Development and evaluation of an automated EPTN-consensus based organ at risk atlas in the brain on MRI.

BACKGROUND AND PURPOSE: During radiotherapy treatment planning, avoidance of organs at risk (OARs) is important. An international consensus-based delineation guideline was recently published with 34 OARs in the brain. We developed an MR-based OAR autosegmentation atlas and evaluated its performance compared to manual delineation. MATERIALS AND METHODS: Anonymized cerebral T1-weighted MR scans (voxel size 0.9 × 0.9 × 0.9 mm3) were available. OARs were manually delineated according to international consensus. Fifty MR scans were used to develop the autosegmentation atlas in a commercially available treatment planning system (Raystation®). The performance of this atlas was tested on another 40 MR scans by automatically delineating 34 OARs, as defined by the 2018 EPTN consensus. Spatial overlap between manual and automated delineations was determined by calculating the Dice similarity coefficient (DSC). Two radiation oncologists determined the quality of each automatically delineated OAR. The time needed to delineate all OARs manually or to adjust automatically delineated OARs was determined. RESULTS: DSC was ≥ 0.75 in 31 (91 %) out of 34 automated OAR delineations. Delineations were rated by radiation oncologists as excellent or good in 29 (85 %) out 34 OAR delineations, while 4 were rated fair (12 %) and 1 was rated poor (3 %). Interobserver agreement between the radiation oncologists ranged from 77-100 % per OAR. The time to manually delineate all OARs was 88.5 minutes, while the time needed to adjust automatically delineated OARs was 15.8 minutes. CONCLUSION: Autosegmentation of OARs enables high-quality contouring within a limited time. Accurate OAR delineation helps to define OAR constraints to mitigate serious complications and helps with the development of NTCP models.

Quality of life among patients with 4 to 10 brain metastases after treatment with whole-brain radiotherapy vs. stereotactic radiotherapy: a phase III, randomized, Dutch multicenter trial.

BACKGROUND: Stereotactic radiotherapy (SRT) is an attractive treatment option for patients with brain metastases (BM), sparing healthy brain tissue and likely controlling local tumors. Most previous studies have focused on radiological response or survival. Our randomized trial (NCT02353000) investigated whether quality of life (QoL) is better preserved using SRT than whole-brain radiotherapy (WBRT) for patients with multiple BM. Recently, we published our trial's primary endpoints. The current report discusses the study's secondary endpoints. METHODS: Patients with 4 to 10 BM were randomly assigned to a standard-arm WBRT (20 Gy in 5 fractions) or SRT group (1 fraction of 15-24 Gy or 3 fractions of 8 Gy). QoL endpoints-such as EQ5D domains post-treatment, the Barthel index, the European Organisation for Research and Treatment of Cancer (EORTC) questionnaires, and the neurocognitive Hopkins Verbal Learning Test-were evaluated. RESULTS: Due to poor accrual resulting from patients' and referrers' preference for SRT, this study closed prematurely. The other endpoints' results were published recently. Twenty patients were available for analysis (n=10 vs. n=10 for the two groups, respectively). Significant differences were observed 3 months post-treatment for the mobility (P=0.041), self-care (P=0.028), and alopecia (P=0.014) EQ5D domains, favoring SRT. This self-care score also persisted compared to the baseline (P=0.025). Multiple EORTC categories reflected significant differences, favoring SRT-particularly physical functioning and social functioning. CONCLUSIONS: For patients with multiple BM, SRT alone led to persistently higher QoL than treatment with WBRT. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02353000.

Atypical meningioma: patterns of postradiotherapy recurrences.

PURPOSE: There is no consensus on a target definition and optimal dose in radiotherapy for atypical meningioma (AM). Insight into the postradiotherapy recurrence pattern is needed for optimal target definition and local control. The objective was to describe the patterns of recurrence after postoperative or salvage radiotherapy in patients with AM. MATERIALS AND METHODS: A retrospective analysis was conducted of patients treated for intracranial AM with (fractionated) stereotactic radiotherapy (FSRT). The relationships between postradiotherapy recurrences, the dura and irradiated volume were established. Moreover, the dose prescriptions and fractionation schedules were converted to a reference to determine the relationship between dose and local control. RESULTS: The included patients received 57 (F)SRT treatments and 73 surgeries. Recurrent disease was found in 21 of 29 patients (72%) and after 39 of 57 (F)SRTs (68%). The median interval to first recurrence was 39.7 months. Of these recurrences, 25 were in-field, 11 were marginal, and 3 were out of field. In-field recurrence rates after biological equivalent doses < 60 Gy or ≥ 60 Gy were 50% and 21%. All recurrences were connected to the dura. Of the marginal recurrences, 64% were within 2 cm and 91% were within 3 cm of the volume receiving the prescribed dose. CONCLUSIONS: AM frequently recurs after radiotherapy. All postradiotherapy recurrences were connected to the dura. Most marginal recurrences occurred within 3 cm of the irradiated abnormal dura. The lowest rate of in-field recurrences occurred after equivalent doses of least 60 Gy in 2 Gy fractions suggesting a dose-effect relationship.

Impact of PTV margin reduction (2 mm to 0 mm) on pseudoprogression in stereotactic radiotherapy of solitary brain metastases.

PURPOSE: To determine the influence of PTV-margin (0 mm versus 2 mm) on the incidence of pseudoprogression (PP) and local tumour control (LC) in patients treated with stereotactic radiotherapy (SRT) for solitary brain metastases. METHODS: Patients were treated on Novalis LINAC. Three dose schedules were used depending on the PTV-size. The PTV-margin was 2-mm prior to 2015 and 0-mm thereafter. MRI-scans were made every three months including a perfusion MRI-scan when pseudoprogression was suspected. We examined the relation of pseudoprogression and local control with the size of PTV-margin. Besides this, the association of dose-volume data of the whole brain (minus GTV) and pseudoprogression was investigated. RESULTS: 121 patients were analyzed (2-mm margin in 84 patients; 0-mm margin in 37 patients). There was no difference in GTV (7.6 cc versus 9.1 cc p = 0.2). At 24 months there was no difference in incidence of pseudoprogression (49% and versus 33%, p = 0.5) and local control in the 2-mm and 0-mm group (82% and versus 79%, p = 1.0). The size of PTV-margin was not associated with PP. Both margin and volume of brain receiving 12 Gy (V12) were not associated with pseudoprogression in patients treated with single fraction. CONCLUSIONS: PTV-margin reduction did not reduce the incidence of pseudoprogression in LINAC-based-SRT for single brain metastases. We did not find a significant association of GTV-PTV margin or V12Gy with the incidence of pseudoprogression in solitary metastases treated with a single fraction. LC rates were similar, indicating margin reduction seems to be safe.

A Dutch phase III randomized multicenter trial: whole brain radiotherapy versus stereotactic radiotherapy for 4-10 brain metastases.

BACKGROUND: The clinical value of whole brain radiotherapy (WBRT) for brain metastases (BM) is a matter of debate due to the significant side effects involved. Stereotactic radiosurgery (SRS) is an attractive alternative treatment option that may avoid these side effects and improve local tumor control. We initiated a randomized trial (NCT02353000) to investigate whether quality of life is better preserved after SRS compared with WBRT in patients with multiple brain metastases. METHODS: Patients with 4-10 BM were randomized between the standard arm WBRT (total dose 20 Gy in 5 fractions) or SRS (single fraction or 3 fractions). The primary endpoint was the difference in quality of life (QOL) at 3 months post-treatment. RESULTS: The study was prematurely closed due to poor accrual. A total of 29 patients (13%) were randomized, of which 15 patients have been treated with SRS and 14 patients with WBRT. The median number of lesions were 6 (range: 4-9) and the median total treatment volume was 13.0 cc3 (range: 1.8-25.9 cc3). QOL at 3 months decreased in the SRS group by 0.1 (SD = 0.2), compared to 0.2 (SD = 0.2) in the WBRT group (P = .23). The actuarial 1-year survival rates were 57% (SRS) and 31% (WBRT) (P = .52). The actuarial 1-year brain salvage-free survival rates were 50% (SRS) and 78% (WBRT) (P = .22). CONCLUSION: In patients with 4-10 BM, SRS alone resulted in 1-year survival for 57% of patients while maintaining quality of life. Due to the premature closure of the trial, no statistically significant differences could be determined.

Proton therapy for selected low grade glioma patients in the Netherlands.

Proton therapy offers an attractive alternative to conventional photon-based radiotherapy in low grade glioma patients, delivering radiotherapy with equivalent efficacy to the tumour with less radiation exposure to the brain. In the Netherlands, patients with favourable prognosis based on tumour and patient characteristics can be offered proton therapy. Radiation-induced neurocognitive function decline is a major concern in these long surviving patients. Although level 1 evidence of superior clinical outcome with proton therapy is lacking, the Dutch National Health Care Institute concluded that there is scientific evidence to assume that proton therapy can have clinical benefit by reducing radiation-induced brain damage. Based on this decision, proton therapy is standard insured care for selected low grade glioma patients. Patients with other intracranial tumours can also qualify for proton therapy, based on the same criteria. In this paper, the evidence and considerations that led to this decision are summarised. Additionally, the eligibility criteria for proton therapy and the steps taken to obtain high-quality data on treatment outcome are discussed.

Dexamethasone for the Prevention of a Pain Flare After Palliative Radiation Therapy for Painful Bone Metastases: The Multicenter Double-Blind Placebo-Controlled 3-Armed Randomized Dutch DEXA Study.

PURPOSE: After radiation therapy for painful bone metastases, up to 44% of patients report a pain flare (PF). Our study compared 2 dose schedules of dexamethasone versus placebo to prevent PF. METHODS AND MATERIALS: This double-blind, randomized, placebo-controlled trial allocated patients with painful bone metastases from solid tumors randomly to receive 8 mg dexamethasone before radiation therapy followed by 3 daily doses (group A), 8 mg dexamethasone followed by 3 doses of placebo (group B), or 4 doses of placebo (group C). Patients reported worst pain scores, study medication side effects, and opioid intake before treatment and thereafter daily for 14 days and on day 28. PF was defined as at least a 2-point increase on a 0 to 10 pain scale with no decrease in opioid intake or a 25% or greater increase in opioid intake with no decrease in pain score, followed by a return to baseline or lower. The primary analysis was by intention to treat with patients who had missing data classified as having a PF. RESULTS: From January 2012 to April 2016, 295 patients were randomized. PF incidence was 38% for group A, 27% for group B, and 39% for group C (P = .07). Although patients in group B had the lowest PF incidence, a relatively high percentage did not return to baseline pain levels, indicating pain progression. The mean duration of PF was 2.1 days for group A, 4.5 days for group B, and 3.3 days for group C (P = .0567). Dexamethasone postponed PF occurrence; in group A 52% occurred on days 2 to 5 versus 73% in group B and 99% in group C (P = .02). Patients in group A reported lower mean pain scores on days 2 to 5 than those in group B or C (P < .001). Side effects were similar. CONCLUSIONS: There was insufficient evidence that dexamethasone reduced the incidence of radiation-induced PF. However, dexamethasone postponed the occurrence of PF and led to lower mean pain scores on days 2 to 5.

Lower doses to hippocampi and other brain structures for skull-base meningiomas with intensity modulated proton therapy compared to photon therapy.

BACKGROUND AND PURPOSE: Radiotherapy of skull-base meningiomas is challenging due to the close proximity of multiple sensitive organs at risk (OARs). This study systematically compared intensity modulated proton therapy (IMPT), non-coplanar volumetric modulated arc therapy (VMAT) and intensity modulated radiotherapy (IMRT) based on automated treatment planning. Differences in OARs sparing, with specific focus on the hippocampi, and low-dose delivery were quantified. MATERIALS AND METHODS: Twenty patients, target diameter >3 cm, were included. Automated plan generation was used to calculate a VMAT plan with three non-coplanar arcs, an IMRT plan with nine non-coplanar beams with optimized gantry and couch angles, and an IMPT plan with three patient-specific selected non-coplanar beams. A prescription dose of 50.4 GyRBE in 28 fractions was used. The same set of constraints and prioritized objectives was used. All plans were rescaled to the same target coverage. Repeated measures ANOVA was used to assess the statistical significance of differences in OAR dose parameters between planning techniques. RESULTS: Compared to VMAT and IMRT, IMPT significantly improved dose conformity to the target volume. Consequently, large dose reductions in OARs were observed. With respect to VMAT, the mean dose and D40% in the bilateral hippocampus were on average reduced by 48% and 74%, respectively (p ≤ 0.005). With IMPT, the mean dose in the normal brain and volumes receiving 20-30 Gy were up to 47% lower (p ≤ 0.01). When comparing IMPT and IMRT, even larger dose differences in those OARs were observed. CONCLUSION: For skull-base meningiomas IMPT allows for a considerable dose reduction in the hippocampi, normal brain and other OARs compared to both non-coplanar VMAT and IMRT, which may lead to a clinically relevant reduction of late neurocognitive side effects.

Evaluation of the Hippocampal Normal Tissue Complication Model in a Prospective Cohort of Low Grade Glioma Patients-An Analysis Within the EORTC 22033 Clinical Trial.

Purpose: To evaluate the performance of the hippocampal normal tissue complication model that relates dose to the bilateral hippocampus to memory impairment at 18 months post-treatment in a population of low-grade glioma (LGG) patients. Methods: LGG patients treated within the radiotherapy-only arm of the EORTC 22033-26033 trial were analyzed. Hippocampal dose parameters were calculated from the original radiotherapy plans. Difference in Rey Verbal Auditory Learning test delayed recall (AVLT-DR) performance pre-and 18 (±4) months post-treatment was compared to reference data from the Maastricht Aging study. The NTCP model published by Gondi et al. was applied to the dosimetric data and model predictions were compared to actual neurocognitive outcome. Results: A total of 29 patients met inclusion criteria. Mean dose in EQD2 Gy to the bilateral hippocampus was 39.8 Gy (95% CI 34.3-44.4 Gy), the median dose to 40% of the bilateral hippocampus was 47.2 EQD2 Gy. The model predicted a risk of memory impairment exceeding 99% in 22 patients. However, only seven patients were found to have a significant decline in AVLT-dr score. Conclusions: In this dataset of only LGG patients treated with radiotherapy the hippocampus NTCP model did not perform as expected to predict cognitive decline based on dose to 40% of the bilateral hippocampus. Caution should be taken when extrapolating this model outside of the range of dose-volume parameters in which it was developed.

The influence of a six degrees of freedom couch and an individual head support in patient positioning in radiotherapy of head and neck cancer.

Reproducible patient positioning is important in radiotherapy (RT) of head-and-neck cancer. We therefore compared set-up errors in head-and-neck RT resulting from three different patient positioning systems. Patients were either treated with a standard head support (SHS) and conventional treatment couch (SHS-3, n = 10), a SHS and rotational couch (SHS-6, n = 10), or an individual head support (IHS) and rotational couch (IHS-6, n = 10). Interfraction mean translation vector lenghts were significantly lower for IHS-6 compared to SHS-3 (0.8 ±â€¯0.3 mm vs. 1.4 ±â€¯0.7 mm, P = 0.001). Intrafraction displacement was comparable among cohorts. This study showed that the use of a six degrees of freedom couch combined with an IHS in head-and-neck RT resulted in better interfraction reproducibility.

Radiation dose constraints for organs at risk in neuro-oncology; the European Particle Therapy Network consensus.

PURPOSE: For unbiased comparison of different radiation modalities and techniques, consensus on delineation of radiation sensitive organs at risk (OARs) and on their dose constraints is warranted. Following the publication of a digital, online atlas for OAR delineation in neuro-oncology by the same group, we assessed the brain OAR-dose constraints in a follow-up study. METHODS: We performed a comprehensive search to identify the current papers on OAR dose constraints for normofractionated photon and particle therapy in PubMed, Ovid Medline, Cochrane Library, Embase and Web of Science. Moreover, the included articles' reference lists were cross-checked for potential studies that met the inclusion criteria. Consensus was reached among 20 radiation oncology experts in the field of neuro-oncology. RESULTS: For the OARs published in the neuro-oncology literature, we summarized the available literature and recommended dose constraints associated with certain levels of normal tissue complication probability (NTCP) according to the recent ICRU recommendations. For those OARs with lacking or insufficient NTCP data, a proposal for effective and efficient data collection is given. CONCLUSION: The use of the European Particle Therapy Network-consensus OAR dose constraints summarized in this article is recommended for the model-based approach comparing photon and proton beam irradiation as well as for prospective clinical trials including novel radiation techniques and/or modalities.

Individual changes in neurocognitive functioning and health-related quality of life in patients with brain oligometastases treated with stereotactic radiotherapy.

BACKGROUND: Recently, it has been shown that at group level, patients with limited brain metastases treated with stereotactic radiotherapy (SRT) maintain their pre-treatment levels of neurocognitive functioning (NCF) and health-related quality of life (HRQoL). The aim of this study was to evaluate NCF and HRQoL changes over time at the individual patient level. METHODS: NCF (seven domains assessed with a standardized test battery) and HRQoL (eight predetermined scales assessed with the EORTC QLQ-C30 and BN20 questionnaires) were measured prior to SRT and at 3 and/or 6 months follow-up. Changes in NCF and HRQoL were evaluated at (1) a domain/scale level and (2) patient level. RESULTS: A total of 55 patients were examined, of which the majority showed stable NCF 3 months after SRT, on both the domain level (78-100% of patients) and patient level (67% of patients). This was different for HRQoL, where deterioration in the different scales was observed in 12-61% of patients, stable scores in 20-71%, and improvement in 16-40%, 3 months after SRT. At patient level, most patients (64%) showed both improvement and deterioration in different HRQoL scales. Results were similar between 3 and 6 months after SRT. CONCLUSION: In line with results at group level, most brain oligometastases patients with ≥ 6 months follow-up and treated with SRT maintained their pre-treatment level of NCF during this period. By contrast, changes in HRQoL scores differed considerably at domain and patient level, despite stable HRQoL scores at group level.

The EPTN consensus-based atlas for CT- and MR-based contouring in neuro-oncology.

PURPOSE: To create a digital, online atlas for organs at risk (OAR) delineation in neuro-oncology based on high-quality computed tomography (CT) and magnetic resonance (MR) imaging. METHODS: CT and 3 Tesla (3T) MR images (slice thickness 1 mm with intravenous contrast agent) were obtained from the same patient and subsequently fused. In addition, a 7T MR without intravenous contrast agent was obtained from a healthy volunteer. Based on discussion between experienced radiation oncologists, the clinically relevant organs at risk (OARs) to be included in the atlas for neuro-oncology were determined, excluding typical head and neck OARs previously published. The draft atlas was delineated by a senior radiation oncologist, 2 residents in radiation oncology, and a senior neuro-radiologist incorporating relevant available literature. The proposed atlas was then critically reviewed and discussed by European radiation oncologists until consensus was reached. RESULTS: The online atlas includes one CT-scan at two different window settings and one MR scan (3T) showing the OARs in axial, coronal and sagittal view. This manuscript presents the three-dimensional descriptions of the fifteen consensus OARs for neuro-oncology. Among these is a new OAR relevant for neuro-cognition, the posterior cerebellum (illustrated on 7T MR images). CONCLUSION: In order to decrease inter- and intra-observer variability in delineating OARs relevant for neuro-oncology and thus derive consistent dosimetric data, we propose this atlas to be used in photon and particle therapy. The atlas is available online at www.cancerdata.org and will be updated whenever required.

Minimal clinically important differences in the EORTC QLQ-C30 and brief pain inventory in patients undergoing re-irradiation for painful bone metastases.

PURPOSE: The EORTC QLQ-C30 and the Brief Pain Inventory (BPI) are validated tools for measuring quality of life (QOL) and the impact of pain in patients with advanced cancer. Interpretation of these instrument scores can be challenging and it is difficult to know what numerical changes translate to clinically significant impact in patients' lives. To address this issue, our study sought to establish the minimal clinically important differences (MCID) for these two instruments in a prospective cohort of patients with advanced cancer and painful bone metastases. METHODS: Both anchor-based and distribution-based methods were used to estimate the MCID scores from patients enrolled in a randomized phase III trial evaluating two different re-irradiation treatment schedules. For the anchor-based method, the global QOL item from the QLQ-C30 was chosen as the anchor. Spearman correlation coefficients were calculated for all items and only those items with moderate or better correlation (|r| ≥ 0.30) with the anchor were used for subsequent analysis. A 10-point difference in the global QOL score was used to classify improvement and deterioration, and the MCID scores were calculated for each of these categories. These results were compared with scores obtained by the distribution-method, which estimates the MCID purely from the statistical characteristics of the sample population. RESULTS: A total of 375 patients were included in this study with documented pain responses and completed QOL questionnaires at 2 months. 9/14 items in the QLQ-C30 and 6/10 items in the BPI were found to have moderate or better correlation with the anchor. For deterioration, statistically significant MCID scores were found in all items of the QLQ-C30 and BPI. For improvement, statistically significant MCID scores were found in 7/9 items of the QLQ-C30 and 2/6 items of the BPI. The MCID scores for deterioration were uniformly higher than the MCIDs for improvement. Using the distribution-based method, there was good agreement between the 0.5 standard deviation (SD) values and anchor-based scores for deterioration. For improvement, there was less agreement and the anchor-based scores were lower than the 0.5 SD values obtained from the distribution-based method. CONCLUSION: We present MCID scores for the QLQ-C30 and BPI instruments obtained from a large cohort of patients with advanced cancer undergoing re-irradiation for painful bone metastases. The results from this study were compared to other similar studies which showed larger MCID scores for improvement compared to deterioration. We hypothesize that disease trajectory and patient expectations are important factors in understanding the contrasting results. The results of this study can guide clinicians and researchers in the interpretation of these instruments.

Late follow-up of the randomized radiation and concomitant high-dose intra-arterial or intravenous cisplatin (RADPLAT) trial for advanced head and neck cancer.

BACKGROUND: The radiation and concomitant high-dose intra-arterial or intravenous cisplatin (RADPLAT) phase III trial compared intra-arterial (IA) to intravenous (IV) cisplatin-based chemoradiation for head and neck cancer. Long-term efficacy and toxicity are reported after a median follow-up of 7.5 years. METHODS: Patients with inoperable squamous cell carcinoma (SCC) of the oropharynx, oral cavity, or hypopharynx, were randomized between radiotherapy (RT) + IA cisplatin 150 mg/m(2) , followed by systemic rescue or RT + I.V. cisplatin 100 mg/m(2) . RT consisted of 46 Gy to the affected and elective areas, followed by a boost of 24 Gy. RESULTS: Among 237 patients, 57 recurred locally, 35 regionally, and 80 locoregionally. There were 32 second primary tumors, 65 distant metastases, and 154 deaths. Locoregional control and overall survival were not different between the treatment arms. Late dysphagia was worse in the I.V. arm (log-rank p = .014). CONCLUSION: IA cisplatin did not improve tumor control compared to I.V. administered cisplatin, despite the higher dose in IA delivery of the drug. © 2015 Wiley Periodicals, Inc. Head Neck 38: E488-E493, 2016.

Neurocognitive functioning and health-related quality of life in patients treated with stereotactic radiotherapy for brain metastases: a prospective study.

BACKGROUND: Stereotactic radiotherapy (SRT) is expected to have a less detrimental effect on neurocognitive functioning and health-related quality of life (HRQoL) than whole-brain radiotherapy. To evaluate the impact of brain metastases and SRT on neurocognitive functioning and HRQoL, we performed a prospective study. METHODS: Neurocognitive functioning and HRQoL of 97 patients with brain metastases were measured before SRT and 1, 3, and 6 months after SRT. Seven cognitive domains were assessed. HRQoL was assessed with the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and BN20 questionnaires. Neurocognitive functioning and HRQoL over time were analyzed with linear mixed models and stratified for baseline Karnofsky performance status (KPS), total metastatic volume, and systemic disease. RESULTS: Median overall survival of patients was 7.7 months. Before SRT, neurocognitive domain and HRQoL scores were lower in patients than in healthy controls. At group level, patients worsened in physical functioning and fatigue at 6 months, while other outcome parameters of HRQoL and cognition remained stable. KPS < 90 and tumor volume >12.6 cm(3) were both associated with worse information processing speed and lower HRQoL scores over 6 months time. Intracranial tumor progression was associated with worsening of executive functioning and motor function. CONCLUSIONS: Prior to SRT, neurocognitive functioning and HRQoL are moderately impaired in patients with brain metastases. Lower baseline KPS and larger tumor volume are associated with worse functioning. Over time, SRT does not have an additional detrimental effect on neurocognitive functioning and HRQoL, suggesting that SRT may be preferred over whole-brain radiotherapy.

Local control rate after the combination of re-irradiation and hyperthermia for irresectable recurrent breast cancer: Results in 248 patients.

BACKGROUND AND PURPOSE: Randomized studies have shown that adding hyperthermia (HT) to re-irradiation (re-RT) improves treatment outcome for patients with breast cancer recurrences. We evaluated the efficacy and side effects in patients treated with re-RT and HT for irresectable locoregional breast cancer recurrences. MATERIAL AND METHODS: From September 1996 to December 2011, 248 patients with a macroscopic breast cancer recurrence were treated with re-RT and HT. Radiotherapy (RT) was applied to a dose of 32 Gy in 4 Gy fractions, twice weekly. HT was prescribed once weekly after RT. Primary endpoints for this analysis were complete response (CR) and local control (LC). Secondary endpoints were overall survival (OS), and toxicity. Patient-, tumor-, and treatment-related characteristics predictive for the endpoints were identified in univariate and multivariate analyses. RESULTS: The median follow-up period was 32 months. The CR rate was 70%. At 1, 3, and 5 years LC was 53%, 40% and 39%, and OS was 66%, 32%, and 18%, respectively. OS after 10 years was 10%. Thermal burns developed in 23% patients, healing with conservative measures. The incidence of 5 years late grade 3 toxicity was 1%. A few patients survived more than 10 years without evidence of disease. CONCLUSIONS: The combination of re-RT and HT results in a high rate of long-term LC with acceptable late toxicity, and many patients remained locally controlled for the rest of their survival period.

Pseudo-progression after stereotactic radiotherapy of brain metastases: lesion analysis using MRI cine-loops.

Stereotactic radiotherapy (SRT) of brain metastasis can lead to lesion growth caused by radiation toxicity. The pathophysiology of this so-called pseudo-progression is poorly understood. The purpose of this study was to evaluate the use of MRI cine-loops for describing the consecutive events in this radiation induced lesion growth. Ten patients were selected from our department's database that had received SRT of brain metastases and had lesion growth caused by pseudo-progression as well as at least five follow-up MRI scans. Pre- and post SRT MRI scans were co-registered and cine-loops were made using post-gadolinium 3D T1 axial slices. The ten cine loops were discussed in a joint meeting of the authors. The use of cine-loops was superior to evaluation of separate MRI scans for interpretation of events after SRT. There was a typical lesion evolution pattern in all patients with varying time course. Initially regression of the metastases was observed, followed by an enlarging area of new contrast enhancement in the surrounding brain tissue. Analysis of consecutive MRI's using cine-loops may improve understanding of pseudo-progression. It probably represents a radiation effect in brain tissue surrounding the irradiated metastasis and not enlargement of the metastasis itself.

Survival over 6 years in a patient with brain metastases from melanoma treated with temozolomide.

Cerebral metastases from melanoma are generally associated with a dismal prognosis with survival ranging from 3 to 6 months after treatment. Systemic chemotherapy for these patients has limited effect and evidence for an overall survival benefit from randomised controlled trials is lacking. We report on a 59-year-old patient with a history of malignant melanoma who presented with multiple cerebral metastases after previous surgery and combined whole brain and stereotactic radiotherapy. She has been in sustained remission and in excellent clinical condition after treatment with continued cycles of oral temozolomide for more than 6 years. To our knowledge, similar prolonged survival has been described only once in patients with multiple cerebral metastases from melanoma. This case demonstrates that temozolomide for metastatic central nervous system (CNS) disease in melanoma patients may be highly effective without CNS toxicity.

Cerebral ganglioneuroblastoma of adult onset: two patients and a review of the literature.

Ganglioneuroblastoma is a rare tumor variant of neuroblastoma. Only five cases have been observed in the adult brain, and we report here on two more adult patients with cerebral ganglioneuroblastoma. Additionally, a review was carried out on all 50 published adult cases with ganglioneuroblastoma, located in the adrenal gland (9), mediastinum (8), retroperitoneal area (7), the brain parenchyma (7), or the spinal cord (3). Median age at onset was 39 years, and 52% of patients were female. For extracranial locations, treatment usually consisted of surgery followed by radiotherapy and adjuvant chemotherapy. Of the cases with cerebral involvement only one patient did not receive any treatment. The other six patients underwent surgical resection and radiation therapy, in four cases followed by chemotherapy with temozolomide. The median survival of cerebral ganglioneuroblastomas was 14 months and did not differ from the whole group of ganglioneuroblastomas (12 months). For cerebral ganglioneuroblastoma, the preferred regimen would seem to be neurosurgical removal, followed by chemoradiotherapy including temozolomide.