PURPOSE:

To quantitatively evaluate dose distribution characteristics achieved with helical tomotherapy (HT) for whole-brain irradiation (WBRT) with integrated boost (IB) to multiple brain metastases in comparison with alternative techniques.

METHODS AND MATERIALS:

Dose distributions for 23 patients with 81 metastases treated with WBRT (30 Gy/10 fractions) and IB (50 Gy) were analyzed. The median number of metastases per patient (Nmets) was 3 (range, 2-8). Mean values of the composite planning target volume of all metastases per patient (PTVmets) and of the individual metastasis planning target volume (PTVind met) were 8.7 ± 8.9 cm(3) (range, 1.3-35.5 cm(3)) and 2.5 ± 4.5 cm(3) (range, 0.19-24.7 cm(3)), respectively. Dose distributions in PTVmets and PTVind met were evaluated with respect to dose conformity (conformation number [CN], RTOG conformity index [PITV]), target coverage (TC), and homogeneity (homogeneity index [HI], ratio of maximum dose to prescription dose [MDPD]). The dependence of dose conformity on target size and Nmets was investigated. The dose distribution characteristics were benchmarked against alternative irradiation techniques identified in a systematic literature review.

RESULTS:

Mean ± standard deviation of dose distribution characteristics derived for PTVmets amounted to CN = 0.790 ± 0.101, PITV = 1.161 ± 0.154, TC = 0.95 ± 0.01, HI = 0.142 ± 0.022, and MDPD = 1.147 ± 0.029, respectively, demonstrating high dose conformity with acceptable homogeneity. Corresponding numbers for PTVind met were CN = 0.708 ± 0.128, PITV = 1.174 ± 0.237, TC = 0.90 ± 0.10, HI = 0.140 ± 0.027, and MDPD = 1.129 ± 0.030, respectively. The target size had a statistically significant influence on dose conformity to PTVmets (CN = 0.737 for PTVmets ≤4.32 cm(3) vs CN = 0.848 for PTVmets >4.32 cm(3), P=.006), in contrast to Nmets. The achieved dose conformity to PTVmets, assessed by both CN and PITV, was in all investigated volume strata well within the best quartile of the values reported for alternative irradiation techniques.

CONCLUSIONS:

HT is a well-suited technique to deliver WBRT with IB to multiple brain metastases, yielding high-quality dose distributions. A multi-institutional prospective randomized phase 2 clinical trial to exploit efficacy and safety of the treatment concept is currently under way.

Background:

Ten to 30% of early breast cancer (EBC) patients develop brain metastasis (BM) during their follow-up. In this study, we aimed to evaluate importance of the lymph node ratio (LNR) in development of BM in EBC cases. Materials and

Methods:

Ninety patients whom had axillary metastases in lymph nodes at their initial diagnosis and developed BM during 5-year follow-up were detected in 950 EBC patients. LNR values were calculated for all patients and after categorization into 4 molecular sub-types as luminal A, luminal B HER-2 (+), HER-2 overexpressing and basal- like. Comparison was with control group patients who had similar characteristics.

Results:

In the comparison of all molecular sub-types of LNR, 54.9% and 28.4% values were found in patients with and without BM respectively (p<0.001). In the comparison of the LNR with control groups, a statistically significant differences were found with luminal A with BM (p=0.001), luminal B HER-2 (p=0.001), HER-2 overexpressing (p=0.027) and basal-like groups (p<0.001). In the evaluation of patients with BM, the highest ratio was found in the basal-like group (67.9%) and there was a statistically significant difference between this group and the others (p=0.048).

Conclusions:

EBC patients developing BM within 5 years follow- up had significantly higher LNRs for all molecular sub-types, especially in the basal-like group. Larger scale studies are now needed for evaluating LNR prognostic importance for EBC regarding BM development.

Since the inception of radiosurgery, the management of brain metastases has become a common problem for neurosurgeons. Although the use of stereotactic radiosurgery and/or whole brain radiation therapy serves to control the majority of disease burden, patients who survive longer than 6-8 months sometimes face the problem of symptomatic radiographically regrowing lesions with few treatment options. Here we investigate the feasibility of use of MRI-guided stereotactic laser induced thermotherapy (LITT) as a novel treatment option for these lesions. Six patients who had previously undergone gamma knife stereotactic radiosurgery for brain metastases were selected. All patients had an initial favorable response to radiosurgery but subsequently developed regrowth of at least one lesion associated with recurrent edema and progressive neurological symptoms requiring ongoing steroids for symptom control. All lesions were evaluated for craniotomy, but were deemed unresectable due to deep location or patient's comorbidities. Stereotactic biopsies were performed prior to the thermotherapy procedure in all cases. LITT was performed using the Visualase system and follow-up MRI imaging was used to determine treatment response. In all six patients biopsy results were negative for tumor and consistent with adverse radiation effects also known as radiation necrosis. Patients tolerated the procedure well and were discharged from the hospital within 48 h of the procedure. In 4/6 cases there was durable improvement of neurological symptoms until death. In all cases steroids were weaned off within 2 months. One patient died from systemic causes related to his cancer a month after the procedure. One patient had regrowth of the lesion 3 months after the procedure and required re-initiation of steroids and standard craniotomy for surgical resection. There were no complications directly related to the thermocoagulation procedure. Stereotactic laser induced thermotherapy is a feasible alternative for the treatment of symptomatic regrowing metastatic lesions after radiosurgery. The procedure carries minimal morbidity and, in this small series, shows some effectiveness in the symptomatic relief of edema and neurological symptoms paralleled by radiographic lesional control. Further studies are necessary to elucidate the safety of this technology.

PURPOSE:

recent developments of second generation Hsp90 inhibitors suggested a potential for development of this class of molecules also in tumors that have become resistant to molecular targeted agents. Disease progression is often due to brain metastases, sometimes related to insufficient drug concentrations within the brain. Our objective was to identify and characterize a novel inhibitor of Hsp90 able to cross the blood-brain barrier (BBB). EXPERIMENTAL

DESIGN:

here is described a detailed biochemical and crystallographic characterization of NMS-E973. Mechanism based anticancer activity was described in cell models, including models of resistance to kinase inhibitors. Pharmacokinetics properties were followed in plasma, tumor, liver and brain. In vivo activity and pharmacodynamics, as well as the PK/PD relationships, were evaluated in xenografts, including an intracranially implanted melanoma model.

RESULTS:

NMS-E973, representative of a novel isoxazole-derived class of Hsp90 inhibitors, binds Hsp90α with subnanomolar affinity and high selectivity towards kinases, as well as other ATPases. It possesses potent antiproliferative activity against tumor cell lines and a favorable pharmacokinetic profile, with selective retention in tumor tissue and ability to cross the blood brain barrier. NMS-E973 induces tumor shrinkage in different human tumor xenografts, and is highly active in models of resistance to kinase inhibitors. Moreover, consistent with its brain penetration, NMS-E973 is active also in an intracranially implanted melanoma model.

CONCLUSIONS:

overall, the efficacy profile of NMS-E973 suggests a potential for development in different clinical settings, including tumors that have become resistant to molecular targeted agents, particularly in cases of tumors which reside beyond the BBB.

OBJECTIVE:

While staging patients with malignant melanoma, cerebral susceptibility artefacts on T2*-weighted/susceptibility-weighted imaging (SWI) sequences without a correlate on contrast-enhanced T1-weighted images can be confusing. Without intravenous contrast enhancement, cavernomas, microhaemorrhages and melanin-containing metastases represent possible differential diagnoses for these findings. The purpose of this study was to find out, how often such lesions correspond to metastases.

METHODS:

Brain MR images (1.5 T) of 408 patients with malignant melanoma but without cerebral metastases in the initial staging by MRI were reviewed retrospectively. Eighteen patients (5 female, 13 male) with malignant melanoma and signal intensity loss on T2*/SWI were included in our study. The average observation period was 19.6 months (6-46 months, 2006-2009).

RESULTS:

In each of these 18 patients between one and seven hypointense lesions on T2*/SWI were found. None of these lesions developed into metastasis.

CONCLUSION:

Focal areas of susceptibility artefacts in the brain parenchyma without corresponding abnormalities in contrast-enhanced T1 weighted images are unlikely to represent brain metastases. KEY POINTS : • In melanoma patients early diagnosis of metastatic brain lesions is mandatory. • Melanin content and haemorrhage are potential reasons for MRI characteristics of melanoma metastases. • Susceptibility-weighted MRI visualises melanin and blood products. • Isolated cerebral susceptibility artefacts do not convert into melanoma metastases. • SWI/T2* sequences cannot replace Gd-enhanced sequences.

Introduction: Primary and metastatic brain tumors remain a major challenge. The most common primary adult malignant brain tumor, glioblastoma (GBM), confers a dismal prognosis as does the development of CNS metastases for most systemic malignancies. Anti-angiogenic therapy has been a major clinical research focus in neuro-oncology over the past 5 years. Areas covered: Culmination of this work includes US FDA accelerated approval of bevacizumab for recurrent GBM and the completion of two placebo-controlled Phase III studies of bevacizumab for newly diagnosed GBM. A multitude of anti-angiogenics are in evaluation for neuro-oncology patients but none has thus far surpassed the therapeutic benefit of bevacizumab. Expert opinion: These agents demonstrate adequate safety and the majority of GBM patients derive benefit. Furthermore, their anti-permeability effect can substantially decrease tumor-associated edema leading to stable or improved neurologic function and quality of life. In particular, anti-angiogenics significantly prolong progression-free survival - a noteworthy achievement in the context of infiltrative and destructive brain tumors like GBM; however, in a manner analogous to other cancers, their impact on overall survival for GBM patients is modest at best. Despite substantial clinical research efforts, many fundamental questions regarding anti-angiogenic agents in brain tumor patients remain unanswered.

The aims of the present study were to investigate how breast cancer (BC) subtypes and treatment affect time to brain metastasis (TTBM). We retrospectively investigated 189 consecutive patients who were diagnosed with brain metastasis (BM) from BC between 2000 and 2009 at Samsung Medical Center. We analyzed TTBM from initial diagnosis of metastatic BC according to subtypes and trastzumab (T) administration before BM diagnosis. The median age of 189 BM patients from BC was 48 years. We divided TTBM into four groups considering BC subtypes and treatment; HR-positive/HER2-negative (n=45), HER2-positive with T before BM development (n=47), HER2-positive without T before BM development (n=39), and TNBC (n=58). The median TTBMs for each group were 17.5 months, 13.7 months, 5.8 months, and 2.9 months, respectively (p<0.001). HER2-positive without T (HR 1.892, p=0.008) and TNBC (HR 1.652, p=0.023) were independently associated with shorter TTBM. In multivariate analysis, HER2-positive without T (hazard ratio 1.725, p=0.002) and TNBC (hazard ratio 1.579, p=0.022) were independent risk factors for worse metastatic OS compared with HR-positive/HER2-negative subtype. TTBMs were shorter in patients with HER2-positive without T and TNBC among BC subtypes. Prospective clinical study for high risk patients for early BM is warranted.

AIMS:

Prostate cancer is very common and is the second most common cause of cancer death in males in Australia; however, brain metastases are exceedingly rare.

MATERIALS AND METHODS:

We review four cases of biopsy-proven brain metastases from prostate cancer and review the relevant literature.

RESULTS:

Three of four patients had acinar adenocarcinoma of prostate with one patient having ductal adenocarcinoma variant on histopathology. Three patients had the brain as the only site of metastatic disease. All patients underwent surgery, and three of four patients underwent adjuvant palliative radiotherapy to the brain.

CONCLUSION:

Brain metastases from prostate cancer are rare, but brain metastases without other sites of metastatic disease are exceedingly rare and may be more common with ductal adenocarcinoma variant.

Brain white matter T2 hyperintensities (WMH) are a frequent MRI finding in adults, both in asymptomatic and in cancer patients. The aim of our study is to determine the relationship between quantitative measures of the volume of WMH and the volume of brain metastatic lesions at the first MRI diagnosis of brain metastases in a population of advanced cancer patients. Brain MRI examinations of 162 consecutive patients were included and 984 brain metastases at first diagnosis were studied. Axial FLAIR images were used to visualize peri-lesional edema and to segment WMH; multiplanar contrast-enhanced T1-weighted TSE images were used to detect, count, segment and measure metastatic lesions. Segmentation of WMH on FLAIR images was performed after linear image registration to eliminate peri-lesional edema from the WMH masks. The distribution of the volumes of metastatic lesions was significantly different (ANOVA, p = 0.003) among all patients and among lung cancer patients (ANOVA, p = 0.003), with higher volumes of metastatic lesions in a higher proportion of patients when WMH were absent. There were no significant differences among groups at the 10 cc threshold of WMH. We found that volumes of brain metastases at the first MR diagnosis in a sample of advanced cancer patients and in the group of lung cancer patients were significantly lower if WMH were present; we suggest that WMH may represent a clinical MRI bio-marker of brain micro-environment resistance to the occurrence of brain metastases.

Brain metastasis is a frequent occurrence in patients with cancer, with devastating consequences. The current animal models for brain metastasis are highly variable, leading to a need for improved in vivo models that recapitulate the clinical disease. Herein, we describe an experimental brain metastasis model that uses ultrasound guidance to perform intracardiac injections. This method is easy to perform, giving consistent and quantitative results. Demonstrating the utility of this method, we have assessed a variety of metastatic cell lines for their ability to develop into brain metastases. Those cell lines that were competent at brain colonization could be detected in the brain vasculature 4 hours after intracardiac injection, and a few adherent cells persisted until colonization occurred. In contrast, those cell lines that were deficient in brain colonization were infrequently found 4 hours after introduction into the arterial circulation and were not detected at later time points. All of these cells were capable of brain colonization after intraparenchymal injection. We propose that adherence to the brain vasculature may be the key limiting step that determines the ability of a cancer cell to form brain metastases successfully. Identifying brain endothelium-specific adhesion molecules may enable development of screening modalities to detect brain-colonizing cancer cells and therapies to prevent these metastatic cells from seeding the brain.