Dummy run for planning of isotoxic dose-escalated radiation therapy for glioblastoma used in the PRIDE trial (NOA-28; ARO-2024-01; AG-NRO-06).

Background: The PRIDE trial (NOA-28; ARO-2024-01; AG-NRO-06; NCT05871021) is designed to determine whether a dose escalation with 75.0 Gy in 30 fractions can enhance the median overall survival (OS) in patients with methylguanine methyltransferase (MGMT) promotor unmethylated glioblastoma compared to historical median OS rates, while being isotoxic to historical cohorts through the addition of concurrent bevacizumab (BEV). To ensure protocol-compliant irradiation planning with all study centers, a dummy run was planned and the plan quality was evaluated. Methods: A suitable patient case was selected and the computed tomography (CT), magnetic resonance imaging (MRI) and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) contours were made available. Participants at the various intended study sites performed radiation planning according to the PRIDE clinical trial protocol. The treatment plans and dose grids were uploaded as Digital Imaging and Communications in Medicine (DICOM) files to a cloud-based platform. Plan quality and protocol adherence were analyzed using a standardized checklist, scorecards and indices such as Dice Score (DSC) and Hausdorff Distance (HD). Results: Median DSC was 0.89, 0.90, 0.88 for PTV60, PTV60ex (planning target volume receiving 60.0 Gy for the standard and the experimental plan, respectively) and PTV75 (PTV receiving 75.0 Gy in the experimental plan), respectively. Median HD values were 17.0 mm, 13.9 mm and 12.1 mm, respectively. These differences were also evident in the volumes: The PTV60 had a volume range of 219.1-391.3 cc (median: 261.9 cc) for the standard plans, while the PTV75 volumes for the experimental plans ranged from 71.5-142.7 cc (median: 92.3 cc). The structures with the largest deviations in Dice score were the pituitary gland (median 0.37, range 0.00-0.69) and the right lacrimal gland (median 0.59, range 0.42-0.78). Conclusions: The deviations revealed the necessity of systematic trainings with appropriate feedback before the start of clinical trials in radiation oncology and the constant monitoring of protocol compliance throw-out the study. Trial registration: NCT05871021.

Stereotactic body radiotherapy with volumetric intensity-modulated arc therapy and flattening filter-free beams: dosimetric considerations.

PURPOSE: The present study comparatively evaluates the impact of energy-matched flattening filter-free (FFF) photon beams with different energy levels on the physical-dosimetric quality of lung and liver stereotactic body radiotherapy (SBRT) treatment plans. METHODS: For this purpose, 54 different lung and liver lesions from 44 patients who had already received SBRT combined with volumetric modulated arc therapy (VMAT) were included in this retrospective planning study. Planning computed tomography scans already available were used for the renewed planning with 6 MV, 6 MV-FFF, 10 MV, and 10 MV-FFF under constant planning objectives. The treatment delivery data, dosimetric distributions, and dose-volume histograms as well as parameters such as the conformity index and gradient indices were the basis for the evaluation and comparison of treatment plans. RESULTS: A significant reduction of beam-on time (BOT) was achieved due to the high dose rates of FFF beams. In addition, we showed that for FFF beams compared to flattened beams of the same energy level, smaller planning target volumes (PTV) require fewer monitor units (MU) than larger PTVs. An equal to slightly superior target volume coverage and sparing of healthy tissue as well as organs at risk in both lung and liver lesions were found. Significant differences were seen mainly in the medium to lower dose range. CONCLUSION: We found that FFF beams together with VMAT represent an excellent combination for SBRT of lung or liver lesions with shortest BOT for 10 MV-FFF but significant dose savings for 6 MV-FFF in lung lesions.

Robotic stereotactic body radiotherapy for localized prostate cancer: final analysis of the German HYPOSTAT trial.

PURPOSE: We report results of the first German prospective multicenter single-arm phase II trial (ARO 2013-06; NCT02635256) of hypofractionated robotic stereotactic body radiotherapy (SBRT) for patients with localized prostate cancer (HYPOSTAT). METHODS: Patients eligible for the HYPOSTAT study had localized prostate cancer (cT1­3 cN0 cM0), Gleason score ≤ 7, prostate-specific antigen (PSA) ≤ 15 ng/ml, prostate volume ≤ 80 cm3, and an International Prostate Symptom Score (IPSS) ≤ 12. Initially, inclusion was limited to patients ≥ 75 years or patients 70-74 years with additional risk factors. The trial protocol was later amended to allow for enrolment of patients aged ≥ 60 years. The treatment consisted of 35 Gy delivered in 5 fractions to the prostate and for intermediate- or high-risk patients, also to the proximal seminal vesicles using the CyberKnife system (Accuray Inc., Sunnyvale, CA, USA). Primary endpoint was the rate of treatment-related gastrointestinal or genitourinary grade ≥ 2 toxicity based on the RTOG scale 12-15 months after treatment. Secondary endpoints were acute toxicity, late toxicity, urinary function, quality of life, and PSA response. RESULTS: From July 2016 through December 2018, 85 eligible patients were enrolled and received treatment, of whom 83 could be evaluated regarding the primary endpoint. Patients mostly had intermediate-risk disease with a median PSA value of 7.97 ng/ml and Gleason score of 7a and 7b in 43.5% and 25.9% of patients, respectively. At the final follow-up 12-15 months after treatment, no patient suffered from treatment-related gastrointestinal or genitourinary grade ≥ 2 toxicity. Acute toxicity was mostly mild, with three grade 3 events, and the cumulative rate of grade ≥ 2 genitourinary toxicity was 8.4% (95% CI 4.1-16.4%). There were no major changes in urinary function or quality of life. The median PSA value dropped to 1.18 ng/ml 12-15 months after treatment. There was one patient who developed distant metastases. CONCLUSION: Robotic SBRT with 35 Gy in 5 fractions was associated with a favorable short-term toxicity profile. Recruitment for the HYPOSTAT­2 trial (ARO-2018­4; NCT03795337), which further analyses the late toxicity of this regimen with a planned sample size of 500 patients, is ongoing.

Maintenance of Energy Homeostasis during Calorically Restricted Ketogenic Diet and Fasting-MR-Spectroscopic Insights from the ERGO2 Trial.

Background: The ERGO2 (Ernaehrungsumstellung bei Patienten mit Rezidiv eines Glioblastoms) MR-spectroscopic imaging (MRSI) subtrial investigated metabolism in patients randomized to calorically restricted ketogenic diet/intermittent fasting (crKD-IF) versus standard diet (SD) in addition to re-irradiation (RT) for recurrent malignant glioma. Intracerebral concentrations of ketone bodies (KB), intracellular pH (pHi), and adenosine triphosphate (ATP) were non-invasively determined. Methods: 50 patients were randomized (1:1): Group A keeping a crKD-IF for nine days, and Group B a SD. RT was performed on day 4-8. Twenty-three patients received an extended MRSI-protocol (1H decoupled 31P MRSI with 3D chemical shift imaging (CSI) and 2D 1H point-resolved spectroscopy (PRESS)) at a 3T scanner at baseline and on day 6. Voxels were selected from the area of recurrent tumor and contralateral hemisphere. Spectra were analyzed with LCModel, adding simulated signals of 3-hydroxybutyrate (ßOHB), acetone (Acn) and acetoacetate (AcAc) to the standard basis set. Results: Acn was the only reliably MRSI-detectable KB within tumor tissue and/or normal appearing white matter (NAWM). It was detected in 4/11 patients in Group A and in 0/8 patients in Group B. MRSI results showed no significant depletion of ATP in tumor tissue of patients at day 6 during crKD-IF, even though there were a significant difference in ketone serum levels between Group A and B at day 6 and a decline in fasting glucose in Group A from baseline to day 6. The tumor specific alkaline pHi was maintained. Conclusions: Our metabolic findings suggest that tumor cells maintain energy homeostasis even with reduced serum glucose levels and may generate additional ATP through other sources.

ERGO2: A Prospective, Randomized Trial of Calorie-Restricted Ketogenic Diet and Fasting in Addition to Reirradiation for Malignant Glioma.

PURPOSE: ERGO2 is the first randomized clinical trial on a calorically restricted ketogenic diet (KD) and intermittent fasting (KD-IF) in addition to reirradiation for recurrent malignant gliomas. METHODS AND MATERIALS: Fifty patients were randomized 1:1 to reirradiation combined with either a calorically unrestricted diet or KD-IF. The KD-IF schedule included 3 days of KD (21-23 kcal/kg/d), followed by 3 days of fasting and again 3 days of KD. Primary endpoint was progression-free survival (PFS) at 6 months (PFS6). Secondary endpoints were PFS, local PFS, overall survival (OS), frequency of epileptic seizures, rate of ketosis and quality of life. RESULTS: Four patients quit the trial before treatment and 3 patients stopped KD-IF prematurely. Of the 20 patients who completed KD-IF, 17 patients developed ketosis at day 6 and glucose levels declined significantly. KD-IF was well-tolerated with a modest weight loss of -2.1 ± 1.8 kg. No severe adverse events attributable to the diet occurred. PFS6 was not significantly different between the 2 groups (KD-IF: 20%; calorically unrestricted diet: 16%). Similarly, no difference in PFS, local PFS6, or OS was observable. Explorative analysis revealed that patients in the KD-IF group who had a glucose level of less than the median (83.5 mg/dL) on day 6 had significantly longer PFS and OS compared with those above the median (P < .05). CONCLUSIONS: KD-IF is feasible and effective in inducing ketosis in heavily pretreated patients with recurrent glioma. However, the short schedule reported here failed to increase the efficacy of reirradiation. CLINICALTRIALS. GOV NUMBER: NCT01754350.

Long-term Follow-up and Patterns of Recurrence of Patients With Oligometastatic NSCLC Treated With Pulmonary SBRT.

INTRODUCTION: This multicenter study aims to analyze outcome as well as early versus late patterns of recurrence following pulmonary stereotactic body radiotherapy (SBRT) for patients with oligometastatic non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: This analysis included 301 patients with oligometastatic NSCLC treated with SBRT for 336 lung metastases. Although treatment of the primary tumor consisted of surgical resection, radiochemotherapy, and/or systemic therapy, pulmonary oligometastases were treated with SBRT. RESULTS: The median follow-up time was 16.1 months, resulting in 2-year overall survival (OS), local control (LC), and distant control (DC) of 62.2%, 82.0%, and 45.2%, respectively. Multivariate analysis identified age (P = .019) and histologic subtype (P = .028), as well as number of metastatic organs (P < .001) as independent prognostic factors for OS. LC was superior for patients with favorable histologic subtype (P = .046) and SBRT with a higher biological effective dose at isocenter (P = .037), whereas DC was inferior for patients with metastases in multiple organs (P < .001) and female gender (P = .027). Early (within 24 months) local or distant progression was observed in 15.3% and 36.5% of the patients. After 24 months, the risk of late local failure was low, with 3- and 4-year local failure rates of only 4.0%, and 7.6%. In contrast, patients remained at a high risk of distant progression with 3- and 4-year failure rates of 13.3% and 24.1%, respectively, with no plateau observed. CONCLUSION: SBRT for pulmonary oligometastatic NSCLC resulted in favorable LC and promising OS. The dominant failure pattern is distant with a continuously high risk of disease progression for many years.

Clinical Results of Mean GTV Dose Optimized Robotic-Guided Stereotactic Body Radiation Therapy for Lung Tumors.

INTRODUCTION: We retrospectively evaluated the efficacy and toxicity of gross tumor volume (GTV) mean dose optimized stereotactic body radiation therapy (SBRT) for primary and secondary lung tumors with and without robotic real-time motion compensation. MATERIALS AND METHODS: Between 2011 and 2017, 208 patients were treated with SBRT for 111 primary lung tumors and 163 lung metastases with a median GTV of 8.2 cc (0.3-174.0 cc). Monte Carlo dose optimization was performed prioritizing GTV mean dose at the potential cost of planning target volume (PTV) coverage reduction while adhering to safe normal tissue constraints. The median GTV mean biological effective dose (BED)10 was 162.0 Gy10 (34.2-253.6 Gy10) and the prescribed PTV BED10 ranged 23.6-151.2 Gy10 (median, 100.8 Gy10). Motion compensation was realized through direct tracking (44.9%), fiducial tracking (4.4%), and internal target volume (ITV) concepts with small (≤5 mm, 33.2%) or large (>5 mm, 17.5%) motion. The local control (LC), progression-free survival (PFS), overall survival (OS), and toxicity were analyzed. RESULTS: Median follow-up was 14.5 months (1-72 months). The 2-year actuarial LC, PFS, and OS rates were 93.1, 43.2, and 62.4%, and the median PFS and OS were 18.0 and 39.8 months, respectively. In univariate analysis, prior local irradiation (hazard ratio (HR) 0.18, confidence interval (CI) 0.05-0.63, p = 0.01), GTV/PTV (HR 1.01-1.02, CI 1.01-1.04, p < 0.02), and PTV prescription, mean GTV, and maximum plan BED10 (HR 0.97-0.99, CI 0.96-0.99, p < 0.01) were predictive for LC while the tracking method was not (p = 0.97). For PFS and OS, multivariate analysis showed Karnofsky Index (p < 0.01) and tumor stage (p ≤ 0.02) to be significant factors for outcome prediction. Late radiation pneumonitis or chronic rip fractures grade 1-2 were observed in 5.3% of the patients. Grade ≥3 side effects did not occur. CONCLUSION: Robotic SBRT is a safe and effective treatment for lung tumors. Reducing the PTV prescription and keeping high GTV mean doses allowed the reduction of toxicity while maintaining high local tumor control. The use of real-time motion compensation is strongly advised, however, well-performed ITV motion compensation may be used alternatively when direct tracking is not feasible.

Treatment planning for spinal radiosurgery : A competitive multiplatform benchmark challenge.

PURPOSE: To investigate the quality of treatment plans of spinal radiosurgery derived from different planning and delivery systems. The comparisons include robotic delivery and intensity modulated arc therapy (IMAT) approaches. Multiple centers with equal systems were used to reduce a bias based on individual's planning abilities. The study used a series of three complex spine lesions to maximize the difference in plan quality among the various approaches. METHODS: Internationally recognized experts in the field of treatment planning and spinal radiosurgery from 12 centers with various treatment planning systems participated. For a complex spinal lesion, the results were compared against a previously published benchmark plan derived for CyberKnife radiosurgery (CKRS) using circular cones only. For two additional cases, one with multiple small lesions infiltrating three vertebrae and a single vertebra lesion treated with integrated boost, the results were compared against a benchmark plan generated using a best practice guideline for CKRS. All plans were rated based on a previously established ranking system. RESULTS: All 12 centers could reach equality (n = 4) or outperform (n = 8) the benchmark plan. For the multiple lesions and the single vertebra lesion plan only 5 and 3 of the 12 centers, respectively, reached equality or outperformed the best practice benchmark plan. However, the absolute differences in target and critical structure dosimetry were small and strongly planner-dependent rather than system-dependent. Overall, gantry-based IMAT with simple planning techniques (two coplanar arcs) produced faster treatments and significantly outperformed static gantry intensity modulated radiation therapy (IMRT) and multileaf collimator (MLC) or non-MLC CKRS treatment plan quality regardless of the system (mean rank out of 4 was 1.2 vs. 3.1, p = 0.002). CONCLUSIONS: High plan quality for complex spinal radiosurgery was achieved among all systems and all participating centers in this planning challenge. This study concludes that simple IMAT techniques can generate significantly better plan quality compared to previous established CKRS benchmarks.

Breathing-motion-compensated robotic guided stereotactic body radiation therapy : Patterns of failure analysis.

PURPOSE: We retrospectively evaluated the patterns of failure for robotic guided real-time breathing-motion-compensated (BMC) stereotactic body radiation therapy (SBRT) in the treatment of tumors in moving organs. PATIENTS AND METHODS: Between 2011 and 2016, a total of 198 patients with 280 lung, liver, and abdominal tumors were treated with BMC-SBRT. The median gross tumor volume (GTV) was 12.3 cc (0.1-372.0 cc). Medians of mean GTV BEDα/ß =10 Gy (BED = biological effective dose) was 148.5 Gy10 (31.5-233.3 Gy10) and prescribed planning target volume (PTV) BEDα/ß =10 Gy was 89.7 Gy10 (28.8-151.2 Gy10), respectively. We analyzed overall survival (OS) and local control (LC) based on various factors, including BEDs with α/ß ratios of 15 Gy (lung metastases), 21 Gy (primary lung tumors), and 27 Gy (liver metastases). RESULTS: Median follow-up was 10.4 months (2.0-59.0 months). The 2­year actuarial LC was 100 and 86.4% for primary early and advanced stage lung tumors, respectively, 100% for lung metastases, 82.2% for liver metastases, and 90% for extrapulmonary extrahepatic metastases. The 2­year OS rate was 47.9% for all patients. In uni- and multivariate analysis, comparatively lower PTV prescription dose (equivalence of 3 × 12-13 Gy) and higher average GTV dose (equivalence of 3 × 18 Gy) to current practice were significantly associated with LC. For OS, Karnofsky performance score (100%), gender (female), and SBRT without simultaneous chemotherapy were significant prognostic factors. Grade 3 side effects were rare (0.5%). CONCLUSIONS: Robotic guided BMC-SBRT can be considered a safe and effective treatment for solid tumors in moving organs. To reach sufficient local control rates, high average GTV doses are necessary. Further prospective studies are warranted to evaluate these points.

Hypo-fractionated SBRT for localized prostate cancer: a German bi-center single treatment group feasibility trial.

BACKGROUND: For prostate cancer treatment, treatment options with minimal side effects are desired. External beam radiation therapy (EBRT) is non-invasive, standard of care and delivered in either conventional fractionation over 8 weeks or with moderate hypo-fractionation over about 5 weeks. Recent advances in radiotherapy technology have made extreme hypo-fractionated stereotactic body radiation therapy (SBRT) of prostate cancer feasible, which has not yet been introduced as a standard treatment method in Germany. Initial results from other countries are promising, but long-term results are not yet available. The aim of this study is to investigate feasibility and effectiveness of SBRT for prostate cancer in Germany. METHODS/DESIGN: This German bi-center single group trial (HYPOSTAT) is designed to evaluate feasibility and effectiveness, as measured by toxicity and PSA-response, respectively, of an extreme hypo-fractionated SBRT regimen with five fractions of 7 Gy in treatment of localized low and intermediate risk prostate cancer. The target volume includes the prostate with or without the base of seminal vesicles depending on risk stratification and uncertainty margins that are kept at 3-5 mm. SBRT treatment is delivered with the robotic CyberKnife system, which was recently introduced in Germany. Acute and late toxicity after one year will be evaluated according to Common Terminology Criteria for Adverse Events (CTCAE v. 4.0), Radiation Therapy Oncology Group (RTOG) and International Prostate Symptom Score (IPSS) Scores. The quality of life will be assessed before and after treatment with the EORTC QLQ C30 questionnaire. Hypothesizing that the proportion of patients with grade 2 side effects or higher is less or equal than 2.8%, thus markedly lower than the standard EBRT percentage (17.5%), the recruitment target is 85 patients. DISCUSSION: The HYPOSTAT trial aims at demonstrating short term feasibility of extreme hypo-fractioned SBRT for the treatment of prostate cancer and might be used as the pilot study for a multi-center multi-platform or for randomized-controlled trials comparing conventional radiotherapy with SBRT for localized prostate cancer in the future. The study concept of patient enrollment, follow up and evaluation by multiple public university clinics and actual patient treatment in dedicated private radiosurgery practices with high-tech radiation equipment is unique for clinical trials. STUDY STATUS: The study is ongoing and currently recruiting patients. TRIAL REGISTRATION: Registration number: NCT02635256 ( clinicaltrials.gov ). Registered 8 December 2015.

Radiotherapy for aneurysmal bone cysts : A rare indication.

BACKGROUND: Aneurysmal bone cysts (ABC) are rapidly growing benign osseous lesions composed of blood-filled channels separated by fibrous septa. Since the value of external beam radiotherapy (EBRT) for ABC has not been well defined, the German Cooperative Group on Radiotherapy for Benign Diseases performed the national register study described herein. PATIENTS AND METHODS: Five German institutions collected data regarding clinical features, treatment concepts, and outcome for patients with ABC who had been referred for local EBRT over the past 30 years. RESULTS: Between 1990 and 2015, 10 patients with ABC were irradiated (5 female/5 male). Median age was 23 years (range 14-40 years). Involved sites were: spine (n = 3), sacrum/pelvis (n = 2), shoulder/scapula (n = 2), humerus (n = 1), femur (n = 1), and radius (n = 1). The median EBRT total and fractional doses were 28 Gy (range 5-40 Gy) and 2 Gy (range 1-2 Gy), respectively. Median follow-up was 65 months (range 12-358 months). Persistent pain relief was achieved for all patients. However, long-term follow-up response data were only available for 7/10 patients. All 7 patients exhibited a radiological response and experienced no recurrent disease activity or pain during follow-up. Acute and late radiogenic toxicities ≥ grade 3 and secondary malignancies were also not observed. CONCLUSION: Primary or adjuvant EBRT seems to be an effective and safe treatment option for persistent or recurrent ABC. Fractionated doses below 30 Gy may be recommended.

Influence of Institutional Experience and Technological Advances on Outcome of Stereotactic Body Radiation Therapy for Oligometastatic Lung Disease.

PURPOSE: Many technological and methodical advances have made stereotactic body radiotherapy (SBRT) more accurate and more efficient during the last years. This study aims to investigate whether experience in SBRT and technological innovations also translated into improved local control (LC) and overall survival (OS). METHODS AND MATERIALS: A database of 700 patients treated with SBRT for lung metastases in 20 German centers between 1997 and 2014 was used for analysis. It was the aim of this study to investigate the impact of fluorodeoxyglucose positron-emission tomography (FDG-PET) staging, biopsy confirmation, image guidance, immobilization, and dose calculation algorithm, as well as the influence of SBRT experience, on LC and OS. RESULTS: Median follow-up time was 14.3 months (range, 0-131.9 months), with 2-year LC and OS of 81.2% (95% confidence interval [CI] 75.8%-85.7%) and 54.4% (95% CI 50.2%-59.0%), respectively. In multivariate analysis, all treatment technologies except FDG-PET staging did not significantly influence outcome. Patients who received pre-SBRT FDG-PET staging showed superior 1- and 2-year OS of 82.7% (95% CI 77.4%-88.6%) and 64.8% (95% CI 57.5%-73.3%), compared with patients without FDG-PET staging resulting in 1- and 2-year OS rates of 72.8% (95% CI 67.4%-78.8%) and 52.6% (95% CI 46.0%-60.4%), respectively (P=.012). Experience with SBRT was identified as the main prognostic factor for LC: institutions with higher SBRT experience (patients treated with SBRT within the last 2 years of the inclusion period) showed superior LC compared with less-experienced centers (P≤.001). Experience with SBRT within the last 2 years was independent from known prognostic factors for LC. CONCLUSION: Investigated technological and methodical advancements other than FDG-PET staging before SBRT did not significantly improve outcome in SBRT for pulmonary metastases. In contrast, LC was superior with increasing SBRT experience of the individual center.

Inverse treatment planning for spinal robotic radiosurgery: an international multi-institutional benchmark trial.

Stereotactic radiosurgery (SRS) is the accurate, conformal delivery of high-dose radiation to well-defined targets while minimizing normal structure doses via steep dose gradients. While inverse treatment planning (ITP) with computerized optimization algorithms are routine, many aspects of the planning process remain user-dependent. We performed an international, multi-institutional benchmark trial to study planning variability and to analyze preferable ITP practice for spinal robotic radiosurgery. 10 SRS treatment plans were generated for a complex-shaped spinal metastasis with 21 Gy in 3 fractions and tight constraints for spinal cord (V14Gy < 2 cc, V18Gy < 0.1 cc) and target (coverage > 95%). The resulting plans were rated on a scale from 1 to 4 (excellent-poor) in five categories (constraint compliance, optimization goals, low-dose regions, ITP complexity, and clinical acceptability) by a blinded review panel. Additionally, the plans were mathemati-cally rated based on plan indices (critical structure and target doses, conformity, monitor units, normal tissue complication probability, and treatment time) and compared to the human rankings. The treatment plans and the reviewers' rankings varied substantially among the participating centers. The average mean overall rank was 2.4 (1.2-4.0) and 8/10 plans were rated excellent in at least one category by at least one reviewer. The mathematical rankings agreed with the mean overall human rankings in 9/10 cases pointing toward the possibility for sole mathematical plan quality comparison. The final rankings revealed that a plan with a well-balanced trade-off among all planning objectives was preferred for treatment by most par-ticipants, reviewers, and the mathematical ranking system. Furthermore, this plan was generated with simple planning techniques. Our multi-institutional planning study found wide variability in ITP approaches for spinal robotic radiosurgery. The participants', reviewers', and mathematical match on preferable treatment plans and ITP techniques indicate that agreement on treatment planning and plan quality can be reached for spinal robotic radiosurgery.

Stereotactic body radiotherapy (SBRT) for medically inoperable lung metastases-A pooled analysis of the German working group "stereotactic radiotherapy".

OBJECTIVES: The current literature on stereotactic body radiotherapy (SBRT) for oligometastatic disease is characterized by small patient cohorts with heterogeneous primary tumors, metastases location and dose regimes. Hence, this study established a multi-institutional database of 700 patients treated with SBRT for pulmonary metastases to identify prognostic factors influencing survival and local control. MATERIALS AND METHODS: All German radiotherapy departments were contacted and invited to participate in this analysis. A total number of 700 patients with medically inoperable lung metastases treated with SBRT in 20 centers between 1997 and 2014 were included in a database. Primary and metastatic tumor characteristics, treatment characteristics and follow-up data including survival, local control, distant metastases, and toxicity were evaluated. Lung metastases were treated with median PTV-encompassing single doses of 12.5Gy (range 3.0-33.0Gy) in a median number of 3 fractions (range 1-13). RESULTS: After a median follow-up time of 14.3 months, 2-year local control (LC) and overall survival (OS) were 81.2% and 54.4%, respectively. In multivariate analysis, OS was most significantly influenced by pretreatment performance status, maximum metastasis diameter, primary tumor histology, time interval between primary tumor diagnosis and SBRT treatment and number of metastases. For LC, independent prognostic factors were pretreatment performance status, biological effective dose (BED) at PTV isocenter (BEDISO) and single fraction (PTV-encompassing) dose in multivariate analysis. Radiation-induced pneumonitis grade 2 or higher was observed in 6.5% of patients. The only factor significantly influencing toxicity was BEDISO (p=0.006). CONCLUSION: SBRT for medically inoperable patients with pulmonary metastases achieved excellent local control and promising overall survival. Important prognostic factors were identified for selecting patients who might benefit most from this therapy approach.

Clinical results of mean GTV dose optimized robotic guided SBRT for liver metastases.

BACKGROUND: We retrospectively evaluated the efficacy and toxicity of gross tumor volume (GTV) mean-dose-optimized and real-time motion-compensated robotic stereotactic body radiation therapy (SBRT) in the treatment of liver metastases. METHODS: Between March 2011 and July 2015, 52 patients were treated with SBRT for a total of 91 liver metastases (one to four metastases per patient) with a median GTV volume of 12 cc (min 1 cc, max 372 cc). The optimization of mean GTV dose was prioritized during treatment planning at the potential cost of planning target volume (PTV) coverage reduction while adhering to safe normal tissue constraints. The delivered median GTV biological effective dose (BED10) was 142.1 Gy10 (range, 60.2 Gy10 -165.3 Gy10) and the prescribed PTV BED10 ranged from 40.6 Gy10 to 112.5 Gy10 (median, 86.1 Gy10). We analyzed local control (LC), progression-free interval (PFI), overall survival (OS), and toxicity. RESULTS: Median follow-up was 17 months (range, 2-49 months). The 2-year actuarial LC, PFI, and OS rates were 82.1, 17.7, and 45.0 %, and the median PFI and OS were 9 and 23 months, respectively. In univariate analysis histology (p < 0.001), PTV prescription BED10 (HR 0.95, CI 0.91-0.98, p = 0.002) and GTV mean BED10 (HR 0.975, CI 0.954-0.996, p = 0.011) were predictive for LC. Multivariate analysis showed that only extrahepatic disease status at time of treatment was a significant factor (p = 0.033 and p = 0.009, respectively) for PFI and OS. Acute nausea or fatigue grade 1 was observed in 24.1 % of the patients and only 1 patient (1.9 %) had a side effect of grade ≥ 2. CONCLUSIONS: Robotic real-time motion-compensated SBRT is a safe and effective treatment for one to four liver metastases. Reducing the PTV prescription dose and keeping a high mean GTV dose allowed the reduction of toxicity while maintaining a high local control probability for the treated lesions.

Bayesian Cure Rate Modeling of Local Tumor Control: Evaluation in Stereotactic Body Radiation Therapy for Pulmonary Metastases.

PURPOSE: Most radiobiological models for prediction of tumor control probability (TCP) do not account for the fact that many events could remain unobserved because of censoring. We therefore evaluated a set of TCP models that take into account this censoring. METHODS AND MATERIALS: We applied 2 fundamental Bayesian cure rate models to a sample of 770 pulmonary metastasis treated with stereotactic body radiation therapy at German, Austrian, and Swiss institutions: (1) the model developed by Chen, Ibrahim and Sinha (the CIS99 model); and (2) a mixture model similar to the classic model of Berkson and Gage (the BG model). In the CIS99 model the number of clonogens surviving the radiation treatment follows a Poisson distribution, whereas in the BG model only 1 dominant recurrence-competent tissue mass may remain. The dose delivered to the isocenter, tumor size and location, sex, age, and pretreatment chemotherapy were used as covariates for regression. RESULTS: Mean follow-up time was 15.5 months (range: 0.1-125). Tumor recurrence occurred in 11.6% of the metastases. Delivered dose, female sex, peripheral tumor location and having received no chemotherapy before RT were associated with higher TCP in all models. Parameter estimates of the CIS99 were consistent with the classical Cox proportional hazards model. The dose required to achieve 90% tumor control after 15.5 months was 146 (range: 114-188) Gy10 in the CIS99 and 133 (range: 101-164) Gy10 in the BG model; however, the BG model predicted lower tumor control at long (≳20 months) follow-up times and gave a suboptimal fit to the data compared to the CIS99 model. CONCLUSIONS: Biologically motivated cure rate models allow adding the time component into TCP modeling without being restricted to the follow-up period which is the case for the Cox model. In practice, application of such models to the clinical setting could allow for adaption of treatment doses depending on whether local control should be achieved in the short or longer term.

Local tumor control probability modeling of primary and secondary lung tumors in stereotactic body radiotherapy.

BACKGROUND AND PURPOSE: To evaluate whether local tumor control probability (TCP) in stereotactic body radiotherapy (SBRT) varies between lung metastases of different primary cancer sites and between primary non-small cell lung cancer (NSCLC) and secondary lung tumors. MATERIALS AND METHODS: A retrospective multi-institutional (n=22) database of 399 patients with stage I NSCLC and 397 patients with 525 lung metastases was analyzed. Irradiation doses were converted to biologically effective doses (BED). Logistic regression was used for local tumor control probability (TCP) modeling and the second-order bias corrected Akaike Information Criterion was used for model comparison. RESULTS: After median follow-up of 19 months and 16 months (n.s.), local tumor control was observed in 87.7% and 86.7% of the primary and secondary lung tumors (n.s.), respectively. A strong dose-response relationship was observed in the primary NSCLC and metastatic cohort but dose-response relationships were not significantly different: the TCD90 (dose to achieve 90% TCP; BED of maximum planning target volume dose) estimates were 176 Gy (151-223) and 160 Gy (123-237) (n.s.), respectively. The dose-response relationship was not influenced by the primary cancer site within the metastatic cohort. CONCLUSIONS: Dose-response relationships for local tumor control in SBRT were not different between lung metastases of various primary cancer sites and between primary NSCLC and lung metastases.

New possibilities for volumetric-modulated arc therapy using the Agility™ 160-leaf multileaf collimator.

PURPOSE: This study compares the quality of intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) plans optimized for an Elekta Agility(TM) (Elekta, Stockholm, Sweden) multileaf collimator (MLC; leaf width 5 mm) and an Elekta MLCi2 (leaf width 10 mm) for complex target volumes (anal, AC; head and neck, H&N and prostate cancer, PC). PATIENTS AND METHODS: For plan comparisons, 15 patients who had been treated with IMRT or VMAT using the MLCi2 were selected. For each patient, a retrospective treatment plan using the MLCi2 for the technique not applied was created, as were treatment plans for both techniques using the Agility(TM) MLC. Dose-volume histograms (DHVs) for planning target volumes (PTVs) and organs at risk (OARs) were compared. Further parameters relating to dose conformity, dose homogeneity and mean dose (Dmean) to the PTV, compliance with the intended OAR dose criteria and overall dose to normal tissue were analyzed. Verification measurements were performed and optimization and treatment times were compared. RESULTS: Compared to the MLCi2 plans, the Agility(TM) IMRT and VMAT plans show better or equivalent results in terms of PTV dose conformity and homogeneity. Compliance with the intended OAR dose criteria does not differ according to technique or MLC type. Slight differences are shown for dose distributions in OARs and normal tissue. Verification measurements show that all plans fulfill the acceptance criteria of a minimum of 95 % matched dose points for the 3 %/3 mm γ criterion. Optimization times for the VMAT plans increase compared to the IMRT plans, whereas treatment times decrease. CONCLUSION: With the MLCi2, treatment of complex target volumes with VMAT was only possible with compromises in terms of target coverage. Using the Agility(TM) MLC, even complex target volumes can be treated with VMAT without compromising target coverage or resulting in higher exposure of OARs or normal tissue.

Spontaneous remission of metastases of cancer of the uterine cervix.

BACKGROUND: Spontaneous remission (SR) is the complete or incomplete disappearance of a disease or cancer despite no or inadequate treatment. SR is a rare event, and only 5 cases of SR of carcinoma of the uterine cervix have been reported so far. CASE REPORT: We report the case of a young woman suffering from carcinoma of the uterine cervix metastasized to the lung, pleura, bone, skin and brain. The primary tumor was removed. After diagnosis of the histologically proven metastases, further palliative treatment was inadequate, except for radiotherapy to the brain. In all other metastases, spontaneous remission occurred. 8 years after the initial diagnosis of metastasis, there is no evidence of active disease. CONCLUSION: SR is a rare but evident phenomenon. Individual features of malignant tumors should be taken into account much more when determining the best treatment for the patient.

Concomitant radiochemotherapy with temozolomide in non-selected patients with newly diagnosed high-grade gliomas.

BACKGROUND: Malignant gliomas still present a medical challenge, despite decades of continuous extensive research with optimization of surgical techniques, radiotherapy and systemic treatments. PATIENTS AND METHODS: From 1999 to 2004, 104 patients with WHO grade III and IVgliomas underwent surgery and received concomitant radiotherapy combined with concomitant oral temozolomide. Patients with progressive disease received sequential 5-day cycles of temozolomide at 28-day intervals. RESULTS: The median overall survival was 19.7 and 15.0 months for patients with WHO grade III versus IV gliomas, respectively. Patient compliance was good and toxicity moderate. The overall survival was as long as 18.0 months in a subgroup of subjects with glioblastoma, performance status >60% and complete radiochemotherapy. CONCLUSION: Although our patients had more negative characteristics (age, performance, biopsy only), the results confirmed those from recently published optimistic phase III trial data and indeed surpassed them in some cases.