The potential of advanced MR techniques for precision radiotherapy of glioblastoma.

As microscopic tumour infiltration of glioblastomas is not visible on conventional magnetic resonance (MR) imaging, an isotropic expansion of 1-2 cm around the visible tumour is applied to define the clinical target volume for radiotherapy. An opportunity to visualize microscopic infiltration arises with advanced MR imaging. In this review, various advanced MR biomarkers are explored that could improve target volume delineation for radiotherapy of glioblastomas. Various physiological processes in glioblastomas can be visualized with different advanced MR techniques. Combining maps of oxygen metabolism (CMRO2), relative cerebral blood volume (rCBV), vessel size imaging (VSI), and apparent diffusion coefficient (ADC) or amide proton transfer (APT) can provide early information on tumour infiltration and high-risk regions of future recurrence. Oxygen consumption is increased 6 months prior to tumour progression being visible on conventional MR imaging. However, presence of the Warburg effect, marking a switch from an infiltrative to a proliferative phenotype, could result in CMRO2 to appear unaltered in high-risk regions. Including information on biomarkers representing angiogenesis (rCBV and VSI) and hypercellularity (ADC) or protein concentration (APT) can omit misinterpretation due to the Warburg effect. Future research should evaluate these biomarkers in radiotherapy planning to explore the potential of advanced MR techniques to personalize target volume delineation with the aim to improve local tumour control and/or reduce radiation-induced toxicity.

Conversion of a colorectal cancer guideline into clinical decision trees with assessment of validity.

OBJECTIVE: The interpretation and clinical application of guidelines can be challenging and time-consuming, which may result in noncompliance to guidelines. The aim of this study was to convert the Dutch guideline for colorectal cancer (CRC) into decision trees and subsequently implement decision trees in an online decision support environment to facilitate guideline application. METHODS: The recommendations of the Dutch CRC guidelines (published in 2014) were translated into decision trees consisting of decision nodes, branches and leaves that represent data items, data item values and recommendations, respectively. Decision trees were discussed with experts in the field and published as interactive open access decision support software (available at www.oncoguide.nl). Decision tree validation and a concordance analysis were performed using consecutive reports (January 2016-January 2017) from CRC multidisciplinary tumour boards (MTBs) at Amsterdam University Medical Centers, location AMC. RESULTS: In total, we developed 34 decision trees driven by 101 decision nodes based on the guideline recommendations. Decision trees represented recommendations for diagnostics (n = 1), staging (n = 10), primary treatment (colon: n = 1, rectum: n = 5, colorectal: n = 9), pathology (n = 4) and follow-up (n = 3) and included one overview decision tree for optimal navigation. We identified several guideline information gaps and areas of inconclusive evidence. A total of 158 patients' MTB reports were eligible for decision tree validation and resulted in treatment recommendations in 80% of cases. The concordance rate between decision tree treatment recommendations and MTB advices was 81%. Decision trees reported in 22 out of 24 non-concordant cases (92%) that no guideline recommendation was available. CONCLUSIONS: We successfully converted the Dutch CRC guideline into decision trees and identified several information gaps and areas of inconclusive evidence, the latter being the main cause of the observed disagreement between decision tree recommendations and MTB advices. Decision trees may contribute to future strategies to optimize quality of care for CRC patients.

Characterisation and classification of oligometastatic disease: a European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus recommendation.

Oligometastatic disease has been proposed as an intermediate state between localised and systemically metastasised disease. In the absence of randomised phase 3 trials, early clinical studies show improved survival when radical local therapy is added to standard systemic therapy for oligometastatic disease. However, since no biomarker for the identification of patients with true oligometastatic disease is clinically available, the diagnosis of oligometastatic disease is based solely on imaging findings. A small number of metastases on imaging could represent different clinical scenarios, which are associated with different prognoses and might require different treatment strategies. 20 international experts including 19 members of the European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer OligoCare project developed a comprehensive system for characterisation and classification of oligometastatic disease. We first did a systematic review of the literature to identify inclusion and exclusion criteria of prospective interventional oligometastatic disease clinical trials. Next, we used a Delphi consensus process to select a total of 17 oligometastatic disease characterisation factors that should be assessed in all patients treated with radical local therapy for oligometastatic disease, both within and outside of clinical trials. Using a second round of the Delphi method, we established a decision tree for oligometastatic disease classification together with a nomenclature. We agreed oligometastatic disease as the overall umbrella term. A history of polymetastatic disease before diagnosis of oligometastatic disease was used as the criterion to differentiate between induced oligometastatic disease (previous history of polymetastatic disease) and genuine oligometastatic disease (no history of polymetastatic disease). We further subclassified genuine oligometastatic disease into repeat oligometastatic disease (previous history of oligometastatic disease) and de-novo oligometastatic disease (first time diagnosis of oligometastatic disease). In de-novo oligometastatic disease, we differentiated between synchronous and metachronous oligometastatic disease. We did a final subclassification into oligorecurrence, oligoprogression, and oligopersistence, considering whether oligometastatic disease is diagnosed during a treatment-free interval or during active systemic therapy and whether or not an oligometastatic lesion is progressing on current imaging. This oligometastatic disease classification and nomenclature needs to be prospectively evaluated by the OligoCare study.

Institutional experience in the treatment of colorectal liver metastases with stereotactic body radiation therapy.

AIM: To investigate whether the impact of dose escalation in our patient population represented an improvement in local control without increasing treatment related toxicity. MATERIALS AND METHODS: A cohort of consecutive patients with colorectal liver metastases treated with stereotactic body radiation therapy (SBRT) between December 2002 and December 2013 were eligible for this study. Inclusion criteria were a Karnofsky performance status ≥80% and, according to the multidisciplinary tumor board, ineligibility for surgery or radiofrequency ablation. Exclusion criteria were a lesion size >6 cm, more than 3 metastases, and treatment delivered with other fractionation scheme than 3 times 12.5 Gy or 16.75 Gy prescribed at the 65-67% isodose. To analyze local control, CT or MRI scans were acquired during follow-up. Toxicity was scored using the Common Toxicity Criteria Adverse Events v4.0. RESULTS: A total of 40 patients with 55 colorectal liver metastases were included in this study. We delivered 37.5 Gy to 32 lesions, and 50.25 Gy to 23 lesions. Median follow-up was 26 and 25 months for these two groups. Local control at 2 and 3 years was 74 and 66% in the low dose group while 90 and 81% was reached in the high dose group. No significant difference in local control between the two dose fractionation schemes could be found. Grade 3 toxicity was limited and was not increased in the high dose group. CONCLUSIONS: SBRT for colorectal liver metastases offers a high chance of local control at long term. High irradiation doses may contribute to enhance this effect without increasing toxicity.

Inter- and intrafraction dose variations in robotic stereotactic body radiation therapy (SBRT) for perihilar cholangiocarcinoma in the prospective phase I STRONG trial.

Using fiducial-marker-based robotic respiratory tumor tracking, we treated perihilar cholangiocarcinoma patients in the STRONG trial with 15 daily fractions of 4 Gy. For each of the included patients, in-room diagnostic-quality repeat CTs (rCT) were acquired pre- and post-dose delivery in 6 treatment fractions to analyze inter- and intrafraction dose variations. Planning CTs (pCTs) and rCTs were acquired in expiration breath-hold. Analogous to treatment, spine and fiducials were used to register rCTs with pCTs. In each rCT, all OARs were contoured, and the target was rigidly copied from the pCT based on grey values. The rCTs acquired were used to calculate the doses to be delivered through the treatment-unit settings. On average, target doses in rCTs and pCTs were similar. However, due to target displacements relative to the fiducials in rCTs, 10% of the rCTs showed PTV coverage losses of >10%. Although target coverages had been planned below desired values in order to protect OARs, many pre-rCTs contained OAR constraint violations: 44.4% for the 6 major constraints. Most OAR dose differences between pre- and post-rCTs were not statistically significant. The dose deviations observed in repeat CTs represent opportunities for more advanced adaptive approaches to enhancing SBRT treatment quality.

Early and late contrast enhancing lesions after photon radiotherapy for IDH mutated grade 2 diffuse glioma.

OBJECTIVE: The interpretation of new enhancing lesions after radiotherapy for diffuse glioma remains a clinical challenge. We sought to characterize and classify new contrast enhancing lesions in a historical multicenter cohort of patients with IDH mutated grade 2 diffuse glioma treated with photon therapy. METHODS: We reviewed all follow-up MRI's of all patients treated with radiotherapy for histologically confirmed, IDH mutated diffuse grade 2 glioma between 1-1-2007 and 31-12-2018 in two tertiary referral centers. Disease progression (PD) was defined in accordance with the RANO criteria for progressive disease in low grade glioma. Pseudoprogression (psPD) was defined as any transient contrast-enhancing lesion between the end of radiotherapy and PD, or any new contrast-enhancing lesion that remained stable over a period of 12 months in patients who did not exhibit PD. RESULTS: A total of 860 MRI's of 106 patients were reviewed. psPD was identified in 24 patients (23%) on 76 MRI's. The cumulative incidence of psPD was 13% at 1 year, 22% at 5 years, and 28% at 10 years. The mean of the observed maximal volume of psPD was 2.4 cc. The median Dmin in psPD lesions was 50.1 Gy. The presence of an 1p/19q codeletion was associated with an increased risk of psPD (subhazard ratio 2.34, p = 0.048). psPD was asymptomatic in 83% of patients. CONCLUSION: The cumulative incidence of psPD in grade 2 diffuse glioma increases over time. Consensus regarding event definition and statistical analysis is needed for comparisons between series investigating psPD.

Transarterial Chemoembolization With Drug-Eluting Beads Versus Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma: Outcomes From a Multicenter, Randomized, Phase 2 Trial (the TRENDY Trial).

PURPOSE: To compare transarterial chemoembolization delivered with drug eluting beads (TACE-DEB) with stereotactioc body radiation therapy (SBRT) in patients with hepatocellular carcinoma (HCC) in a multicenter randomized trial. METHODS AND MATERIALS: Patients were included if they were eligible for TACE. They could also be recruited if they required treatment prior to liver transplantation. A maximum of four TACE-DEB procedures and ablation after incomplete TACE-DEB were both allowed. SBRT was delivered in six fractions of 8-9Gy. Primary end point was time to progression (TTP). Secondary endpoints were local control (LC), overall survival (OS), response rate (RR), toxicity, and quality of life (QoL). The calculated sample size was 100 patients. RESULTS: Between May 2015 and April 2020, 30 patients were randomized to the study. Due to slow accrual the trial was closed prematurely. Two patients in the SBRT arm were considered ineligible leaving 16 patients in the TACE-DEB arm and 12 in the SBRT arm. Median follow-up was 28.1 months. Median TTP was 12 months for TACEDEB and 19 months for SBRT (p=0.15). Median LC was 12 months for TACE-DEB and >40 months (not reached) for SBRT (p=0.075). Median OS was 36.8 months for TACEDEB and 44.1 months for SBRT (p=0.36). A post-hoc analysis showed 100% for SBRT 1- and 2-year LC, and 54.4% and 43.6% for TACE-DEB (p=0.019). Both treatments resulted in RR>80%. Three episodes of possibly related toxicity grade ≥3 were observed after TACE-DEB. No episodes were observed after SBRT. QoL remained stable after both treatment arms. CONCLUSIONS: In this trial, TTP after TACE-DEB was not significantly improved by SBRT, while SBRT showed higher local antitumoral activity than TACE-DEB, without detrimental effects on OS, toxicity and QoL. To overcome poor accrual in randomized trials that include SBRT, and to generate evidence for including SBRT in treatment guidelines, international cooperation is needed.

Accurate CT∕MR vessel-guided nonrigid registration of largely deformed livers.

PURPOSE: Computer tomography (CT) scans are used for designing radiotherapy treatment plans. However, the tumor is often better visible in magnetic resonance (MR) images. For liver stereotactic body radiation therapy (SBRT), the planning CT scan is acquired while abdominal compression is applied to reduce tumor motion induced by breathing. However, diagnostic MR scans are acquired under voluntary breath-hold without the compression device. The resulting large differences in liver shape hinder the alignment of CT and MR image sets, which severely limits the integration of the information provided by these images. The purpose of the current study is to develop and validate a nonrigid registration method to align breath-hold MR images with abdominal-compressed CT images, using vessels that are automatically segmented within the liver. METHODS: Contrast-enhanced MR and CT images of seven patients with liver cancer were used for this study. The registration method combines automatic vessel segmentation with an adapted version of thin-plate spline robust point matching. The vessel segmentation uses a multiscale vesselness measure, which allows vessels of various thicknesses to be segmented. The nonrigid registration is point-based, and progressively improves the correspondence and transformation between two point sets. Moreover, the nonrigid registration is capable of identifying and handling outliers (points with no counterpart in the other set). We took advantage of the strengths of both methods and created a multiscale registration algorithm. First, thick vessels are registered, then with each new iteration thinner vessels are included in the registration (strategy A). We compared strategy A to a straightforward approach where vessels of various diameters are segmented and subsequently registered (strategy B). To assess the transformation accuracy, residual distances were calculated for vessel bifurcations. For anatomical validation, residual distances were calculated for additional anatomical landmarks within the liver. To estimate the extent of deformation, the residual distances for the aforementioned anatomical points were calculated after rigid registration. RESULTS: Liver deformations in the range of 2.8-10.7 mm were found after rigid registration of the CT and MR scans. Low residual distances for vessel bifurcations (average 1.6, range 1.3-1.9 mm) and additional anatomical landmarks (1.5, 1.1-2.4 mm) were found after nonrigid registration. A large amount of outliers were identified (25%-55%) caused by vessels present in only one of the image sets and false positives in the vesselness measure. The nonrigid registration was capable of handling these outliers as was demonstrated by the low residual distances. Both strategies yielded very similar results in registration accuracy, but strategy A was faster than strategy B (≥2.0 times). CONCLUSIONS: An accurate CT∕MR vessel-guided nonrigid registration for largely deformed livers was developed, tested, and validated. The method, combining vessel segmentation and point matching, was robust against differences in the segmented vessels. The authors conclude that nonrigid registration is required for accurate alignment of abdominal-compressed and uncompressed liver anatomy. Alignment of breath-hold MR and abdominal-compressed CT images can be used to improve tumor localization for liver SBRT.

Accurate assessment of a Dutch practical robustness evaluation protocol in clinical PT with pencil beam scanning for neurological tumors.

BACKGROUND AND PURPOSE: Scenario-based robust optimization and evaluation are commonly used in proton therapy (PT) with pencil beam scanning (PBS) to ensure adequate dose to the clinical target volume (CTV). However, a statistically accurate assessment of the clinical application of this approach is lacking. In this study, we assess target dose in a clinical cohort of neuro-oncological patients, planned according to the DUPROTON robustness evaluation consensus, using polynomial chaos expansion (PCE). MATERIALS AND METHODS: A cohort of the first 27 neuro-oncological patients treated at HollandPTC was used, including realistic error distributions derived from geometrical and stopping-power prediction (SPP) errors. After validating the model, PCE-based robustness evaluations were performed by simulating 100.000 complete fractionated treatments per patient to obtain accurate statistics on clinically relevant dosimetric parameters and population-dose histograms. RESULTS: Treatment plans that were robust according to clinical protocol and treatment plansin which robustness was sacrificed are easily identified. For robust treatment plans on average, a CTV dose of 3 percentage points (p.p.) more than prescribed was realized (range +2.7 p.p. to +3.5 p.p.) for 98% of the sampled fractionated treatments. For the entire patient cohort on average, a CTV dose of 0.1 p.p. less than prescribed was achieved (range -2.4 p.p. to +0.5 p.p.). For the 6 treatment plans in which robustness was clinically sacrificed, normalized CTV doses of 0.98, 0.94(7)1, 0.94, 0.91, 0.90 and 0.89 were realized. The first of these was clinically borderline non-robust. CONCLUSION: The clinical robustness evaluation protocol is safe in terms of CTV dose as all plans that fulfilled the clinical robustness criteria were also robust in the PCE evaluation. Moreover, for plans that were non-robust in the PCE-based evaluation, CTV dose was also lower than prescribed in the clinical evaluation.

Local Control After Stereotactic Body Radiation Therapy for Liver Tumors.

PURPOSE: To quantitatively evaluate published experiences with hepatic stereotactic body radiation therapy (SBRT), to determine local control rates after treatment of primary and metastatic liver tumors and to examine whether outcomes are affected by SBRT dosing regimen. METHODS AND MATERIALS: We identified published articles that reported local control rates after SBRT for primary or metastatic liver tumors. Biologically effective doses (BEDs) were calculated for each dosing regimen using the linear-quadratic equation. We excluded series in which a wide range of BEDs was used. Individual lesion data for local control were extracted from actuarial survival curves, and data were aggregated to form a single dataset. Actuarial local control curves were generated using the Kaplan-Meier method after grouping lesions by disease type and BED (<100 Gy10 vs >100 Gy10). Comparisons were made using log-rank testing. RESULTS: Thirteen articles met all inclusion criteria and formed the dataset for this analysis. The 1-, 2-, and 3-year actuarial local control rates after SBRT for primary liver tumors (n = 431) were 93%, 89%, and 86%, respectively. Lower 1- (90%), 2- (79%), and 3-year (76%) actuarial local control rates were observed for liver metastases (n = 290, log-rank P = .011). Among patients treated with SBRT for primary liver tumors, there was no evidence that local control is influenced by BED within the range of schedules used. For liver metastases, on the other hand, outcomes were significantly better for lesions treated with BEDs exceeding 100 Gy10 (3-year local control 93%) than for those treated with BEDs of ≤100 Gy10 (3-year local control 65%, P < .001). CONCLUSIONS: Stereotactic body radiation therapy for primary liver tumors provides high rates of durable local control, with no clear evidence for a dose-response relationship among commonly utilized schedules. Excellent local control rates are also seen after SBRT for liver metastases when BEDs of >100 Gy10 are utilized.

Radiation Dose-Volume Effects for Liver SBRT.

Stereotactic body radiation therapy (SBRT) has emerged as an effective, noninvasive treatment option for primary liver cancer and metastatic disease occurring in the liver. Although SBRT can be highly effective for establishing local control in hepatic malignancies, a tradeoff exists between tumor control and normal tissue complications. The objective of the present study was to review the normal tissue dose-volume effects for SBRT-induced liver and gastrointestinal toxicities and derive normal tissue complication probability 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.

The Dutch-Belgian Registry of Stereotactic Body Radiation Therapy for Liver Metastases: Clinical Outcomes of 515 Patients and 668 Metastases.

PURPOSE: Although various studies have reported that stereotactic body radiation therapy (SBRT) for liver metastases has high local control rates and relatively low toxicity, most series included a small number of patients. We aimed to validate these outcomes in a large multi-institution patient cohort treated in accordance with a common protocol. METHODS AND MATERIALS: A shared web-based registry of patients with liver metastases treated with SBRT was developed by 13 centers (12 in the Netherlands and 1 in Belgium). All the centers had previously agreed on the items to be collected, the fractionation schemes, and the organs-at-risk constraints to be applied. Follow-up was performed at the discretion of the centers. Patient, tumor, and treatment characteristics were entered in the registry. Only liver metastases treated individually as independent targets and with at least 1 radiologic follow-up examination were considered for local control analysis. Toxicity of grade 3 or greater was scored according to the Common Terminology Criteria of Adverse Events (v4.03). RESULTS: Between January 1, 2013, and July 31, 2019, a total of 515 patients were entered in the web-based registry. The median age was 71 years. In total, 668 liver metastases were registered, and 447 were included for local control analysis. The most common primary tumor origin was colorectal cancer (80.3%), followed by lung cancer (8.9%) and breast cancer (4%). The most-used fractionation scheme was 3x18-20 Gy (36.0%), followed by 8x7.5 Gy (31.8%), 5x11-12 Gy (25.5%), and 12x5 Gy (6.7%). The median follow-up time was 1.1 years for local control and 2.3 years for survival. Actuarial 1-year local control was 87%; 1-year overall survival was 84%. Toxicity of grade 3 or greater was found in 3.9% of the patients. CONCLUSIONS: This multi-institutional study confirms the high rates of local control and limited toxicity in a large patient cohort. Stereotactic body radiation therapy should be considered a valuable part of the multidisciplinary approach to treating liver metastases.

Stereotactic Body Radiation Therapy after Chemotherapy for Unresectable Perihilar Cholangiocarcinoma: The STRONG Trial, a Phase I Safety and Feasibility Study.

BACKGROUND: In unresectable pCCA, the standard of care is palliative chemotherapy. We investigated the feasibility and safety of adding stereotactic body radiation therapy (SBRT) after chemotherapy. METHODS: Patients with unresectable pCCA, stage T1-T4N0-N1M0, ECOG 0-1, having finished 6-8 cycles of cisplatin and gemcitabine without disease progression were eligible. SBRT was planned in 15 fractions of 3.0-4.5 Gy. The primary endpoints were feasibility (defined as completing SBRT as planned) and toxicity, evaluated within 3 months after SBRT (CTCAE v4.03). A conventional "3 + 3" design was used, corresponding to a sample size of 6 patients. Dose-limiting toxicity (DLT) was defined as grade ≥ 4 hepatobiliary or grade ≥ 3 gastrointestinal toxicity. The secondary endpoints, measured from the start of radiotherapy, were local control, progression-free survival, overall survival, and quality of life (QoL). ClinicalTrials.gov identifier: NCT03307538. RESULTS: Six patients were enrolled between November 2017 and March 2020. SBRT was delivered as planned. All patients were treated with 60Gy (15 × 4.0Gy). No SBRT-related DLT was observed. The most common grade ≥ 3 toxicity was cholangitis (n = 5). The median follow-up was 14 months. The 12-month local control rate was 80%. We observed no substantial changes in QoL. CONCLUSION: In patients with unresectable pCCA with stable disease after palliative chemotherapy, adding SBRT is feasible and safe. The observed local control merits an additional evaluation of effectiveness.

Proton beam therapy for liver cancers.

Proton beam therapy (PBT) delivers less dose to nearby normal organs compared to X-ray therapy (XRT), which is particularly relevant for treating liver cancers given that both mean and low liver dose are among the most significant predictors of radiation induced liver disease (RILD). High-dose PBT has been shown to achieve excellent long-term tumor control with minimal toxicity in hepatocellular carcinoma (HCC) patients. Increasing data support ablative PBT for patients with unresectable cholangiocarcinoma or liver metastases, especially those with larger tumors not suitable for XRT.

Defining oligometastatic disease from a radiation oncology perspective: An ESTRO-ASTRO consensus document.

BACKGROUND: Recognizing the rapidly increasing interest and evidence in using metastasis-directed radiotherapy (MDRT) for oligometastatic disease (OMD), ESTRO and ASTRO convened a committee to establish consensus regarding definitions of OMD and define gaps in current evidence. METHODS: A systematic literature review focused on curative intent MDRT was performed in Medline, Embase and Cochrane. Subsequent consensus opinion, using a Delphi process, highlighted the current state of evidence and the limitations in the available literature. RESULTS: Available evidence regarding the use of MDRT for OMD mostly derives from retrospective, single-centre series, with significant heterogeneity in patient inclusion criteria, definition of OMD, and outcomes reported. Consensus was reached that OMD is largely independent of primary tumour, metastatic location and the presence or length of a disease-free interval, supporting both synchronous and metachronous OMD. In the absence of clinical data supporting a maximum number of metastases and organs to define OMD, and of validated molecular biomarkers, consensus supported the ability to deliver safe and clinically meaningful radiotherapy with curative intent to all metastatic sites as a minimum requirement for defining OMD in the context of radiotherapy. Systemic therapy induced OMD was identified as a distinct state of OMD. High-resolution imaging to assess and confirm OMD is crucial, including brain imaging when indicated. Minimum common endpoints such as progression-free and overall survival, local control, toxicity and quality-of-life should be reported; uncommon endpoints as deferral of systemic therapy and cost were endorsed. CONCLUSION: While significant heterogeneity exists in the current OMD definitions in the literature, consensus was reached on multiple key questions. Based on available data, OMD can to date be defined as 1-5 metastatic lesions, a controlled primary tumor being optional, but where all metastatic sites must be safely treatable. Consistent definitions and reporting are warranted and encouraged in ongoing trials and reports generating further evidence to optimize patient benefits.

Individualized automated planning for dose bath reduction in robotic radiosurgery for benign tumors.

OBJECT: To explore the use of automated planning in robotic radiosurgery of benign vestibular schwannoma (VS) tumors for dose reduction outside the planning target volume (PTV) to potentially reduce risk of secondary tumor induction. METHODS: A system for automated planning (AUTOplans) for VS patients was set up. The goal of AUTO- planning was to reduce the dose bath, including the occurrence of high dose spikes leaking from the PTV into normal tissues, without worsening PTV coverage, OAR doses, or treatment time. For 20 VS patients treated with 1x12 Gy, the AUTOplan was compared with the plan generated with conventional, manual trial-and-error planning (MANplan). RESULTS: With equal PTV coverage, AUTOplans showed clinically negligible differences with MANplans in OAR sparing (largest mean difference for all OARs: ΔD2% = 0.2 Gy). AUTOplan dose distributions were more compact: mean/maximum reductions of 23.6/53.8% and 9.6/28.5% in patient volumes receiving more than 1 or 6 Gy, respectively (p<0.001). AUTOplans also showed smaller dose spikes with mean/maximum reductions of 22.8/37.2% and 14.2/40.4% in D2% for shells at 1 and 7 cm distance from the PTV, respectively (p<0.001). CONCLUSION: Automated planning for benign VS tumors highly outperformed manual planning with respect to the dose bath outside the PTV, without deteriorating PTV coverage or OAR sparing, or significantly increasing treatment time.

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.

Consensus Report From the Miami Liver Proton Therapy Conference.

An international group of 22 liver cancer experts from 18 institutions met in Miami, Florida to discuss the optimal utilization of proton beam therapy (PBT) for primary and metastatic liver cancer. There was consensus that PBT may be preferred for liver cancer patients expected to have a suboptimal therapeutic ratio from XRT, but that PBT should not be preferred for all patients. Various clinical scenarios demonstrating appropriateness of PBT vs. XRT were reviewed.

Reduction of respiratory liver tumor motion by abdominal compression in stereotactic body frame, analyzed by tracking fiducial markers implanted in liver.

PURPOSE: To investigate in a three-dimensional framework the effectiveness and reproducibility of reducing the respiratory motion of liver tumors using abdominal compression in a stereotactic body frame. METHODS AND MATERIALS: A total of 12 patients with liver tumors, who were treated with stereotactic body radiotherapy, were included in this study. These patients had three gold fiducial markers implanted in the healthy liver tissue surrounding the tumor. Fluoroscopic videos were acquired on the planning day and before each treatment fraction to visualize the motion of the fiducial markers during free breathing and varying levels of abdominal compression. Software was developed to track the fiducial markers and measure their excursions. RESULTS: Abdominal compression reduced the patient group median excursion by 62% in the craniocaudal and 38% in the anteroposterior direction with respect to the median free-breathing excursions. In the left-right direction, the median excursion increased 15% (maximal increase 1.6 mm). The median residual excursion was 4.1 mm in the craniocaudal, 2.4 mm in the anteroposterior, and 1.8 mm in the left-right direction. The mean excursions were reduced by compression to <5 mm in all patients and all directions, with two exceptions (craniocaudal excursion reduction of 20.5 mm to 7.4 mm and of 21.1 mm to 5.9 mm). The residual excursions reproduced well during the treatment course, and the craniocaudal excursions measured on the treatment days were never significantly (alpha = 0.05) greater than on the planning days. Fine tuning the compression did not considerably change the excursion on the treatment days. CONCLUSIONS: Abdominal compression effectively reduced liver tumor motion, yielding small and reproducible excursions in three dimensions. The compression level established at planning could have been safely used on the treatment days.