Hypofractionated Stereotactic Body Radiotherapy Research Articles

Assessment of interfraction dose variation in pancreas SBRT using daily simulation MR images

Pancreatic Cancer is associated with poor treatment outcomes compared to other cancers. High local control rates have been achieved by using hypofractionated stereotactic body radiotherapy (SBRT) to treat pancreatic cancer. Challenges in delivering SBRT include close proximity of several organs at risk (OARs) and target volume inter and intra fraction positional variations. Magnetic resonance image (MRI) guided radiotherapy has shown potential for online adaptive radiotherapy for pancreatic cancer, with superior soft tissue contrast compared to CT. The aim of this study was to investigate the variability of target and OAR volumes for different treatment approaches for pancreatic cancer, and to assess the suitability of utilizing a treatment-day MRI for treatment planning purposes. Ten healthy volunteers were scanned on a Siemens Skyra 3 T MRI scanner over two sessions (approximately 3 h apart), per day over 5 days to simulate an SBRT daily simulation scan for treatment planning. A pretreatment scan was also done to simulate patient setup and treatment. A 4D MRI scan was taken at each session for internal target volume (ITV) generation and assessment. For each volunteer a treatment plan was generated in the Raystation treatment planning system (TPS) following departmental protocols on the day one, first session dataset (D1S1), with bulk density overrides applied to enable dose calculation. This treatment plan was propagated through other imaging sessions, and the dose calculated. An additional treatment plan was generated on each first session of each day (S1) to simulate a daily replan process, with this plan propagated to the second session of the day. These accumulated mock treatment doses were assessed against the original treatment plan through DVH comparison of the PTV and OAR volumes. The generated ITV showed large variations when compared to both the first session ITV and daily ITV, with an average magnitude of 22.44% ± 13.28% and 25.83% ± 37.48% respectively. The PTV D95 was reduced by approximately 23.3% for both plan comparisons considered. Surrounding OARs had large variations in dose, with the small bowel V30 increasing by 128.87% when compared to the D1S1 plan, and 43.11% when compared to each daily S1 plan. Daily online adaptive radiotherapy is required for accurate dose delivery for pancreas cancer in the absence of additional motion management and tumour tracking techniques.

Accounting for fractionation and heterogeneous dose distributions in the modelling of osteoradionecrosis in oropharyngeal carcinoma treatment

Background and purposeOsteoradionecrosis (ORN) of the mandible is a severe complication following radiotherapy (RT). With a renewed interest in hypofractionation for head and neck radiotherapy, more information concerning ORN development after high fraction doses is important. The aim of this explorative study was to develop a model for ORN risk prediction applicable across different fractionation schemes using Equivalent Uniform Doses (EUD). Material and methodsWe performed a retrospective cohort study in 334 oropharyngeal squamous cell carcinoma (OPSCC) patients treated with either a hypofractionated Stereotactic Body Radiation Therapy (HF-SBRT) boost or conventional Intensity Modulated Radiation Therapy (IMRT). ORN was scored with the CTCAE v5.0. HF-SBRT and IMRT dose distributions were converted into equivalent dose in 2 Gy fractions (α/β = 0.85 Gy) and analyzed using EUD. The parameter a that led to an EUD that best discriminated patients with and without grade ≥ 2 ORN was selected. Patient and treatment-related risk factors of ORN were analyzed with uni- and multivariable regression analysis. ResultsA total of 32 patients (9.6%) developed ORN grade ≥ 2. An EUD(a = 8) best discriminated between ORN and non-ORN (AUC = 0.71). In multivariable regression, pre-RT extractions (SHR = 2.34; p = 0.012), mandibular volume (SHR = 1.04; p = 0.003), and the EUD(a = 8) (SHR = 1.14; p < 0.001) were significantly associated with ORN. ConclusionRisk models for ORN based on conventional DVH parameters cannot be directly applied to HF-SBRT fractionation schemes and dose distributions. However, after correcting for fractionation and non-uniform dose distributions using EUD, a single model can distinguish between ORN and non-ORN after conventionally fractionated radiotherapy and hypofractionated boost treatments.

Cellular Damage in the Target and Out-Of-Field Peripheral Organs during VMAT SBRT Prostate Radiotherapy: An In Vitro Phantom-Based Study.

Simple SummaryNew developments show that patients with prostate cancer can benefit from radiotherapy delivered with a hypo-fractionated regimen. The aim of our study was to investigate the effect of hypo-fractionated stereotactic body radiation therapy (SBRT) of prostate cancer on out-of-field organs. We used a humanoid phantom to irradiate prostate cells in conditions similar to patient therapy, using SBRT planning. Our results show that radiation doses in the location of the intestine and lung resulted in significantly higher radiation doses than the further locations. We observed a high radiotoxic effect in the cells irradiated in the prostate, and a small increase in DNA damage and cell killing in the intestine location. Gene expression analysis revealed significant enrichment of the biological processes related to the radiation response in the prostate. In the lung and thyroid, the enrichment of several gene groups was revealed, however the processes were not clearly related to the response to radiation. Our study provides extensive data on out-of-field safety of prostate SBRT.Hypo-fractionated stereotactic body radiation therapy (SBRT) is an effective treatment for prostate cancer (PCa). Although many studies have investigated the effects of SBRT on the prostate and adjacent organs, little is known about the effects further out-of-field. The aim of this study was to investigate, both in vitro and in a quasi-humanoid phantom, the biological effects (using a dose-scaling approach) of radiation in the out-of-field peripheral organs delivered by 6 MV volumetric modulated arc therapy (VMAT) SBRT in a prostate cancer model. Healthy prostate cells were irradiated in a phantom at locations corresponding to the prostate, intestine, lung, thyroid, and brain. Seven 10 Gy fractions of VMAT SBRT were delivered to the target in a single session without intermission (scaled-up method). Radiochromic films were used to measure the doses. The radiobiological response was assessed by measuring DNA breaks, the cell survival fraction, and differences in gene expression profile. Our results showed a strong, multiparametric radiobiological response of the cells in the prostate. Outside of the radiation field, the highest doses were observed in the intestine and lung. A small increase (not statistically significant) in DNA damage and cell death was observed in the intestines. Several gene groups (cell cycle, DNA replication) were depleted in the lung and thyroid (DNA replication, endocytosis), but further analysis revealed no changes in the relevant biological processes. This study provides extensive evidence of the types and extent of radiobiological responses during VMAT SBRT in a prostate cancer model. Additional research is needed to determine whether the radiobiological effects observed in the peripheral organs are validated in a clinical context.

A detailed process map for clinical workflow of a new biology-guided radiotherapy (BgRT) machine.

PurposeBiology‐guided radiotherapy (BgRT) is a new external beam radiation therapy modality combining PET‐CT with a linear accelerator that has the potential to track and treat one or more tumors in real‐time. The use of PET and radiopharmaceutical tracers introduces new processes that are different from the existing treatment processes. In this study, we have developed a process map for the clinical implementation of a prototype BgRT machine.MethodsA team of 13 members from various radiation therapy disciplines at our institution participated in developing a prospective process map for a prototype BgRT machine. The methodology provided by the AAPM TG 100 report was followed. In particular, the steps unique to the BgRT workflow, using hypofractionated stereotactic body radiation therapy with fluorodeoxyglucose radiolabeled with fluorine‐18 (FDG) to guide beam delivery, were analyzed.ResultsThe multi‐disciplinary team in the department of radiation oncology at our institution developed a prospective process map for the clinical BgRT workflow. By focusing on the appropriate level of detail, 15 major subprocesses, 133 steps, and 248 substeps were identified and the process map was agreed upon as being useful, implementable, and manageable. Seventy‐four steps from nine subprocesses, 55.6% of the whole process, were analyzed to be the BgRT unique steps. They originate mainly from: (1) acquiring multiple PET images at the BgRT machine with separate patient visits, (2) creating a unique biological treatment volume for BgRT plan (PTVBgRT), and (3) BgRT plan optimization and treatment delivery using PET images.ConclusionUsing BgRT to irradiate multiple metastases in the same session will impact clinical workflow, thus a graphical process map depicting the new clinical workflow with an appropriate level of detail is critical for efficient, safe, and high‐quality care. The prospective process map will guide the successful setup and use of the new BgRT system.

Stereotactic body radiation combined with oncolytic vaccinia virus induces potent anti-tumor effect by triggering tumor cell necroptosis and DAMPs.

Radiation is an integral part of cancer therapy. With the emergence of oncolytic vaccinia virus immunotherapy, it is important to study the combination of radiation and vaccinia virus in cancer therapy. In this study, we investigated the anti-tumor effect of and immune mechanisms underlying the combination of high-dose hypofractionated stereotactic body radiotherapy (SBRT) and oncolytic vaccinia virus in preclinical murine models. The combination enhanced the in vivo anti-tumor effect and increased the numbers of splenic CD4+Ki-67+ helper T lymphocytes and CD8+Ki-67+ cytotoxic T lymphocytes. Combinational therapy also increased tumor-infiltrating CD3+CD4+ helper T lymphocytes and CD3+CD8+ cytotoxic T lymphocytes, but decreased tumor-infiltrating regulatory T cells. In addition, SBRT combined with oncolytic vaccinia virus enhanced in vitro cell death, partly through necroptosis, and subsequent release of damage-associated molecular patterns (DAMPs), and shifted the macrophage M1/M2 ratio. We concluded that SBRT combined with oncolytic vaccinia virus can trigger tumor cell necroptosis and modify macrophages through the release of DAMPs, and then generate potent anti-tumor immunity and effects. Thus, combined therapy is potentially an important strategy for clinical cancer therapy.

High-dose hypofractionated stereotactic body radiotherapy for spinal chordoma.

Spinal chordoma is locally aggressive and has a high rate of recurrence, even after en bloc resection. Conventionally fractionated adjuvant radiation leads to suboptimal tumor control, and data regarding hypofractionated regimens are limited. The authors hypothesized that neoadjuvant stereotactic body radiotherapy (SBRT) may overcome its intrinsic radioresistance, improve surgical margins, and allow preservation of critical structures during surgery. The purpose of this study is to review the feasibility and early outcomes of high-dose hypofractionated SBRT, with a focus on neoadjuvant SBRT. Electronic medical records of patients with spinal chordoma treated using image-guided SBRT between 2009 and 2019 at a single institution were retrospectively reviewed. Twenty-eight patients with 30 discrete lesions (24 in the mobile spine) were included. The median follow-up duration was 20.8 months (range 2.3-126.3 months). The median SBRT dose was 40 Gy (range 15-50 Gy) in 5 fractions (range 1-5 fractions). Seventeen patients (74% of those with newly diagnosed lesions) received neoadjuvant SBRT, of whom 15 (88%) underwent planned en bloc resection, all with negative margins. Two patients (12%) developed surgical wound-related complications after neoadjuvant SBRT and surgery, and 4 (two grade 3 and two grade 2) experienced postoperative complications unrelated to the surgical site. Of the remaining patients with newly diagnosed lesions, 5 received adjuvant SBRT for positive or close surgical margins, and 1 received SBRT alone. Seven recurrent lesions were treated with SBRT alone, including 2 after failure of prior conventional radiation. The 2-year overall survival rate was 92% (95% confidence interval [CI] 71%-98%). Patients with newly diagnosed chordoma had longer median survival (not reached) than those with recurrent lesions (27.7 months, p = 0.006). The 2-year local control rate was 96% (95% CI 74%-99%). Among patients with radiotherapy-naïve lesions, no local recurrence was observed with a biologically effective dose ≥ 140 Gy, maximum dose of the planning target volume (PTV) ≥ 47 Gy, mean dose of the PTV ≥ 39 Gy, or minimum dose to 80% of the PTV ≥ 36 Gy (5-fraction equivalent doses). All acute toxicities from SBRT were grade 1-2, and no myelopathy was observed. Neoadjuvant high-dose, hypofractionated SBRT for spinal chordoma is safe and does not increase surgical morbidities. Early outcomes at 2 years are promising, although long-term follow-up is pending.

Variation of Tumor Volume During Moderate Hypo-Fractionated Stereotactic Body Radiation Therapy for Lung Cancer.

AimTo investigate the variation of tumor volume during moderate hypo-fractionated stereotactic body radiation therapy (SBRT).Patients and MethodsTwenty patients, who received SBRT at our institution, were included in the analysis. A prescribed dose was 56 Gy at iso-center in seven fractions. Tumor volumes before and during SBRT were calculated. In order to investigate factors affecting the variation of tumor volume in RT 2 (after first irradiation) and RT 7 (after last irradiation), various parameters were verified by the Mann-Whitney U test.ResultsWith regard to the low maximum standardized uptake values (SUVmax) group, transient increase of tumor volume was found in RT 2, and tumor volume reduction was hardly found in RT 7. With regard to the high SUVmax group, a transient increase was not found, and a definite reduction was found in the treatment course.ConclusionAccurate prediction of tumor volume variation is required for more accurate treatment, such as adaptive radiation therapy.

Safety and Efficacy of Virtual Prostatectomy With Single-Dose Radiotherapy in Patients With Intermediate-Risk Prostate Cancer

Ultra-high single-dose radiotherapy (SDRT) represents a potential alternative to curative extreme hypofractionated stereotactic body radiotherapy (SBRT) in organ-confined prostate cancer. To compare toxic effect profiles, prostate-specific antigen (PSA) responses, and quality-of-life end points of SDRT vs extreme hypofractionated SBRT. The PROSINT single-institution phase 2 randomized clinical trial accrued, between September 2015 and January 2017, 30 participants with intermediate-risk prostate cancer to receive SDRT or extreme hypofractionated SBRT. Androgen deprivation therapy was not permitted. Data were analyzed from March to May 2020. Patients were randomized in a 1:1 ratio to receive 5 × 9 Gy SBRT (control arm) or 24 Gy SDRT (test arm). The primary end point was toxic effects; the secondary end points were PSA response, PSA relapse-free survival, and patient-reported quality of life measured with the International Prostate Symptom Score (IPSS) and Expanded Prostate Cancer Index Composite (EPIC)-26 questionnaires. A total of 30 men were randomized; median (interquartile range) age was 66.3 (61.2-69.9) and 73.6 (64.7-75.9) years for the SBRT and SDRT arms, respectively. Time to appearance and duration of acute and late toxic effects were similar in the 2 trial arms. Cumulative late actuarial urinary toxic effects did not differ for grade 1 (hazard ratio [HR], 0.41; 90% CI, 0.13-1.27) and grade 2 or greater (HR, 1.07; 90% CI, 0.21-5.57). Actuarial grade 1 late gastrointestinal (GI) toxic effects were comparable (HR, 0.37; 90% CI, 0.07-1.94) and there were no grade 2 or greater late GI toxic effects. Declines in PSA level to less than 0.5 ng/mL occurred by 36 months in both study arms. No PSA relapses occurred in favorable intermediate-risk disease, while in the unfavorable category, the actuarial 4-year PSA relapse-free survival values were 75.0% vs 64.0% (HR, 0.76; 90% CI, 0.17-3.31) for SBRT vs SDRT, respectively. The EPIC-26 median summary scores for the genitourinary and GI domains dropped transiently at 1 month and returned to pretreatment scores by 3 months in both arms. The IPSS-derived transient late urinary flare symptoms occurred at 9 to 18 months in 20% (90% CI, 3%-37%) of patients receiving SDRT. In this randomized clinical trial among patients with intermediate-risk prostate cancer, SDRT was safe and associated with low toxicity, and the tumor control and quality-of-life end points closely match the SBRT arm outcomes. Further studies are encouraged to explore indications for SDRT in the cure of prostate cancer. ClinicalTrials.gov Identifier: NCT02570919.

A unified multi-activation (UMA) model of cell survival curves over the entire dose range for calculating equivalent doses in stereotactic body radiation therapy (SBRT), high dose rate brachytherapy (HDRB), and stereotactic radiosurgery (SRS).

PurposeApplication of linear‐quadratic (LQ) model to large fractional dose treatments is inconsistent with observed cell survival curves having a straight portion at high doses. We have proposed a unified multi‐activation (UMA) model to fit cell survival curves over the entire dose range that allows us to calculate EQD2 for hypofractionated SBRT, SRT, SRS, and HDRB.MethodsA unified formula of cell survival S=n/eDDo+n‐1 using only the extrapolation number of n and the dose slope of Do was derived. Coefficient of determination, R2, relative residuals, r, and relative experimental errors, e, normalized to survival fraction at each dose point, were calculated to quantify the goodness in modeling of a survival curve. Analytical solutions for α and β, the coefficients respectively describe the linear and quadratic parts of the survival curve, as well as the α/β ratio for the LQ model and EQD2 at any fractional doses were derived for tumor cells undertaking any fractionated radiation therapy.ResultsOur proposed model fits survival curves of in‐vivo and in‐vitro tumor cells with R2 > 0.97 and r < e. The predicted α, β, and α/β ratio are significantly different from their values in the LQ model. Average EQD2 of 20‐Gy SRS of glioblastomas and melanomas metastatic to the brain, 10‐Gy × 5 SBRT of the lung cancer, and 7‐Gy × 5 HDRB of endometrial and cervical carcinomas are 36.7 (24.3–48.5), 114.1 (86.6–173.1),, and 45.5 (35–52.6) Gy, different from the LQ model estimates of 50.0, 90.0, and 49.6 Gy, respectively.ConclusionOur UMA model validated through many tumor cell lines can fit cell survival curves over the entire dose range within their experimental errors. The unified formula theoretically indicates a common mechanism of cell inactivation and can estimate EQD2 at all dose levels.

Extending hypofractionated stereotactic body radiotherapy to tumours larger than 70cc – effects and side effects

Background and purpose Stereotactic body radiotherapy (SBRT) for tumours ≥5 cm is poorly studied and its utility and feasibility is uncertain. We here report the Karolinska experience of SBRT in this setting. Material and methods All patients had a gross tumour volume (GTV) ≥70 cc, a prescribed physical dose of at least 40 Gy and received treatment between 1995–2012. Results We included 164 patients with 175 tumours located in the thorax (n = 86), the liver (n = 27) and the abdomen (n = 62) and treated with a median prescribed dose (BEDα/β 10Gy) of 80 Gy (71.4–113). One- and 2- year local control rates were 82% and 61%. In multivariate analyses, minimum dose to the GTV and histological subtype were associated with local control. Renal cell carcinoma (RCC) histology showed the most favourable local control − 94% at 2 years for all histologies. Thirty-seven patients experienced grade 3–5 toxicity most likely related to SBRT. Seven of the ten patients with grade 5 toxicity, had a centrally located tumour in the thorax. Conclusion SBRT of tumours >5 cm in diameter may be an option for peripherally located lung and abdominal tumours. Histological origin and tumour location should be considered before treatment.

Phase 3 Multi-Center, Prospective, Randomized Trial Comparing Single-Dose 24 Gy Radiation Therapy to a 3-Fraction SBRT Regimen in the Treatment of Oligometastatic Cancer

This prospective phase 3 randomized trial was designed to test whether ultra high single-dose radiation therapy (24 Gy SDRT) improves local control of oligometastatic lesions compared to a standard hypofractionated stereotactic body radiation therapy regimen (3 × 9 Gy SBRT). The secondary endpoint was to assess the associated toxicity and the impact of ablation on clinical patterns of metastatic progression. Between November 2010 and September 2015, 117 patients with 154 oligometastatic lesions (≤5/patient) were randomized in a 1:1 ratio to receive 24 Gy SDRT or 3 × 9 Gy SBRT. Local control within the irradiated field and the state of metastatic spread were assessed by periodic whole-body positron emission tomography/computed tomography and/or magnetic resonance imaging. Median follow-up was 52 months. A total of 59 patients with 77 lesions were randomized to 24 Gy SDRT and 58 patients with 77 lesions to 3 × 9 Gy SBRT. The cumulative incidence of local recurrence for SDRT-treated lesions was 2.7% (95% confidence interval [CI], 0%-6.5%) and 5.8% (95% CI, 0.2%-11.5%) at years 2 and 3, respectively, compared with 9.1% (95% CI, 2.6%-15.6%) and 22% (95% CI, 11.9%-32.1%) for SBRT-treated lesions (P = .0048). The 2- and 3-year cumulative incidences of distant metastatic progression in the SDRT patients were 5.3% (95% CI, 0%-11.1%), compared with 10.7% (95% CI, 2.5%-18.8%) and 22.5% (95% CI, 11.1%-33.9%), respectively, for the SBRT patients (P = .010). No differences in toxicity were observed. The study confirms SDRT as a superior ablative treatment, indicating that effective ablation of oligometastatic lesions is associated with significant mitigation of distant metastatic progression.

RADT-21. NATIONAL PRACTICE PATTERNS AND OUTCOMES OF STEREOTACTIC BODY RADIOTHERAPY VS. CONVENTIONAL EXTERNAL BEAM RADIOTHERAPY FOR SPINAL METASTASES

Abstract INTRODUCTION Up to 10% of cancer patients experience spinal cord compression from metastatic disease. Palliation and local control were traditionally pursued with conventional external beam radiotherapy (cEBRT), but advancements in image-guidance and intensity-modulation for stereotactic body radiotherapy (SBRT) have dramatically changed the management of these lesions. Herein we evaluate the national practice patterns and outcomes associated with cEBRT vs. SBRT. METHODS U.S. patients newly diagnosed with metastatic cancer necessitating RT to the spine were identified from the National Cancer Database (2004-2016), stratified by RT modality and cancer type, and evaluated using multivariable logistic regression and Cox proportional hazards. RESULTS 34,759 U.S. patients required spinal RT within 3 months of initial stage 4 cancer presentation, primarily for lung adenocarcinoma (25%), lung small cell carcinoma (14%), and prostatic (12%) metastases. Patients overwhelming received cEBRT (30Gy/10; 50%), followed by hypo-fractionated SBRT (15-30Gy/2-6; 11%) and single-fraction SBRT (i.e. stereotactic radiosurgery, SRS; 15-24Gy/1; 0.9%); whereas 38% received another regimen (e.g. 30-37.5Gy/12-15 or 40Gy/20). From 2004→2016, the rates of single-fraction SRS (0.4→1.9%) and hypo-fractionated SBRT (13.1→23.6%) increased, whereas cEBRT (86.5→74.4%) decreased. SBRT was significantly more likely to be utilized at academic hospitals as compared to cEBRT (OR 0.57; 95% CI: 0.49-0.66; p&amp;lt; 0.01). SBRT was more likely utilized for elderly or high comorbidity patients and varied across cancer types. Survival analysis indicated that across all cancer types, single-fraction SRS, was independently associated with improved overall survival compared to cEBRT (HR 1.51; 95%CI: 1.31-1.74; p&amp;lt; 0.01) after adjusting for patient characteristics, care setting, tumor type and systemic treatment. CONCLUSIONS Through analysis of cancer registry data, we found that practice patterns of RT for spinal metastases have been evolving nationally, with an increase in the use of SBRT. Single-fraction SBRT was associated with improved adjusted OS. Notably, we found that utilization of SBRT lags in the community setting.

Stereotactic body radiotherapy (SBRT) for central and ultracentral node-negative lung tumors.

Advancements in imaging and radiotherapy (RT) techniques have allowed for remarkably precise delivery of high radiation dose per treatment fraction to intrathoracic targets. As a non-invasive therapeutic modality (compared to surgery), stereotactic body radiotherapy (SBRT) is an attractive option for patients with early-stage non-small cell lung cancers and oligometastases, especially for older patients with significant comorbidities and pre-existing pulmonary dysfunction. However, the outcomes and side effect profile of SBRT are highly dependent on tumor location, especially if the tumor is located centrally (within 2 cm of the proximal bronchial tree (PBT)] or ultracentrally (touching or within 1 cm of the mediastinum, esophagus, and PBT). In this focused review, we will examine the contemporary practice and principles of using hypofractionated RT or SBRT for central and ultracentral thoracic tumors. We will identify future directions on how this practice may be incorporated into the increasingly complicated modern paradigm of lung cancer treatments which now include immunotherapy along with proton beam radiotherapy.

A multicenter prospective phase II study of postoperative hypofractionated stereotactic body radiotherapy (SBRT) in the treatment of early-stage oropharyngeal and oral cavity cancers with high risk margins: the STEREO POSTOP GORTEC 2017-03 trial

BackgroundPrimary surgery is usually the mainstay treatment in early-stage oropharyngeal and oral cavity cancer. Typically, neck surgery is performed. Negative tumor margins are recommended (> 5 mm). If feasible, re-resection of any positive margin is preferred. Otherwise, postoperative radiotherapy is required. Adjuvant postoperative radiotherapy can be limited to the primary site for patients with pT1-T2 tumors and negative neck exploration. Currently, both fractionated external beam radiotherapy and brachytherapy can have a role in the postoperative management of early-stage oropharyngeal and oral cavity cancer with high risk margins. Another possible alternative could be postoperative stereotactic body radiotherapy (SBRT). The aim of this study is to evaluate postoperative SBRT in the treatment of early-stage oropharyngeal and oral cavity cancer with high risk margins.MethodsThe STEREO POSTOP study is a national, open-label, non-randomized phase II trial within the GORTEC network. Patients with early-stage oropharyngeal and oral cavity cancers with high risk margins indicating the need for postoperative radiation are eligible for enrollment. SBRT consists of a total dose of 36 Gy in 6 fractions over 2 weeks. The primary endpoint is severe late toxicity defined as 2-year toxicity of grade ≥ 3 according to CTCAE V4.03 classification. The secondary endpoints include acute toxicity (≤ 3 months), local and locoregional control, disease-free and overall survival, quality of life of patients, nutritional impact and predictive factors of toxicity. The experimental design chosen is a one-step Fleming plan design without interim analysis as the primary endpoint will be evaluated at a 2-year follow-up. Ninety patients will be recruited. The study was started in January 2018 with a 4-year enrollment period and an estimated completion in January 2024.DiscussionThis study is the first prospective trial to evaluate head and neck cancer postoperative SBRT in the setting of early-stage oropharyngeal and oral cavity cancers with high risk margins. SBRT is an attractive option because it delivers a highly conformal dose of radiation in a limited number of fractions (like brachytherapy but with less contraindication), with steep dose gradients resulting in reduced normal tissue irradiation and with a short overall treatment time.Trial registrationClinicaltrials.gov: NCT03401840, registered on 17-1-2018. Identifier in French National Agency for the Safety of Medicines and Health Products (ANSM): N°ID - RCB 2017-A02058–45, registered on July 2017.Protocol version: Version 3 dated from 25th November 2019.

Implementing research in to clinical practice; A report of the implementation of the printout trial at the Edinburgh cancer centre

Keywords: Stereotactic Body Radiotherapy Prostate; Printout; Breath Analysis. Introduction: The Printout (Using breath analysis to PRedIct Normal TissUe and Tumour response during prostate SBRT) [1] Trial is a prostate stereotactic body radiotherapy (SBRT) pilot study currently being undertaken at the Edinburgh Cancer Centre. The primary objective is to establish the possibility of measuring biomarkers in breath samples to monitor an individual’s response to radiotherapy . It is hoped to gain enough data from the pilot to progress to a larger scale study. Responsibility for the running of the trial including patient screening, recruitment, treatment delivery, data collection and management has been delegated to radiographers. Method and Materials: Printout patients attend for a multi parametric MRI scan, transperineal implantation of the raypilot prostate tracking device [2] and a planning CT scan as an outpatient during one day. A SBRT treatment plan is constructed using the rigidly fused MRI and CT scan. A dose of 36.25Gy is delivered in 5 fractions by a Varian Trubeam linear accelerator over 7 days, with breath samples acquired before and after each session. Kilovoltage imaging, CBCT and raypilot are used to monitor and verify treatment position. Patient reported outcome measures (PROMS) questionnaires are completed prior to treatment delivery, immediately on completion of treatment and at regular follow up appointments. Results: 5 patients have participated in the trial. Early data suggests hypofractionated SBRT can be delivered safely to the prostate gland using the Raypilot Device as a motion management system. PROMS have reported toxicities which are well tolerated, with the regime itself a very welcome alternative to conventional fractionation. Data regarding heterogeneity factors has yet to be reported. Conclusion/ Discussion: The Printout Trial is the first time radiographers in the department have been involved in both the technical and administration part of trial set up and design. Recruitment, although slow initially, has improved and it is hoped that one patient per month will now be enrolled. The trial has demonstrated the vital role radiographers play in radiotherapy research and also problems which can arise from the regulations surrounding research governance. Numerical References 1 Scottish Cancer Research Network south East edinburgh cancer centre wetsern general hospital . Using Breath Analysis to PRedIct Normal TissUe and Tumour response during prostate cancer SBRT[cited july 2019] available from http://www.sescrn.org.uk 2 Raypilot Micropos Medical Limited .www.micropos.se/products/

Impact of SBRT fractionation in hypoxia dose painting - Accounting for heterogeneous and dynamic tumor oxygenation.

Tumor hypoxia, often found in nonsmall cell lung cancer (NSCLC), implies an increased resistance to radiotherapy. Pretreatment assessment of tumor oxygenation is, therefore, warranted in these patients, as functional imaging of hypoxia could be used as a basis for dose painting. This study aimed at investigating the feasibility of using a method for calculating the dose required in hypoxic subvolumes segmented on 18 F-HX4 positron emission tomography (PET) imaging of NSCLC. Positron emission tomography imaging data based on the hypoxia tracer 18 F-HX4 of 19 NSCLC patients were included in the study. Normalized tracer uptake was converted to oxygen partial pressure (pO2 ) and hypoxic target volumes (HTVs) were segmented using a threshold of 10mmHg. Uniform doses required to overcome the hypoxic resistance in the target volumes were calculated based on a previously proposed method taking into account the effect of interfraction reoxygenation, for fractionation schedules ranging from extremely hypofractionated stereotactic body radiotherapy (SBRT) to conventionally fractionated radiotherapy. Gross target volumes ranged between 6.2 and 859.6cm3 , and the hypoxic fraction<10mmHg between 1.2% and 72.4%. The calculated doses for overcoming the resistance of cells in the HTVs were comparable to those currently prescribed in clinical practice as well as those previously tested in feasibility studies on dose escalation in NSCLC. Depending on the size of the HTV and the distribution of pO2 , HTV doses were calculated as 43.6-48.4Gy for a three-fraction schedule, 51.7-57.6Gy for five fractions, and 59.5-66.4Gy for eight fractions. For patients in whom the HTV pO2 distribution was more favorable, a lower dose was required despite a bigger volume. Tumor control probability was lower for single-fraction schedules, while higher levels of tumor control probability were found for schedules employing several fractions. The method to account for heterogeneous and dynamic hypoxia in target volume segmentation and dose prescription based on 18 F-HX4-PET imaging appears feasible in NSCLC patients. The distribution of oxygen partial pressure within HTV could impact the required prescribed dose more than the size of the volume.

Systematic Review of the Incidence of Chest Wall Toxicity Following Stereotactic Body Radiation Therapy for Early Stage Non-Small Cell Lung Cancer

Stereotactic body radiation therapy (SBRT) is well tolerated with high local control rates in patients with stage I and stage II medically inoperable non-small cell lung cancer (NSCLC). Radiation-induced chest wall pain (CWP) and rib fracture (RF) are unique late adverse effects after hypo-fractionated SBRT, however there is variability in the literature on the true incidence and risk factors for CWP and RF in patients with long-term follow-up. We performed a systematic review to determine the pooled incidence of CWP and RF in patients with early stage NSCLC treated with SBRT. A comprehensive literature search following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines of English-language published records from 2001-2017 was undertaken using MEDLINE and EMBASE. Titles and abstracts were screened independently by a primary and secondary reviewer. A third reviewer resolved discrepancies. Full-text publication review and data extraction were performed by the primary reviewer. Observational studies and randomized controlled trials were included, while case reports, case series of <20 patients, letters and commentaries were excluded. A total of 548 records were identified through database search. Following abstract exclusion, 73 full-text articles were assessed for eligibility. Of these, 24 were excluded as they did not meet inclusion criteria. Forty-nine full text publications comprising 5919 patients met the inclusion criteria. The median patient age was 67-81 years and median follow-up varied from 12-84 months. Most studies were retrospective in nature. The number of patients evaluated in these studies varied from 22-772. Radiation doses ranged from 16-70 Gy in 1-10 fractions. Results across studies were heterogeneous due to differences in grading, tumor location and the observational nature of the studies. Nonetheless, the pooled incidence of reported CWP was estimated to be 6.8%, and the estimated pooled incidence of reported RF was 4.5%. A total of 24 studies reported grade of CWP toxicity; of these, 57 of 313 patients with CWP (18.2%) reported grade 3 and 4 pain (no grade 5 reported). A total of 18 studies reported RF toxicity grading; of these, grade 3 and 4 toxicity was observed in 13 of 114 patients (11%) who had RF. In the studies that reported SBRT dosimetry, a high chest wall V30 was an important common predictor of CWP and RF. Results from this review demonstrate low rates of CWP and RF following SBRT across a broad spectrum of stage I and II NSCLC patients. However, tumor location, accurate reporting of toxicity and dose-fractionation schemes may relatively increase or decrease these rates. Prospective correlation with dose/volume metrics and assessment of quality of life will further improve understanding of the effects of CWP and RF following SBRT.

Prostate Clinical Outlook Visualization System for Patients and Clinicians Considering Cyberknife Treatment—A Personalized Approach

Background: When a patient presents with localized prostate cancer, referral for radiation oncology consultation includes a discussion of likely outcomes of therapy. Among current radiation treatments for prostate cancers, hypo-fractionated stereotactic body radiation therapy (SBRT) has gained clinical acceptance based on efficacy, short duration of treatment, and the potential radiobiological advantages. The Prostate Clinical Outlook Visualization System (PCOVS) was developed to provide the patient and the clinician with a tool to visualize probable treatment outcomes using institutional, patient specific data for comparing results of treatment. Methods: We calculated the prostate cancer outcomes—for each prospective patient using the EPIC-26 quality of life parameters based on clinical outcomes data of 580 prostate cancer patients who were treated with SBRT. We applied Kaplan-Meier analysis using the ASTRO definition for biochemical recurrence (BCR) free survival and likely outcome and the PCOVS nomogram to calculate parameters for quality of life. Open-source R, RShiny, and MySQL were used to develop a modularized architecture system. Results: The PCOVS presents patient specific risk scores in a gauge chart style and risk free probability bar plots to compare the treatment data of patients treated with SBRT. The PCOVS generates reports, in PDF, which consists of a comparison charts of risk free probabilities late effects and gauge charts of risk scores. This system is now being expanded as a web-based service to patients. Conclusions: The PCOVS visualized patient specific likely outcomes were compared to treatment data from a single department, helping the patient and the clinician to visualize likely outcomes. The PCOVS approach can be expanded to other specialties of oncology with the flexible, modularized architecture, which can be customized by changing independent modules.

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

BackgroundFor 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/designThis 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.DiscussionThe 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 statusThe study is ongoing and currently recruiting patients.Trial registrationRegistration number: NCT02635256 (clinicaltrials.gov). Registered 8 December 2015.

Prostate clinical outlook visualization for patients and clinicians considering cyberknife treatment: A personalized approach.

e16549 Background: When a patient presents with localized prostate cancer, referral for radiation oncology consultation includes a discussion of likely outcomes of therapy. Among current radiation treatments for prostate cancers, hypo-fractionated stereotactic body radiation therapy (SBRT) has gained clinical acceptance based on efficacy, short duration of treatment and potential radiobiological advantages. The prostate Clinical Outlook (PCO) visualization system was developed to provide the patient and the clinician with a tool to visualize probable treatment outcomes using institutional, patient specific data for comparing results of treatment. Methods: We calculated the prostate cancer outlooks for each prospective patient using the EPIC-26 quality of life parameters based on clinical outcomes data of 580 cyberknife SBRT treated prostate cancer patients. We applied Kaplan-Meier analysis using the ASTRO method for disease free likely outcome and the PCO nomogram to calculate parameters for quality of life. Open source R, R/Shiny, and MySQL were used to develop a modularized architecture system. Results: PCO presents patient specific risk scores in a gauge chart style and risk free probability bar plots to compare treatment data of cyberknife patients. PCO generates reports, in PDF and HTML, which consist of a comparison chart of risk free probabilities and gauge charts of risk scores. This system is now being expanded as a web-based service to patients. Conclusions: PCO visualized patient specific likely outcomes were compared to treatment data from a single department, helping the patient and the clinician to visualize likely outcomes. The PCO approach can be expanded to other specialties of oncology with the flexible, modularized architecture which can be customized by changing parameter variables for the modules.