Ablative Doses Of Radiation Research Articles

Stereotactic centralized ablative radiation therapy: A novel methodology in treating bulky tumor and its technical realization.

159 Background: Bulky tumors pose significant challenges to traditional treatment modalities such as surgery, chemotherapy, and conventional radiotherapy. This study introduces a novel therapeutic approach named as Stereotactic-Core-Ablative-Radiation-Therapy (SCART), designed to deliver an ablative dose to a substantial core of the bulky tumor while quickly decreasing to a lower dose at the tumor periphery. Methods: A SCART-Treatment-Volume (STV) at the core of the GTV was predefined to administer an ablative radiation dose, aiming to induce DNA damage in cancer cells and potentially trigger biological cancer-killing effects. Utilizing Linac-based VMAT or Cyberknife techniques with 6MV photon beams, multiple radiation fields intersect and optimize at STV, generating an ablative dose at the STV. The dose rapidly diminishes to a safe level at the edge of GTV sparing the surrounding tissue. In the phase-1 trial, nineteen patients with 21 bulky tumors enrolled, receiving SCART at five dose levels (15GyX1, 15GyX2, 15GyX3, 18GyX3, 21GyX3, and 24GyX3), while maintaining the GTV's peripheral dose at 5Gy each fraction. Results: All patients completed treatment with average beam-on time of 8.9min and average treatment time of 18.5min. Mean follow-up time is 15.4 month. No grade-III or higher toxicity was observed. 7/19 patients still survive, with the overall survival of 40% at 30 months. Mean tumor volume shrinks by 60% between initial 301cc and post-SCART volumes of 118cc. Long-term follow-up revealed that 14/21 tumors achieved Partial Response, 2/21 Complete-Response, 3/21 Stable-Disease, and 1/21 Progressive-Disease, leading to an encouraging local control of 95%. Conclusions: SCART emerges as a safe and effective strategy for treating bulky malignant tumors, demonstrating excellent local control and overall survival. Multiple treatment courses were feasible. The results from phase-1 study suggest that SCART could revolutionize the treatment landscape for bulky tumors, offering a promising avenue for further exploration and application in clinical practice.

Hypofractionated Stereotactic Radiosurgery in the Management of Brain Metastases.

Stereotactic radiosurgery (SRS) is an important weapon in the management of brain metastases. Single-fraction SRS is associated with local control rates ranging from approximately 70% to 100%, which are largely dependent on lesion and postoperative cavity size. The rates of local control and improved neurocognitive outcomes compared with conventional whole-brain radiation therapy have led to increased adoption of SRS in these settings. However, when treating larger targets and/or targets located in eloquent locations, the risk of normal tissue toxicity and adverse radiation effects within healthy brain tissue becomes significantly higher. Thus, hypofractionated SRS has become a widely adopted approach, which allows for the delivery of ablative doses of radiation while also minimizing the risk of toxicity. This approach has been studied in multiple retrospective reports in both the postoperative and intact settings. While there are no reported randomized data to date, there are trials underway evaluating this paradigm. In this article, we review the role of hypofractionated SRS in the management of brain metastases and emerging data that will serve to validate this treatment approach. Pertinent articles and references were obtained from a comprehensive search of PubMed/MEDLINE and clinicaltrials.gov .

Radiation Segmentectomy for Hepatocellular Carcinoma.

The application of trans-arterial radioembolization (TARE) with Yttrium-90, historically a palliative treatment option for patients with advanced hepatocellular carcinoma (HCC), is evolving. Radiation segmentectomy (RADSEG), the segmental delivery of an ablative radiation dose, is a treatment option for patients with earlier-stage HCC. This review presents an in-depth exploration of RADSEG, emphasizing its technical considerations, dosimetry advancements, and patient selection. The integration of RADSEG into the Barcelona Clinic Liver Cancer (BCLC) paradigm will be highlighted. RADSEG outcomes concerning safety and efficacy will be explored and compared with traditional locoregional cancer treatments like trans-arterial chemoembolization (TACE), percutaneous thermal ablation, and surgical resection, with an eye on future directions and considerations.

Abstract A005: A multi-institutional randomized phase III trial of chemotherapy alone versus chemotherapy and ablative 5-fraction MRI-guided adaptive radiation therapy for locally advanced pancreatic cancer (LAP-ABLATE)

Abstract Background: Prospective studies demonstrate that chemotherapy and non-ablative radiation therapy (RT) achieve superior locoregional control (LRC) although have not improved overall survival (OS) relative to chemotherapy alone for patients with locally advanced pancreatic cancer (LAPC). Emerging data suggest that significant radiation dose escalation may further enhance LRC, and it has been hypothesized that in a subset of patients this may improve OS. However, delivering ablative radiation dose in 5 or fewer fractions with computerized tomography (CT) guidance is associated with unacceptable rates of grade 3-5 toxicity. Safe dose escalation can be facilitated by radiation delivery systems that utilize magnetic resonance image (MRI) guidance and on-table adaptive replanning. A growing body of literature describes promising efficacy and safety of ablative 5-fraction stereotactic MRI-guided adaptive radiation therapy (SMART) for LAPC compared to historical non-ablative outcomes. Based on these encouraging results, the LAP-ABLATE trial has been designed to test the hypothesis that ablative SMART improves OS. Methods: The LAP-ABLATE trial is a multi-institutional group sequential randomized phase III study for patients with LAPC. Patients are eligible after first receiving 4-6 months of (modified)FOLFIRINOX or gemcitabine/nab-paclitaxel with either stable or responding disease. Other key eligibility criteria include CA 19-9 <180 U/mL and no contraindication to undergoing MRI scans. Patients are randomized (1:2) to receiving no ablative SMART (arm A) versus ablative SMART (arm B), with subsequent systemic therapy or surgery being optional in both arms. Ablative SMART will be delivered using the MRIdian Linac, a 0.35 Tesla MRI-guided linear accelerator. The prescribed dose is 50 Gy to gross disease and 33 Gy to elective regions in 5 fractions using a simultaneous integrated boost (SIB). The primary objective is to compare 2-year OS with secondary objectives including assessment of LRC, distant metastasis free survival (DMFS), progression-free survival (PFS), quality of life (QOL), and toxicity. Randomization will be stratified by participating center, baseline CA 19-9 level and induction chemotherapy regimen. Target accrual is 267 patients (arm A: 89, arm B: 178). Discussion: The LAP-ABLATE trial is the first prospective randomized phase III study designed to compare OS in LAPC patients following induction systemic therapy randomized to with or without ablative 5-fraction RT. Citation Format: Michael D. Chuong, Jessica M. Frakes, Kathryn E. Mittauer, James Good, Josh Kim, Daniel Chang, Dae Won Kim, Stefanie Corradini, Luca Boldrini, Mokenge Malafa, Eileen O'Reilly. A multi-institutional randomized phase III trial of chemotherapy alone versus chemotherapy and ablative 5-fraction MRI-guided adaptive radiation therapy for locally advanced pancreatic cancer (LAP-ABLATE) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A005.

225Ac-iPSMA-RGD for Alpha-Therapy Dual Targeting of Stromal/Tumor Cell PSMA and Integrins

Prostate-specific membrane antigens (PSMAs) are frequently overexpressed in both tumor stromal endothelial cells and malignant cells (stromal/tumor cells) of various cancers. The RGD (Arg-Gly-Asp) peptide sequence can specifically detect integrins involved in tumor angiogenesis. This study aimed to preclinically evaluate the cytotoxicity, biokinetics, dosimetry, and therapeutic efficacy of 225Ac-iPSMA-RGD to determine its potential as an improved radiopharmaceutical for alpha therapy compared with the 225Ac-iPSMA and 225Ac-RGD monomers. HEHA-HYNIC-iPSMA-RGD (iPSMA-RGD) was synthesized and characterized by FT-IR, UV-vis, and UPLC mass spectroscopy. The cytotoxicity of 225Ac-iPSMA-RGD was assessed in HCT116 colorectal cancer cells. Biodistribution, biokinetics, and therapeutic efficacy were evaluated in nude mice with induced HCT116 tumors. In vitro results showed increased DNA double-strand breaks through ROS generation, cell apoptosis, and death in HCT116 cells treated with 225Ac-iPSMA-RGD. The results also demonstrated in vivo cytotoxicity in cancer cells after treatment with 225Ac-iPSMA-RGD and biokinetic and dosimetric properties suitable for alpha therapy, delivering ablative radiation doses up to 237 Gy/3.7 kBq to HCT116 tumors in mice. Given the phenotype of HCT116 cancer cells, the results of this study warrant further dosimetric and clinical studies to determine the potential of 225Ac-iPSMA-RGD in the treatment of colorectal cancer.

RBIO-10. NEUROMODULATORY EFFECT AND DOSE RESPONSE OF FUNCTIONAL RADIOSURGERY ON CORTICAL NEURONS

Abstract PURPOSE The effects of functional radiosurgery on neuronal circuits remain poorly understood. Neurons of the prefrontal cortex communicate via precisely-timed action potentials that control cognition. Here, we examined the dose response of ablative radiation dose on the patterns of communication of neural circuits in prefrontal acute slices. Materials and METHODS Escalating doses from 20 Gy to 100 Gy of ablative radiation were applied to rodent cortical neurons using the robotic Radiosurgery device (CyberKnife(R) G4). Neuronal communication within irradiated prefrontal slices were compared to control slices (sham radiation); and assessed by plating slices on a multielectrode array that captured high-resolution (18 kHz) extracellular activity across 4,096 channels simultaneously. Comparisons also with recordings of slices treated with a pro-epileptiform solution and finally, correlated with staining for cell death. RESULTS Compared to control slices (mean rate of 0.06 Hz), the post-radiosurgery slices yielded a 40-fold increase in discharge rates (mean rate of 2.87 Hz for 20 Gy, 2.44 Hz for 50 Gy, and 1.95 Hz for 100 Gy radiation). Pearson cross-correlations were computed across all pairs of channels, yielding a matrix of 4,096-by-4,096 interactions. Radiated slices exhibited decreased correlations relative to control slices. A total of 7,446 neuronal interactions were above a threshold correlation of 0.5 in control slices, compared to none following a 20 Gy dose, 50 interactions following a 50 Gy dose and 28 interactions following a 100 Gy dose. Slices treated with pro-epileptiform solution slices yielded large seizure-like events characterized by increased discharge rates and increased pairwise correlations. CONCLUSION Post-radiosurgery slices yielded a unique signature of neuronal activity with increased rates; but with a pronounced decrease in correlations; suggesting diminished communication across neurons to create a neuro-modulatory effect on target tissue; or result in cognitive toxicity on organ-at-risk respectively.

The Safety and Efficacy of SCART for Bulky Metastatic or Recurrent Cancer, a Phase I Study

We are proposing a new treatment methodology, (called Stereotactic Centralized Ablative Radiation Therapy, (SCART), for bulky or metastatic tumors, which is based on the principles of SFRT, by using SBRT methods to deliver an ablative radiation dose to the central portion of the target while keeping the dose to surrounding normal tissue to a relatively low level. We performed a prospective dose escalation study of SCART for bulky metastatic or recurrent cancer. The purpose of the study was to determine dose-limiting toxicities (DLTs) and the Maximum Tolerated Dose (MTD) of SCART. This study was registered at ClinicalTrials.gov Identifier: NCT0488198, and approved at Foshan Chancheng Hospital. Patients with unresectable solid "bulky" nonhematological malignancies with limited treatment options were enrolled and received SCART with a prescription to the central spot in the tumor with a peripheral dose to the tumor edge at around 20% isodose line of the prescription dose. Five dose levels were proposed. The primary endpoint was the maximum tolerated dose (MTD), defined as the highest dose where zero of three or one of six patients experienced grade 3 dose-limiting toxicity (DLT), scored according to the Common Toxicity Criteria for Adverse Events v. 4.03, up to 6 months after SCART. A total of 21 patients received SCART and have eligible data for study follow-up. The dose was escalated for two patients to 24 GyX3. No grade 3 toxicity was observed in any of the enrolled patients. The median SCART dose was 18 Gy (range: 15 - 24). Six out of the 18 patients with data for overall survival (OS) died, and the median time to death was 16.29 months (range: 0.99 - 25.58). Three patients out of the 15 patients with available data for local recurrence (LR) were found to have an LR and the median time to LR was 16.01 months (range: 0.99 - 25.58). There appears to be a trend of tumors decreasing from the patient's first visit date, or pre-SCART, to their final volume post-SCART. The mean percent change for tumor shrinkage between first visit volumes and post-SCART volumes was 49.49% (SD: 40.89, p-value:0.009). Of 15 patients with available data for progression free survival, 9 had a local recurrence or were deceased. Estimated median survival (i.e., when survival is 50%) was equal to16.80 months (95% CI = 13.90, NA). The survival rate at 12 months and 24 months were72.22% and 24.07%, respectively. Of 15 patients with available data for time to local recurrence, 3 people had a local recurrence. The percent of patients that were free from local recurrence at one and two years after the beginning of SCART treatment was 85.56% for both. Despite the high dose delivered and the excellent local control achieved; the incidence of Any toxicity was unexpectedly low. Multiple courses of SCART are possible. The optimal dose, volume and timing of SCART still need more study.

Could Poor Outcomes for Patients with Limited Lung Function Treated with SAbR Necessitate PULSAR?

Stereotactic ablative radiotherapy (SAbR) employs precise targeting and delivery of ablative radiation doses in patients with medically inoperable early-stage non-small cell lung cancer, as well as patients with pulmonary metastases. SAbR is well tolerated with few studies reporting a minimal decline in pulmonary function tests (PFTs). However, poor pulmonary function is considered a risk factor for radiation induced lung toxicity. Personalized Ultrafractionated Stereotactic Adaptive Radiotherapy (PULSAR) is an adaptive radiation therapy regimen where radiation pulses are delivered over longer periods of time, thereby allowing for modification of the treatment based on the patient's response, as well as limiting toxicities. As such, we hypothesize that treating patients with poor pulmonary function using a PULSAR approach is better tolerated in when compared to patients treated with SAbR. We performed a retrospective review of our institutional database of patients treated with SAbR to lung lesions from 2005 to 2022. We assessed the overall survival in stage-matched patients with normal vs poor lung function who received SAbR (40 patients in each cohort). Patients with decreased lung function included those with a diagnosis of moderate/severe COPD, restrictive lung disease, or patients needing home oxygen at the time of treatment. We then analyzed PFTs changes for patients receiving SAbR, and evaluated these changes relative to treatment delivery. Stage-matched Kaplan-Meier analysis of patients with normal vs poor lung function receiving SAbR revealed a statistically significant difference in survival with Log-rank test p = 0.007. Of the patients with PFTs, 45 (90%) received SAbR with two to three treatments weekly, while 5 (10%) were treated on a PULSAR regimen with one fraction every week to three weeks. No trends or significant differences are observed in the changes of total lung capacity (TLC), the first second of exhalation (FEV1), forced vital capacity (FVC) or FEV1/FVC ratios. However, we did note variations in the diffusing capacity of the lung for carbon monoxide (DLCO). The mean difference in DLCO for the SAbR and PULSAR groups were -26.07% (95% CI: -31.28 to -20.87, p < 0.0001), and -10.52% (95% CI: -40.74 to 19.69, p = 0.388), respectively. We observed a significant difference in overall survival between patients with normal vs poor lung function receiving SAbR. In a preliminary analysis, we discovered a small decline in DLCO for patients treated with regularly scheduled SAbR treatments. In the patients treated on the PULSAR regimen, however, this change in DLCO is not statistically significant. While this data suggests that increasing the time frame between individual doses of radiation may result in better toleration of radiotherapy in this patient population, the sample size of patients treated via PULSAR is limited, and longer follow-up is needed to further evaluate the potential benefits.

P03.07.B DOSIMETRIC ACCURACY OF CYBERKNIFE STEREOTACTIC RADIOSURGERY FOR BENIGN PERIOPTIC TUMOR

Abstract BACKGROUND The Cyberknife (CK) SRS delivers a highly focused ablative radiation dose to tumors to effectively control tumors with minimized radiation toxicity to surrounding normal tissues. This study aimed to evaluate the dosimetric accuracy of Cyberknife (CK) for benign perioptic tumor using patient specific head phantom. METHODS Patient specific head phantoms was fabricated using a 3D-printer to be dosimetrically equivalent to actual target regions of benign perioptic tumor case treated via Cyberknife radiosurgery. Head phantom QA plan was produced using the original CK contour set (target and optic nerve). The head phantom containing the Gafchromic EBT3 film was irradiated using Cyberknife 6D skull tracking method. The dose distributions calculated by MultiPlan Treatment Planning System (version 5.6) was compared with those measured by film dose using gamma analysis method. After moved rotating (1 degree) and translating (1-5mm) the couch table prior to beam delivery, we checked the 6D skull tracking accuracy according to the beam irradiation. RESULTS Gamma passing rates for the 2%/1 mm and 2%/2 mm criteria was found to be 84.11 ± 2.12% and 93.61±1.39% greater than the acceptance criteria 80% and 90%. The difference between measured and calculated dose to the optic nerve in contact with the tumor was less than 3%. CONCLUSION Dosimetric verification with patient-specific head phantoms could be successfully implemented as the evaluation method for CK perioptic tumor radiosurgery delivery with 6D skull tracking system.

Local control and survival after stereotactic body radiation therapy of early-stage lung cancer patients in Slovenia.

Stereotactic body radiation therapy (SBRT) precisely and non-invasively delivers ablative radiation dose to tumors in early-stage lung cancer patients who are not candidates for surgery or refuse it. The aim of research was to evaluate local control, overall survival (OS), local progression free survival (LPFS), distant metastases free survival (DMFS), disease free survival (DFS) and toxicity in early-stage lung cancer patients treated with SBRT in a single tertiary cancer centre. We retrospectively evaluated medical records and radiation treatment plan parameters of 228 tumors irradiated in 206 early-stage lung cancer patients between 2016 and 2021 at the Institute of Oncology Ljubljana. After 25 months of median follow up, 68 of 206 (33%) patients died. Median OS was 46 months (CI 36-56), 1-year, 2-year and 3-year OS were 87%, 74% and 62% and 5-year OS was 31%. A total of 45 disease progressions have been identified in 41 patients. Local progress only was noticed in 5 (2%) patients, systemic progress in 32 (16%) and combined systemic and local in 4 (2%) patients. Local control rate (LCR) at 1 year was 98%, at 2 and 3 years 96% and 95% at 5 years. The 1-, 2- and 3-year LPFS were 98%, 96% and 94%, respectively and 5-year LPFS was 82%. One, 2-, 3- and 5-year DFS were 89%, 81%, 72% and 49%, respectively. Among 28 toxicities recorded only one was Grade 4 (pneumonitis), all others were Grade 1 or 2. No differences in LCR, LPFS, DFS were found in univariate analysis comparing patient, tumor, and treatment characteristics. For OS the only statistically significant difference was found in patients with more than 3 comorbidities compared to those with less comorbidities. Early lung cancer treated with SBRT at single tertiary cancer centre showed that LCR, LPFS, DFS, DMFS and OS were comparable to published studies. Patients with many comorbidities had significantly worse overall survival compared to those with less comorbidities. No other significant differences by patient, tumor, or treatment characteristics were found for DMFS, LPFS, and DFS. Toxicity data confirmed that treatment was well tolerated.

Cyberknife treatment for different types of tumor

CyberKnife radiosurgery is a frameless, image guided robotic stereotactic radiosurgical system (IGR-SRS) which uses potent, ablative radiation dose with limited treatment volume. The main aim of this study is to provide knowledge of this treatment for different types of tumor. To deliver radiation treatment from multiple angles, with real time target tracking through a combined orthogonal radiograph imaging and optic motion tracking system cyberKnife is a new and advanced technique. Radiation is delivered to the tumor within a predetermined range, for this an object recognition computer algorithm and a fudicial marker placed within a tumor. CyberKnife treatment cost USD 6,800 (Indian Rupees approx. 4,89,000). In this review you will get idea about different types of tumor get treated with cyberKnife radiosurgery (SRS). CyberKnife have submillimeter accuracy in metastatic brain tumor. By giving appropriate tracking method for stage I lung cancer and lung oligometastases stereotactic radiotherapy is an efficient treatment. So, at well-defined tumor sites cyberKnife is a new stereotactic body radiation therapy which delivers high dose of radiation in short period of time. For head and neck tumor treatment cyberKnife is most widely used. This treatment is helpful for adrenal gland tumor and prostate tumor, spinal metastases.

Stereotactic Body Radiation Therapy Salvage for Lymph Node Recurrent Prostate Cancer in the Era of PSMA PET Imaging.

Our understanding of patterns of prostate cancer recurrence after primary treatment of localized disease has significantly evolved since the development of positron emission tomography (PET) agents targeting prostate cancer. Previously, most biochemical recurrences were not associated with imaging correlates when restaging with computed tomography (CT), magnetic resonance imaging (MRI), or bone scintigraphy and, hence, were typically assumed to represent occult metastases. A rising prostate specific antigen (PSA) after previous local therapy prompting a PET scan showing uptake limited to regional lymph nodes is an increasingly common clinical scenario as advanced prostate cancer imaging becomes more widely utilized. The optimal management strategy for patients who have lymph node recurrent prostate cancer is both unclear and evolving, particularly in terms of local and regionally directed therapies. Stereotactic body radiation therapy (SBRT) utilizes ablative radiation doses with steep gradients to achieve local tumor control while sparing nearby normal tissues. SBRT is an attractive therapeutic modality due to its efficacy, favorable toxicity profile, and flexibility to administer elective doses to areas of potential occult involvement. The purpose of this review is to briefly describe how SBRT is being implemented in the era of PSMA PET for the management of solely lymph node recurrent prostate cancer. SBRT has been shown to effectively control individual lymph node tumor deposits within the pelvis and retroperitoneum for prostate cancer and is well-tolerated with a favorable toxicity profile. However, a major limitation thus far has been the lack of prospective trials supporting the use of SBRT for oligometastatic nodal recurrent prostate cancer. As further trials are conducted, its exact role in the treatment paradigm of recurrent prostate cancer will be better established. Although PET-guided SBRT appears feasible and potentially beneficial, there is still considerable uncertainty about the use of elective nodal radiotherapy (ENRT) in patients with nodal recurrent oligometastatic prostate cancer. PSMA PET has undoubtedly advanced imaging of recurrent prostate cancer, revealing anatomic correlates for disease recurrence that previously went undetected. At the same time, SBRT continues to be explored in prostate cancer with feasibility, a favorable risk profile, and satisfactory oncologic outcomes. However, much of the existing literature comes from the pre-PSMA PET era and integration of this novel imaging approach has led to greater focus on new and ongoing clinical trials to rigorously evaluate this approach and compare to other established treatment modalities utilized for oligometastatic, nodal recurrence of prostate cancer.

The clinical relevance of margins in frameless stereotactic radiosurgery for intact brain metastases: A randomized trial of 0 vs 2 mm margins.

TPS2080 Background: Stereotactic radiosurgery (SRS) is a commonly utilized treatment strategy for brain metastases which offers a relatively low rate of morbidity and high rate of local control. SRS delivers an ablative dose of radiation in a single session to a limited target volume while minimizing dose to surrounding normal tissue. Image-guided linear accelerator (LINAC)-based frameless SRS has enabled effective, safe delivery of high dose radiation without the discomfort and logistical complications associated with use of a rigid frame. Localization errors during frameless SRS vary depending on the specific LINAC configuration and immobilization technique. The clinical relevance of potential inaccuracies in localization with frameless SRS remains controversial. When employing frameless systems, many centers will account for set-up uncertainties by adding a circumferential margin of 1-3 mm around the GTV to create a planning target volume (PTV). This PTV expansion ensures adequate tumor coverage if target motion occurs, but exposes more normal brain tissue to radiation and may increase the risk of adverse events, chiefly radionecrosis. There is limited literature available to guide radiation oncologists on the appropriate choice of margin size, if any, for frameless SRS. There are no randomized data evaluating the safety and efficacy of omitting the margin entirely. Given the paucity of data examining margin extent and the potentially significant consequences for treatment efficacy and morbidity, we propose a phase II randomized prospective clinical trial evaluating 0 vs 2 mm marginal GTV to PTV expansions for treating patients with intact brain metastases with frameless SRS. Methods: Eligible patients will have brain metastases from solid tumors with ECOG performance status of 0-2 and life expectancy of &gt;3 months. Patients must have 1 - 5 newly diagnosed well-circumscribed, measurable intraparenchymal brain metastases with maximum tumor diameter ≤3.0 cm. At least one lesion must be ≥ 0.5 cm in maximum diameter to be considered measurable. SRS will be delivered in a single fraction to either 20 Gy or 18 Gy dependent on tumor size. Importantly, PTV margin randomization is blinded and occurs after delineation of tumor volume by radiation oncologist to not bias contouring based on knowledge of margin randomization. This is two-armed multi-center phase II randomized controlled trial. The trial is powered to demonstrate non- inferiority of the experimental arm with regard to the primary endpoint of local PFS at 6 months and the superiority of the experimental arm with regard to the secondary endpoint of radionecrosis or pseudoprogression. We expect the total study duration, from the start of screening for the first participant until the end of follow-up for the last one, to be approximately six years. We plan to accrue 166 patients to this trial at all sites. Clinical trial information: NCT02747303 .

Surgical outcomes after neoadjuvant ablative dose radiation among patients with borderline resectable and locally advanced pancreas cancer from the multi-institutional phase 2 Stereotactic MR-Guided Adaptive Radiation Therapy (SMART) trial.

718 Background: Acute grade 3+ toxicity was rare in the multi-institutional phase 2 stereotactic MR-guided on-table adaptive radiation therapy (SMART) trial (NCT03621644) for locally advanced and borderline resectable pancreatic cancer (LAPC/BRPC). Surgery may be considered after ablative SMART although the feasibility and safety of this is not well understood. Postoperative outcomes of the subset of patients in the SMART trial are examined here. Methods: Trial eligibility included BRPC or LAPC without metastases after a minimum of 3 months of induction chemotherapy. All patients received SMART prescribed to 50 Gy in 5 fractions using an integrated 0.35T MR-radiation therapy device equipped with cutting edge soft tissue tracking, automatic beam gating, and on-table adaptive replanning. Surgery was permitted after SMART, often after multi-disciplinary review. Perioperative details and postoperative outcomes, including morbidity, mortality, and overall survival (OS), were analyzed. Results: 136 patients across 13 sites were enrolled between 2019-2022. 44 patients (32.4%) had surgery after SMART (33 BRPC, 11 LAPC). Surgical procedures included pancreaticoduodenectomy (81.8%), distal pancreatectomy with splenectomy (9.1%), total pancreatectomy (6.8%), and distal pancreatectomy with celiac axis resection (2.3%). 52.3% required vascular resection/reconstruction, a majority of which were venous resections (65.2%), with a smaller proportion needing both venous/arterial (21.7%), or arterial (13%). Surgery was performed after a mean 51.4 ± 52.8 days from SMART. Postoperative hospitalization was 10.5 ± 8.9 days. Nine patients (20.5%) had Clavien-Dindo complications of grade III or higher; 3 deaths resulted from post-pancreatectomy hemorrhage in patients who had portal vein resection. One-year OS in patients who had surgery versus no surgery after SMART was 66% vs. 43%, respectively. Conclusions: These are the first prospectively evaluated surgical outcomes after 5-fraction ablative SMART for BRPC/LAPC. The rate of surgery for BRPC compares favorably to radiated patients on the Alliance A021501 trial. Despite the use of ablative radiation dose and frequent need for vascular resection, the incidence of serious surgical complications was similar to what is reported after non-ablative radiation therapy. However, several deaths occurred after surgery and we therefore we urge caution when considering surgery after ablative radiation therapy. Further analysis of other variables such as the time between SMART and surgery, approaches to vascular resections, and discrete events such as delayed gastric emptying, operative duration, and post-operative pancreatic fistula are needed to better understand the surgical morbidity seen in these patients. Clinical trial information: NCT03621644 .

Safety and feasibility of pancreas resection after a-smart in pancreatic cancer:Multicenter analysis

Background: Neoadjuvant chemotherapy coupled with radiotherapy (RT) may provide survival benefits when compared to upfront surgery in patients with borderline resectable pancreatic cancer. It is hypothesized that delivering precise, ablative doses of radiation allows for improved outcomes without increasing significant treatment-related toxicity. The purpose of the present study is to evaluate the safety and feasibility of surgical resection after neoadjuvant ablative stereotactic magnetic resonance-guided adaptive radiation therapy (A-SMART) in patients with pancreatic cancer.

Radiation therapy prior to CAR T-cell therapy in lymphoma: impact on patient outcomes

Introduction Anti CD19 chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment paradigm for patients with refractory or recurrent (R/R) diffuse large B-cell lymphomas (DLBCL). Nonetheless, most patients ultimately progress. The use of bridging or salvage radiotherapy (RT) in combination with CAR T-cell therapy has been proposed as potential strategies to improve patient outcomes, but consensus is currently lacking as to which, if either, approach is effective. Areas covered We reviewed the immunologic and molecular mechanisms of resistance and the current retrospective data on patterns-of-failure, clinical risk factors, and treatment outcomes in patients undergoing CAR T-cell therapy, with and without bridging or salvage RT. Expert opinion We believe that current basic and clinical evidence supports the use of comprehensive, ablative bridging irradiation (CABI), as opposed to low-dose bridging or salvage radiotherapy, as a promising strategy to improve CAR T-cell therapy outcomes in patients with R/R DLBCL. This potential benefit is likely greatest in patients with high tumor burden and/or localized disease, who are both at elevated risk of local recurrence and can often be safely and comprehensively treated with ablative radiation doses (EQD2 >39Gy). Hypothesis-driven clinical trials are needed prospectively assess the impact of radiation on outcomes in patients undergoing CAR T-cell therapy.

Chancen und Grenzen der stereotaktisch fraktionierten Hochpräzisionsbestrahlung beim nichtkleinzelligen Lungenkarzinom im Stadium I/II

BackgroundFractionated stereotactic body radiotherapy (SBRT) can achieve excellent tumor control with good toxicity profiles and maintained quality of life through non-invasive application of ablative radiation dose in patients with early stage non-small-cell lung cancer (ES-NSCLC).Materials and methodsThe current standard and challenges of SBRT for patients with ES-NSCLC are presented. Recommendations from guidelines and literature are also discussed.ResultsFor inoperable patients, SBRT is considered the standard of care and is superior to conventionally fractionated RT and radiofrequency ablation (RFA) in survival data. For operable patients, resection remains the standard, even if studies show good local control rates, toxicity profiles, and quality of life for SBRT. Only risk-adapted fractionation schemes should be used in patients with central ES-NSCLC; in patients with interstitial lung disease (ILD), increased risk of toxicity must be weighed against the indication. Another challenge is to improve systemic control and survival, which is addressed by combining SBRT with checkpoint inhibitors.ConclusionsThe innovative technique of extracranial SBRT has undergone exorbitant developments in recent years and represents an established treatment alternative to surgery and RFA that is already recommended for inoperable patients with ES-NSCLC and is to be considered for operable patients. Challenges in the use of SBRT are treatment of centrally localized tumors, patients suffering from pulmonary diseases and the combination of SBRT with systemic therapy, which is the subject of current studies.

A safety study of intraoperative radiation therapy following stereotactic body radiation therapy and multi-agent chemotherapy in the treatment of localized pancreatic adenocarcinoma: study protocol of a phase I trial

BackgroundLocalized pancreatic adenocarcinoma carries a poor prognosis even after aggressive therapy. Up to 40% of patients may develop locoregional disease as the first site of failure. As such, there may be a role for intensification of local therapy such as radiation therapy. Radiation dose escalation for pancreatic cancer is limited by proximity of the tumor to the duodenum. However, the duodenum is removed during Whipple procedure, allowing the opportunity to dose escalate with intraoperative radiation therapy (IORT). Although prior studies have shown potential benefit of IORT in pancreatic cancer, these studies did not utilize ablative doses (biologically effective dose [BED10] > 100 Gy). Furthermore, the optimal radiation target volume in this setting is unclear. There has been increased interest in a “Triangle Volume” (TV), bordered by the celiac axis, superior mesenteric artery, common hepatic artery, portal vein, and superior mesenteric vein. Dissection of this area, has been advocated for by surgeons from Heidelberg as it contains extra-pancreatic perineural and lymphatic tracts, which may harbor microscopic disease at risk of mediating local failure. Interestingly, a recent analysis from our institution indicated that nearly all local failures occur in the TV. Therefore, the purpose of this protocol is to evaluate the safety of delivering an ablative radiation dose to the TV with IORT following neoadjuvant chemotherapy and stereotactic body radiation therapy (SBRT).MethodsPatients with non-metastatic pancreatic adenocarcinoma centered in the head or neck of the pancreas will be enrolled. Following treatment with multi-agent neoadjuvant chemotherapy, patients will undergo SBRT (40 Gy/5 fractions) followed by IORT (15 Gy/1 fraction) to the TV during the Whipple procedure. The primary objective is acute (< 90 days) toxicity after IORT measured by Clavien-Dindo classification. Secondary objectives include late (> 90 days) toxicity after IORT measured by Clavien-Dindo classification, overall survival, local progression-free survival, distant metastasis-free survival, and progression-free survival.DiscussionIf the results show that delivering an ablative radiation dose to the TV with IORT after neoadjuvant chemotherapy and SBRT is safe and feasible, it warrants further investigation in a phase II trial to evaluate efficacy of this approach.Trial Registration This study was registered at ClinicalTrials.gov on 12/2/2021 (NCT05141513). https://clinicaltrials.gov/ct2/show/NCT05141513

Dose-Escalated Ablative Radiotherapy as Definitive Treatment for Unresectable and Recurrent Intrahepatic Cholangiocarcinoma

<h3>Purpose/Objective(s)</h3> Treatment of intrahepatic cholangiocarcinoma remains a clinical challenge with noted short survival. Ablative doses of radiation may provide durable response in this setting. We hypothesized that dose escalated radiotherapy in the setting intrahepatic cholangiocarcinoma would provide disease control and minimal toxicity. Here, we report the efficacy and safety of hypofractionated ablative radiotherapy (RT) in the setting of intrahepatic cholangiocarcinoma from a single institution. <h3>Materials/Methods</h3> Consecutive patients treated with definitive-intent RT for a diagnosis of intrahepatic cholangiocarcinoma between 2016-2022 were identified. Clinical and dosimetric data were retrospectively collected. Patients treated with a biological equivalent dose (BED₁₀) of less than 80 Gy were excluded. Toxicities were evaluated based on Common Terminology Criteria for Adverse Events (CTCAE) v5.0 criteria. Kaplan Meier analysis was utilized to calculate progression free survival (PFS) and overall survival (OS). <h3>Results</h3> Twenty-five patients were identified. Two patients (7%) received prior surgery with local recurrence and 12 patients (48%) received chemotherapy prior to RT. RT was delivered by MRI-guidance in 16 patients (64%) and CT-guidance in the remaining 9 patients (36%). RT doses ranged between 50 to 75 Gy (median 67.5 Gy) in 5 to 25 fractions (median 15) for a median BED₁₀ of 90.2 (range: 87.3 - 113.7 Gy). Median PFS and OS for all patients were 24.8 months (range: 12.5 – 37.1), and 50.6 months (range: 39.7 – 62.5 months) respectively. Overall treatment was well tolerated. Most common side effects reported included grade 1 fatigue and grade 1 nausea seen in 8 (32%) and 5 (20%) patients respectively. One patient (4%) exhibited grade 3 abdominal pain and ascites requiring hospitalization. No grade 4 or 5 toxicities were observed. <h3>Conclusion</h3> Dose escalation in the setting of intrahepatic cholangiocarcinoma appears to be a safe and effective treatment. Prolonged survival with definitive-intent ablative radiotherapy is possible in appropriately selected patients. Further studies are warranted to investigate this approach in a prospective setting.

Predicting the Achievable Ablative Radiation Dose Coverage to Gross Tumor Volumes in Pancreatic Cancer Patients

<h3>Purpose/Objective(s)</h3> Ablative radiation therapy (RT) in pancreas cancer is associated with durable control of the primary tumor leading to favorable survival outcomes. A key planning goal is to achieve ablative dose (> 100 Gy BED) to the gross tumor volume (GTV), while still respecting organ-at-risk (OAR) dose constraints. However, the GTVs are typically located near radiosensitive OARs such as small bowel, large bowel, and stomach. This makes predicting V100 coverage to the GTV difficult to assess a priori. Each patient's GTV and OAR location, shape, and volume vary significantly and introduces uncertainty to the achievable GTV V100. Currently, achievable GTV V100 coverage is determined through trial and error as the planner explores tradeoffs between OAR sparing and prescription dose coverage. Iterative planning is time and labor intensive. In this study, we present a customized patient anatomy dependent prediction formula that can be used to guide the planning goals and improve planning speed and quality. <h3>Materials/Methods</h3> The minimum GTV coverage prediction formula was empirically derived as below Gf=fGTV - [fs × (1-fGTV)/3] + [(1-fs) × (1-fGTV)/20] ± 4% Gf: GTV V100 prediction value OARs=Small bowel + Large bowel + Stomach+ Duodenum OARs_5.5mm: OARs with 5.5mm 3D expansion fGTV: VGTV- OARs_5.5mm / VGTV fs: SOAR / SGTV VGTV: GTV volume VGTV- OARs_5.5mm: GTV volume subtract OARs with 5.5mm 3D margin SGTV: total number CT slices with GTV SOAR: total number CT slices with OARs within 3cm from the GTV Using this formula, 30 patients were randomly selected for testing efficacy. Patient plans were prescribed with dose painting to 3750cGy and 6750cGy in 15 fractions with GTVs intending to receive 6750cGy. Plans were generated using 2 or 3 6X VMAT full arcs with jaw tracking. If the original GTV coverage differed by 4% below the predicted GTV coverage, it was replanned with same treatment field geometry to verify the reliability of the prediction value. <h3>Results</h3> For the 30 patients, the GTV size ranged from 10.8 cc to 183.9cc. The fGTV and fs factor ranged from 0.61 -1 and 0 - 1. The GTV coverage for 17 out of the 30 patients was within the predicted GTV coverage range. The remaining patients had GTV coverage more than 4% below the predicted value with differences ranging from 5.1% to 22.3%. For these 13 patients, the GTV coverage improved to within the predicting formula range by adding a high priority minimum GTV coverage dose constraint to the optimization parameters. <h3>Conclusion</h3> The presented formula can sufficiently predict achievable GTV coverage while accommodating patient-specific anatomy and GTV volume sizes. The prediction formula is a stable tool to assist planners during the optimization process while maintaining plan quality. Future developments will include adjusting the formula to accommodate different prescription doses.