W.S.C. Eppinga

Evaluation of high ipsilateral subventricular zone radiation therapy dose in glioblastoma: a pooled analysis.

PURPOSE Cancer stem cells (CSCs) may play a role in the recurrence of glioblastoma. They are believed to originate from neural stem cells in the subventricular zone (SVZ). Because of their radioresistance, we hypothesized that high doses of radiation (>59.4 Gy) to the SVZ are necessary to control CSCs and improve progression-free survival (PFS) or overall survival (OS) in glioblastoma. METHODS AND MATERIALS 173 patients with glioblastoma pooled from 2 academic centers were treated with resection followed by chemoradiation therapy. The SVZ was segmented on computed tomography to calculate radiation doses delivered to the presumptive CSC niches. The relationships between high SVZ doses and PFS and OS were examined using Cox proportional hazards models. Five covariates were included to estimate their impact on PFS or OS: ipsilateral and contralateral SVZ doses, clinical target volume dose, age, and extent of resection. RESULTS Median PFS and OS were 10.4 and 19.6 months for the cohort. The mean ipsilateral SVZ, contralateral SVZ, and clinical target volume doses were 49.2, 35.2, and 60.1 Gy, respectively. Twenty-one patients who received high ipsilateral SVZ dose (>59.4 Gy) had significantly longer median PFS (12.6 vs 9.9 months, P=.042) and longer OS (25.8 vs 19.2 months, P=.173). On multivariate analysis, high radiation therapy doses to ipsilateral SVZ remained a statistically significant independent predictor of improved PFS but not of OS. The extent of surgery affected both PFS and OS on multivariate analysis. CONCLUSION High radiation therapy doses to ipsilateral CSC niches are associated with improved PFS in glioblastoma.

Spine Stereotactic Body Radiotherapy: Indications, Outcomes, and Points of Caution:

Study Design: A broad narrative review. Objectives: The objective of this article is to provide a technical review of spine stereotactic body radiotherapy (SBRT) planning and delivery, indications for treatment, outcomes, complications, and the challenges of response assessment. The surgical approach to spinal metastases is discussed with an overview of emerging minimally invasive techniques. Methods: A comprehensive review of the literature was conducted on the techniques, outcomes, and developments in SBRT and surgery for spinal metastases. Results: The optimal management of patients with spinal metastases is complex and requires multidisciplinary assessment from an oncologic team that is familiar with the shifting paradigm as a consequence of evolving techniques in surgery and stereotactic radiation, as well as new developments in systemic agents. The Spinal Instability Neoplastic Score and the epidural spinal cord compression (Bilsky) grading system are useful tools that facilitate communication among oncologic team members and can direct management by providing a baseline assessment of risks prior to therapy. The combined multimodality approach with “separation surgery” followed by postoperative spine SBRT achieves thecal sac decompression, improves tumor control, and avoids complications that may be associated with more extensive surgery. Conclusion: Spine SBRT is a highly effective treatment that is capable of delivering ablative doses to the target while sparing the critical organs-at-risk, chiefly the critical neural tissues, within a short and manageable schedule. At the same time, surgery occupies an important role in select patients, particularly with the expanding availability and expertise in minimally invasive techniques. With rapid adoption of spine SBRT in centers outside of the academic setting, it is imperative for the practicing oncologist to understand the relevance and application of these evolving concepts.

Comparing conVEntional RadioTherapy with stereotactIC body radiotherapy in patients with spinAL metastases : study protocol for an randomized controlled trial following the cohort multiple randomized controlled trial design

BackgroundStandard radiotherapy is the treatment of first choice in patients with symptomatic spinal metastases, but is only moderately effective. Stereotactic body radiation therapy is increasingly used to treat spinal metastases, without randomized evidence of superiority over standard radiotherapy. The VERTICAL study aims to quantify the effect of stereotactic radiation therapy in patients with metastatic spinal disease.Methods/designThis study follows the ‘cohort multiple Randomized Controlled Trial’ design. The VERTICAL study is conducted within the PRESENT cohort. In PRESENT, all patients with bone metastases referred for radiation therapy are enrolled. For each patient, clinical and patient-reported outcomes are captured at baseline and at regular intervals during follow-up. In addition, patients give informed consent to be offered experimental interventions. Within PRESENT, 110 patients are identified as a sub cohort of eligible patients (i.e. patients with unirradiated painful, mechanically stable spinal metastases who are able to undergo stereotactic radiation therapy). After a protocol amendment, also patients with non-spinal bony metastases are eligible. From the sub cohort, a random selection of patients is offered stereotactic radiation therapy (n = 55), which patients may accept or refuse. Only patients accepting stereotactic radiation therapy sign informed consent for the VERTICAL trial. Non-selected patients (n = 55) receive standard radiotherapy, and are not aware of them serving as controls. Primary endpoint is pain response after three months. Data will be analyzed by intention to treat, complemented by instrumental variable analysis in case of substantial refusal of the stereotactic radiation therapy in the intervention arm.DiscussionThis study is designed to quantify the treatment response after (stereotactic) radiation therapy in patients with symptomatic spinal metastases. This is the first randomized study in palliative care following the cohort multiple Randomized Controlled Trial design. This design addresses common difficulties associated with classic pragmatic randomized controlled trials, such as disappointment bias in patients allocated to the control arm, slow recruitment, and poor generalizability.Trial registrationThe Netherlands Trials Register number NL49316.041.14. ClinicalTrials.gov registration number NCT02364115. Date of trial registration February 1, 2015.

Dosimetric feasibility of the hybrid Magnetic Resonance Imaging (MRI)-linac System (MRL) for brain metastases: The impact of the magnetic field

BACKGROUND AND PURPOSE We aimed to investigate the suitability of treating patients with single brain metastases using stereotactic radiosurgery (SRS) with the MRL and to characterize the dosimetric impact at tissue-air interfaces resulting primarily from the electron return effect (ERE). MATERIAL AND METHODS 24 patients treated for intact single brain metastases were analyzed. Three radiotherapy plans with the same prescribed dose were generated for each case: (1) noncoplanar volumetric modulated arc therapy (VMAT), (2) coplanar step-and-shoot intensity modulated radiotherapy (IMRT) on the MRL in the absence (MRLB=0), and (3) in the presence of the transverse magnetic field (MRLB=1.5). The plans were evaluated using cumulative dose-volume histograms and by calculation of Paddick conformity index (CI), V100%, V12Gy minus gross tumor volume (V12Gy - GTV), and V2Gy. At tissue-air boundaries, the dosimetric impact of the magnetic field was quantified using a 5 mm rim of tissue. RESULTS All plans met the target coverage and organs-at-risk planning objectives. Differences between all investigated dosimetric parameters significantly favored the VMAT plans as compared to the MRLB=0 and MRLB=1.5 plans, except for V2Gy. The mean V12Gy - GTV and V2Gy marginally favored the MRLB=0 plans compared to the MRLB=1.5 plans (mean difference: 0.45 cm3, p = 0.0019 and 16.46 cm3, p < 0.0001, respectively). The presence of the magnetic field resulted in a statistically significant but small increase in mean dose and D2cc in the skin (0.08 Gy, p < 0.0001 and 0.6 Gy, p < 0.0001, respectively) and around air cavities (0.07 Gy, p = 0.0092 and 0.3 Gy, p = 0.0004, respectively). CONCLUSIONS It is feasible to generate stereotactic radiation plans that satisfy clinical requirements using the MRL in the setting of single brain metastases. The dosimetric impact of the magnetic field including the ERE at tissue-air boundaries is minor and does not negatively impact target conformity or dose gradient.

Inter-observer agreement in GTV delineation of bone metastases on CT and impact of MR imaging: A multicenter study

BACKGROUND AND PURPOSE The use of Stereotactic Body Radiotherapy (SBRT) for bone metastases is increasing rapidly. Therefore, knowledge of the inter-observer differences in tumor volume delineation is essential to guarantee precise dose delivery. The aim of this study is to compare inter-observer agreement in bone metastases delineated on different imaging modalities. MATERIAL AND METHODS Twenty consecutive patients with bone metastases treated with SBRT were selected. All patients received CT and MR imaging in treatment position prior to SBRT. Five observers from three institutions independently delineated gross tumor volume (GTV) on CT alone, CT with co-registered MRI and MRI alone. Four contours per imaging modality per patient were available, as one set of contours was shared by 2 observers. Inter-observer agreement, expressed in generalized conformity index [CIgen], volumes of contours and contours center of mass (COM) were calculated per patient and imaging modality. RESULTS Mean GTV delineated on MR (45.9±52.0cm3) was significantly larger compared to CT-MR (40.2±49.4cm3) and CT (34.8±41.8cm3). A considerable variation in CIgen was found on CT (mean 0.46, range 0.15-0.75) and CT-MRI (mean 0.54, range 0.17-0.71). The highest agreement was found on MRI (mean 0.56, range 0.20-0.77). The largest variations of COM were found in anterior-posterior direction for all imaging modalities. CONCLUSIONS Large inter-observer variation in GTV delineation exists for CT, CT-MRI and MRI. MRI-based GTV delineation resulted in larger volumes and highest consistency between observers.

Superior target delineation for stereotactic body radiotherapy of bone metastases from renal cell carcinoma on MRI compared to CT

BACKGROUND In metastatic renal cell carcinoma (mRCC) there has been a treatment shift towards targeted therapy, which has resulted in improved overall survival. Therefore, there is a need for better local control of the tumor and its metastases. Image-guided stereotactic body radiotherapy (SBRT) in bone metastases provides improved symptom palliation and local control. With the use of SBRT there is a need for accurate target delineation. The hypothesis is that MRI allows for better visualization of the extend of bone metastases in mRCC and will optimize the accuracy of tumor delineation for stereotactic radiotherapy purposes, compared with CT only. METHODS From 2013 to 2016, patients who underwent SBRT for RCC bone metastases were included. A planning CT and MRI were performed in radiotherapy treatment position. Gross tumor volumes (GTV) in both CT and MRI were delineated. Contouring was performed by a radiation oncologist specialized in bone metastases and verified by a radiologist, based on local consensus contouring guidelines. In both CT and MRI, the GTV volumes, conformity index (CI) and distance between the centers of mass (dCOM) were compared. RESULTS Nine patients with 11 RCC bone metastases were included. The GTV volume as defined on MRI was in all cases larger or at least as large as the GTV volume on CT. The median GTV volume on MRI was 33.4 mL (range 0.2-247.6 mL), compared to 18.1 mL on CT (range 0.1-195.9) (P=0.013). CONCLUSIONS Contouring of RCC bone metastases on MRI resulted in clinically relevant and statistically significant larger lesions (mean increase 41%) compared with CT. MRI seems to represent the extend of the GTV in RCC bone metastases more accurately. Contouring based on CT-only could result in an underestimation of the actual tumor volume, which may cause underdosage of the GTV in SBRT treatment plans.

Re-salvage MRI-guided Focal High-dose-rate Brachytherapy for Locally Recurrent Prostate Cancer

Prostate cancer recurrences are common, even with twenty-first-century primary prostate cancer treatment modalities. The most common salvage treatment is (delayed) hormonal therapy, which is often associated with serious side-effects. Due to the risk of significant toxicity, whole-gland targeted salvage treatments remain unpopular. Consequently, developments in focal therapies have arisen. Magnetic resonance imaging (MRI)-guided focal salvage high-dose-rate brachytherapy (HDR-BT) is a novel treatment aiming for minimal toxicity in recurrent prostate cancer patients. Repeating focal treatment could, therefore, be possible in case of post-salvage recurrence. We report the case of a 77-year-old man who underwent repeat focal HDR-BT.

The use of a simultaneous integrated boost in spinal stereotactic body radiotherapy to reduce the risk of vertebral compression fractures: a treatment planning study

In the management of spinal metastases, stereotactic radiotherapy (SBRT) is an emerging technique intended to deliver a high-radiation dose precisely to the target [1]. Concern has been raised about the dose-fractionation schemes used in spinal SBRT as the risk of vertebral compression fractures (VCF) have been reported to be as high as 40% [2]. These rates are much higher compared to conventional radiotherapy, which is typically below 5% [3]. It was hypothesized that radiation effects in the form of bone and tumor necrosis compromise the ability of the vertebrae to withstand the axial loading forces, leading to an increased risk of VCF [4]. Clinicopathologic samples of spinal metastases, obtained after SBRT, showed radiation-induced tumor and osteonecrosis, giving evidence for this hypothesis [5,6]. More support for this hypothesis is provided by studies assessing VCF risk in patients receiving high-dose radiation for primary tumors in the thoracic or abdominal region, showing that vertebral fractures are mostly seen in the high-dose regions [7]. Prevention of VCF is challenging because the metastatic lesions lie within the segment at risk. A simultaneous integrated boost (SIB) dose delivery approach might mitigate the risk of SBRT-induced VCF by boosting the gross tumor volume (GTV) with the non-affected bone included in the clinical target volume (CTV). Currently, a SIB planning design has not been formally compared with a non-SIB approach. In this study, we report on the dosimetric feasibility of a SIB SBRT approach in the treatment of spinal metastases.

Perineal recurrence of prostate cancer six years after trans-perineal brachytherapy.

We report a case of perineal recurrence of prostate cancer 6 years after low-dose-rate (LDR) brachytherapy for localized prostate cancer. The most common approach to treat such perineal masses, including those occurring after prior biopsy or surgery, is local excision. We report the use of stereotactic radiotherapy with volumetric modulated arc therapy (VMAT) as a novel non-invasive, potentially curative, and patient-friendly alternative to local excision.