spread, number of brain metastases, performance status and other variables was collected. Uni- and multivariate tests were performed. Results - Median survival was 16.5 months (single brain metastasis) and 9.8 months (2–4, comparable survival for 2, 3 and 4), respectively (p = 0.001). After 5 years, 15 and 2% of the patients were still alive. In patients alive after 2 years, added median survival was 23 months and the probability of being alive 5 years after treatment was 26%. In multivariate analysis, extracranial metastases were not significantly associated with survival, while primary tumor control was. Conclusion - Long-term survival beyond 5 years is possible in a minority of patients with oligometastatic brain disease, in particular those with a single brain metastasis. The presence of extracranial metastases to one site should not be regarded a barrier towards maximum brain-directed therapy

Approaches to improve metabolic stability of a statine-based GRP receptor antagonist.

The bombesin receptor family, in particular the gastrin-releasing peptide receptor (GRPr), is an attractive target in the field of nuclear oncology due to the high density of these receptors on the cell surface of several human tumors. The successful clinical implementation of (64)Cu-CB-TE2A-AR06, (68)Ga-RM2 and (68)Ga-NODAGA-MJ9, prompted us to continue the development of GRPr-antagonists. The aim of the present study was to assess if N-terminal modulations of the statine-based GRPr-antagonist influence the binding affinity, the pharmacokinetic performance and the in vivo metabolic stability. METHODS The GRPr-antagonist (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) was functionalized with the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) via the spacer 4-amino-1-carboxymethyl-piperidine (Pip) and the amino acid N-Methyl-β-Ala, to obtain NMe-RM2 and labeled with (68)Ga and (177)Lu. The GRPr affinity of the corresponding metalloconjugates determined using [(125)I-Tyr(4)]-BN as radioligand. In vitro evaluation included internalization studies using PC3 cells. The (68)Ga-conjugate was evaluated in PC3 xenografts by biodistribution and PET studies, while investigations on the metabolic stability and plasma protein binding were performed. RESULTS The half maximum inhibitory concentrations (IC50) of the metalloconjugates, using [(125)I-Tyr(4)]-BN, are in the low nanomolar range. PC3-cell culture binding studies of both metallated NMe-RM2 and RM2 show high GRPr-bound activity and low internalization. Metabolic studies showed that (68)Ga-NMe-RM2 and (68)Ga-RM2 are being cleaved in a similar fashion into three metabolites, with a good proportion of about 50% of the remaining blood activity at 15min post injection (p.i.) being represented by the intact radiotracer. (68)Ga-NMe-RM2 was shown to target specifically PC3 xenografts, with high and sustained tumor uptake of about 13% IA/g within a time frame of 3h. The PET images clearly visualized the tumor. CONCLUSIONS The relatively high percentage of the remaining intact radiotracer in blood 15min post injection sufficiently enables in vivo targeting of GRPr positive tumors, finding which has been also shown in clinical trials

Accelerated hyper-versus normofractionated radiochemotherapy with temozolomide in patients with glioblastoma: a multicenter retrospective analysis

Background and Purpose The standard treatment of glioblastoma patients consists of surgery followed by normofractionated radiotherapy (NFRT) with concomitant and adjuvant temozolomide chemotherapy. Whether accelerated hyperfractionated radiotherapy (HFRT) yields comparable results to NFRT in combination with temozolomide has only sparsely been investigated. The objective of this study was to compare NFRT with HFRT in a multicenter analysis. Materials and Methods A total of 484 glioblastoma patients from four centers were retrospectively pooled and analyzed. Three-hundred-ten and 174 patients had been treated with NFRT (30 × 1.8 Gy or 30 × 2 Gy) and HFRT (37 × 1.6 Gy or 30 × 1.8 Gy twice/day), respectively. The primary outcome of interest was overall survival (OS) which was correlated with patient-, tumor- and treatment-related variables via univariable and multivariable Cox frailty models. For multivariable modeling, missing covariates were imputed using multiple imputation by chained equations, and a sensitivity analysis was performed on the complete-cases-only dataset. Results After a median follow-up of 15.7 months (range 0.8-88.6 months), median OS was 16.9 months (15.0-18.7 months) in the NFRT group and 14.9 months (13.2-17.3 months) in the HFRT group (p = 0.26). In multivariable frailty regression, better performance status, gross-total versus not gross-total resection, MGMT hypermethylation, IDH mutation, smaller planning target volume and salvage therapy were significantly associated with longer OS (all p < 0.01). Treatment differences (HFRT versus NFRT) had no significant effect on OS in either univariable or multivariable analysis. Conclusions Since HFRT with temozolomide was not associated with worse OS, we assume HFRT to be a potential option for patients wishing to shorten their treatment time