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.

External validation of the lung-molGPA to predict survival in patients treated with stereotactic radiotherapy for brain metastases of non-small cell lung cancer.

BACKGROUND: In the era of personalized medicine, individualized prognostic models with tumor characteristics are needed to inform patients about survival. Before clinical use, external validation of such models by an independent group is needed. An updated version of the graded prognostic assessment (GPA) estimates survival in patients with brain metastases (BMs) of non-small cell lung cancer (NSCLC). This is the first external validation of the updated Lung-molGPA in patients treated with stereotactic radiotherapy (SRT) for one or more BMs. MATERIALS AND METHODS: Patients treated with SRT for BMs from NSCLC adenocarcinoma were retrospectively included. GPA score was calculated for each patient based on six prognostic factors including age, Karnofsky Performance Status, number of BMs, extracranial metastases, EGFR/ALK status, and PD-L1 expression. Kaplan-Meier analysis evaluated survival probability. Impact of individual prognostic factors on survival was assessed by univariate and multivariate analyses using the Cox proportional hazard model. Predictive performance was evaluated using discrimination (C-statistic) and calibration (Brier test). RESULTS: The cohort (n = 241) was divided into four prognostic groups. Overall median survival was 15 months. Predicted and observed median survival were similar between the original and validation cohorts, apart from the most favorable prognostic group. With adequate C-statistics and Brier scores, the Lung-molGPA provided accurate survival predictions. CONCLUSION: The Lung-molGPA accurately predicted survival in our European population, except for an overestimation of survival in the small most favorable prognostic group. This prognostic model was externally validated and is therefore useful for counseling of patients with BMs of NSCLC adenocarcinoma.

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.

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.

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.

Outcome of radiotherapy in T1 glottic carcinoma: a population-based study.

We evaluated the radiation outcome and prognostic factors in a population-based study of early (T1N0M0) glottic carcinoma. Survival parameters and prognostic factors were evaluated by uni- and multivariate analysis in 316 consecutive irradiated patients with T1 glottic carcinoma in the Comprehensive Cancer Center West region of the western Netherlands. Median follow-up was 70 months (range 1-190 months). Five and ten-year local control was 86 and 84%. Disease specific survival was 97% at 5 and 10 years. In multivariate analysis, pre-existent laryngeal hypertrophic laryngitis was the only predictive factor for local control (relative risk = 3.0, P = 0.02). Comorbidity was prognostic for overall survival. No factor was predictive for disease specific survival. Pre-existent laryngeal hypertrophic laryngitis is a new risk factor associated with reduced local control in T1 glottic carcinoma treated with radiotherapy.

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.

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.

Long-term improvement in treatment outcome after radiotherapy and hyperthermia in locoregionally advanced cervix cancer: an update of the Dutch Deep Hyperthermia Trial.

PURPOSE: The local failure rate in patients with locoregionally advanced cervical cancer is 41-72% after radiotherapy (RT) alone, whereas local control is a prerequisite for cure. The Dutch Deep Hyperthermia Trial showed that combining RT with hyperthermia (HT) improved 3-year local control rates of 41-61%, as we reported earlier. In this study, we evaluate long-term results of the Dutch Deep Hyperthermia Trial after 12 years of follow-up. METHODS AND MATERIALS: From 1990 to 1996, a total of 114 women with locoregionally advanced cervical carcinoma were randomly assigned to RT or RT+HT. The RT was applied to a median total dose of 68 Gy. The HT was given once weekly. The primary end point was local control. Secondary end points were overall survival and late toxicity. RESULTS: At the 12-year follow-up, local control remained better in the RT+HT group (37% vs. 56%; p=0.01). Survival was persistently better after 12 years: 20% (RT) and 37% (RT+HT; p=0.03). World Health Organization (WHO) performance status was a significant prognostic factor for local control. The WHO performance status, International Federation of Gynaecology and Obstetrics (FIGO) stage, and tumor diameter were significant for survival. The benefit of HT remained significant after correction for these factors. European Organization for Research and Treatment of Cancer Grade 3 or higher radiation-induced late toxicities were similar in both groups. CONCLUSIONS: For locoregionally advanced cervical cancer, the addition of HT to RT resulted in long-term major improvement in local control and survival without increasing late toxicity. This combined treatment should be considered for patients who are unfit to receive chemotherapy. For other patients, the optimal treatment strategy is the subject of ongoing research.

Single- versus multiple-fraction radiotherapy in patients with painful bone metastases: cost-utility analysis based on a randomized trial.

BACKGROUND: Radiotherapy is an effective palliative treatment for cancer patients with painful bone metastases. Although single- and multiple-fraction radiotherapy are thought to provide equal palliation, which treatment schedule provides better value for the money is unknown. We compared quality-adjusted life expectancy (the overall valuation of the health of the patients) and societal costs for patients receiving either single- or multiple-fraction radiotherapy. METHODS: A societal cost-utility analysis was performed on a Dutch randomized, controlled trial of 1157 patients with painful bone metastases that compared pain responses and quality of life from a single-fraction treatment schedule of 8 Gy with a treatment schedule of six fractions of 4 Gy each. The societal values of life expectancies were assessed with the EuroQol classification system (EQ-5D) questionnaire. A subset of 166 patients also answered additional questionnaires to estimate nonradiotherapy and nonmedical costs. Statistical tests were two-sided. RESULTS: Comparing the single- and multiple-fraction radiotherapy schedules, no differences were found in life expectancy (43.0 versus 40.4 weeks, P =.20) or quality-adjusted life expectancy (17.7 versus 16.0 weeks, P =.21). The estimated cost of radiotherapy, including retreatments and nonmedical costs, was statistically significantly lower for the single-fraction schedule than for the multiple-fraction schedule ($2438 versus $3311, difference = $873, 95% confidence interval [CI] on the difference = $449 to $1297; P<.001). The estimated difference in total societal costs was larger, also in favor of the single-fraction schedule, but it was not statistically significant ($4700 versus $6453, difference = $1753, 95% CI on the difference = -$99 to $3604; P =.06). For willingness-to-pay between $5000 and $40 000 per quality-adjusted life year, the single-fraction schedule was statistically significantly more cost-effective than the multiple-fraction schedule (P< or =.05). CONCLUSIONS: Compared with multiple-fraction radiotherapy, single-fraction radiotherapy provides equal palliation and quality of life and has lower medical and societal costs, at least in The Netherlands. Therefore, single-fraction radiotherapy should be considered as the palliative treatment of choice for cancer patients with painful bone metastases.

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.

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.

SMART syndrome: a late reversible complication after radiation therapy for brain tumours.

With intensified treatment leading to longer survival, complications of therapy for brain tumours are more frequently observed. Regarding radiation therapy, progressive and irreversible white matter disease with cognitive decline is most feared. We report on four patients with reversible clinical and radiological features occurring years after radiation for brain tumours, suggestive for the so called SMART syndrome (stroke-like migraine attacks after radiation therapy). All four patients (males, age 36-60 years) had been treated with focal brain radiation for a primary brain tumour or with whole-brain radiation therapy for brain metastases. Ranging from 2 to 10 years following radiation therapy patients presented with headache and focal neurological deficits, suggestive for tumour recurrence. Two patients also presented with focal seizures. MRI demonstrated typical cortical swelling and contrast enhancement, primarily in the parieto-occipital region. On follow-up both clinical and MRI features improved spontaneously. Three patients eventually proved to have tumour recurrence. The clinical and radiological picture of these patients is compatible with the SMART syndrome, a rare complication of radiation therapy which is probably under recognized in brain tumour patients. The pathophysiology of the SMART syndrome is poorly understood but bears similarities with the posterior reversible encephalopathy syndrome (PRES). These four cases underline that the SMART syndrome should be considered in patients formerly treated with radiation therapy for brain tumours, who present with new neurologic deficits. Before the diagnosis of SMART syndrome can be established other causes, such as local tumour recurrence, leptomeningeal disease or ischemic disease should be ruled out.

Tumor volume as prognostic factor in chemoradiation for advanced head and neck cancer.

BACKGROUND: Tumor volume is an important predictor of outcome in radiotherapy alone. Its significance in concomitant chemoradiation (CCRT) is much less clear. We analyzed the prognostic value of primary tumor volume for advanced head and neck squamous cell carcinoma (HNSCC) treated with CCRT. METHODS: Three hundred sixty patients treated with definitive CCRT for advanced HNSCC were selected. The pretreatment MRI or CT scan was used to calculate the primary tumor volume. Median follow-up was 19.8 months. RESULTS: The average primary tumor volume was 37.0 cm³ (range, 2.1-182.7 cm³; median, 28.7 cm³). Multivariate analysis showed a significant effect of tumor volume on local control. The hazard ratio for a local recurrence increased by 14% per 10 cm³ volume increase (95% CI, 8% to 21%). There was no significant independent effect of T and N status on local control. CONCLUSION: For advanced HNSCC, tumor volume is more powerful for predicting outcome after CCRT than TNM status.

Stereotactic radiotherapy of intracranial tumors: a comparison of intensity-modulated radiotherapy and dynamic conformal arc.

PURPOSE: Intensity-modulated radiotherapy (IMRT) and dynamic conformal arc (DCA) are two state-of-the-art techniques for linac-based stereotactic radiotherapy (SRT) using the micromultileaf collimator. The purpose of this planning study is to examine the relative merits of these techniques in the treatment of intracranial tumors. MATERIALS AND METHODS: SRT treatment plans were made for 25 patients with a glioma or meningioma. For all patients, we made an IMRT and a DCA plan. Plans were evaluated using: target coverage, conformity index (CI), homogeneity index (HI), doses in critical structures, number of monitor units needed, and equivalent uniform dose (EUD) in planning target volume (PTV) and critical structures. RESULTS: In the overall comparison of both techniques, we found adequate target coverage in all cases; a better mean CI with IMRT in concave tumors (p = 0.027); a better mean HI with DCA in meningiomas, complex tumors, and small (< 92 mL) tumors (p = 0.000, p = 0.005, and p = 0.005, respectively); and a higher EUD in the PTV with DCA in convex tumors (gliomas) and large tumors (p = 0.000 and p = 0.003, respectively). In all patients, significantly more monitor units were needed with IMRT. The results of the overall comparison did not enable us to predict the preference for one of the techniques in individual patients. The DCA plan was acceptable in 23 patients and the IMRT plan in 19 patients. DCA was preferred in 18 of 25 patients. CONCLUSIONS: DCA is our preferred SRT technique for most intracranial tumors. Tumor type, size, or shape do not predict a preference for DCA or IMRT.