Stereotactic Body Radiation Therapy (SBRT) for Pancreatic Cancer: A Radiosurgery Society Case-Based Practical Guidelines to Challenging Cases.

The use of radiation therapy (RT) for pancreatic cancer continues to be controversial despite recent technical advances. Improvements in systemic control have created an evolving role for RT and the need for improved local tumor control but currently no standardized approach exists. Advances in stereotactic body radiation therapy (SBRT), motion management, real time image guidance and adaptive therapy have renewed hopes of improved outcomes in this devastating disease with one of the lowest survival rates. This case-based guide provides a practical framework for delivering SBRT for locally advanced pancreatic cancer. In conjunction with multidisciplinary care, an intradisciplinary approach should guide treatment of the high-risk cases outlined within these guidelines for prospective peer review and treatment safety discussions.

Watch and Wait in Rectal Cancer Patients with Residual Mucin on MRI following Neoadjuvant Therapy.

BACKGROUND: Neoadjuvant therapy (NAT) leads to a clinical complete response (cCR) in a significant proportion of patients with locally advanced rectal cancer (LARC), allowing for possible nonoperative management. The presence of mucin on MRI after NAT leads to uncertainty about residual disease and appropriateness of a watch-and-wait (WW) strategy in patients with no evidence of disease on proctoscopy (endoscopic cCR). METHODS: MRI reports for LARC patients seen between July 2016 and January 2020 at Memorial Sloan Kettering Cancer Center were queried for presence of mucin in the tumor bed on MRI following NAT. Clinicodemographic, pathologic, and outcome data were compiled and analyzed. RESULTS: Of 71 patients with mucin on post-treatment MRI, 20 had a cCR and 51 had abnormalities on endoscopy and/or physical exam. One patient with a cCR opted out of WW; thus, 19 patients (27%) entered WW and 52 patients (73%) were planned for surgery (Non-WW). Of the 19 WW patients, 15 (79%) have had no local regrowth with median follow-up of 50 months (range, 29-76 months), while 4 (21%) experienced regrowth between 9 and 29 months after neoadjuvant therapy. Of the 52 patients who were planned to have surgery (Non-WW), 49 underwent resection while 3 developed metastatic disease that precluded curative-intent surgery. Five (10%) of the 49 patients who underwent surgery, including the one with an endoscopic cCR, had a pathologic complete response. CONCLUSIONS: The presence of mucin after NAT for LARC does not preclude WW management in otherwise appropriate candidates who achieve an endoscopic cCR.

Clinicogenomic predictors of outcomes in patients with hepatocellular carcinoma treated with immunotherapy.

INTRODUCTION: Immune checkpoint inhibitor (ICI) combinations extend overall survival (OS) while anti-PD-1/L1 monotherapy is non-inferior to sorafenib in treatment-naïve, patients with advanced hepatocellular carcinoma (HCC). Clinicogenomic features are posited to influence patient outcomes. METHODS: The primary objective of this retrospective study was to define the clinical, pathologic, and genomic factors associated with outcomes to ICI therapy in patients with HCC. Patients with histologically confirmed advanced HCC treated with ICI at Memorial Sloan Kettering Cancer Center from 2012 to 2022 were included. Association between clinical, pathological, and genomic characteristics were assessed with univariable and multivariable Cox regression model for progression-free survival (PFS) and OS. RESULTS: Two-hundred and forty-two patients were treated with ICI-based therapy. Patients were predominantly male (82%) with virally mediated HCC (53%) and Child Pugh A score (70%). Median follow-up was 28 months (0.5-78.4). Median PFS for those treated in 1st line, 2nd line and ≥ 3rd line was 4.9 (range: 2.9-6.2), 3.1 (2.3-4.0), and 2.5 (2.1-4.0) months, respectively. Median OS for those treated in 1st line, 2nd line, and ≥ 3rd line was 16 (11-22), 7.5 (6.4-11), and 6.4 (4.6-26) months, respectively. Poor liver function and performance status associated with worse PFS and OS, while viral hepatitis C was associated with favorable outcome. Genetic alterations were not associated with outcomes. CONCLUSION: Clinicopathologic factors were the major determinates of outcomes for patients with advanced HCC treated with ICI. Molecular profiling did not aid in stratification of ICI outcomes. Future studies should explore alternative biomarkers such as the level of immune activation or the pretreatment composition of the immune tumor microenvironment.

Salvage Ablative Radiotherapy for Isolated Local Recurrence of Pancreatic Adenocarcinoma following Definitive Surgery.

Introduction: The rate of isolated locoregional recurrence after surgery for pancreatic adenocarcinoma (PDAC) approaches 25%. Ablative radiation therapy (A-RT) has improved outcomes for locally advanced disease in the primary setting. We sought to evaluate the outcomes of salvage A-RT for isolated locoregional recurrence and examine the relationship between subsequent patterns of failure, radiation dose, and treatment volume. Methods: We conducted a retrospective analysis of all consecutive participants who underwent A-RT for an isolated locoregional recurrence of PDAC after prior surgery at our institution between 2016 and 2021. Treatment consisted of ablative dose (BED10 98-100 Gy) to the gross disease with an additional prophylactic low dose (BED10 < 50 Gy), with the elective volume covering a 1.5 cm isotropic expansion around the gross disease and the circumference of the involved vessels. Local and locoregional failure (LF and LRF, respectively) estimated by the cumulative incidence function with competing risks, distant metastasis-free and overall survival (DMFS and OS, respectively) estimated by the Kaplan-Meier method, and toxicities scored by CTCAE v5.0 are reported. Location of recurrence was mapped to the dose region on the initial radiation plan. Results: Among 65 participants (of whom two had two A-RT courses), the median age was 67 (range 37-87) years, 36 (55%) were male, and 53 (82%) had undergone pancreaticoduodenectomy with a median disease-free interval to locoregional recurrence of 16 (range, 6-71) months. Twenty-seven participants (42%) received chemotherapy prior to A-RT. With a median follow-up of 35 months (95%CI, 26-56 months) from diagnosis of recurrence, 24-month OS and DMFS were 57% (95%CI, 46-72%) and 22% (95%CI, 14-37%), respectively, while 24-month cumulative incidence of in-field LF and total LRF were 28% (95%CI, 17-40%) and 36% (95%CI 24-48%), respectively. First failure after A-RT was distant in 35 patients (53.8%), locoregional in 12 patients (18.5%), and synchronous distant and locoregional in 10 patients (15.4%). Most locoregional failures occurred in elective low-dose volumes. Acute and chronic grade 3-4 toxicities were noted in 1 (1.5%) and 5 patients (7.5%), respectively. Conclusions: Salvage A-RT achieves favorable OS and local control outcomes in participants with an isolated locoregional recurrence of PDAC after surgical resection. Consideration should be given to extending high-dose fields to include adjacent segments of at-risk vessels beyond direct contact with the gross disease.

Penile-scrotal erythrodysesthesia among rectal cancer patients receiving fluoropyrimidine-based chemoradiation: a case report series.

BACKGROUND: Palmar-plantar erythrodysesthesia (PPE) is a slowly developing cutaneous reaction commonly experienced by patients treated with fluoropyrimidines. While erythrodysesthesia normally presents in a palmar-plantar distribution, it can also present with genital involvement, but this presentation is likely underreported and incorrectly attributed to an acute reaction from radiation therapy. This article aims to define erythrodysesthesia of the penis and scrotum as a rare but significant side effect of capecitabine. CASE PRESENTATION: We identified five cases of moderate to severe penis and scrotal erythrodysesthesia over a 2-year period at a large tertiary cancer center, representing an estimated incidence of 3.6% among male patients with rectal cancer who were treated with fluoropyrimidine-based chemoradiation within our institution. CONCLUSIONS: Improved understanding of erythrodysesthesia involving the penis and scrotum can facilitate early identification and treatment of symptoms, and possibly prevent the discontinuation or delay of cancer treatment in patients treated with capecitabine and similar drugs. These clinical advances would improve and prolong patient quality of life during cancer treatment and prevent complications that result in hospitalization.

Histopathologic Changes after Yttrium-90 Radioembolization of Colorectal Liver Metastases: A Pilot Feasibility Study.

PURPOSE: To evaluate the histopathologic changes and potential correlations of tumor absorbed dose (TAD) after yttrium-90 transarterial radioembolization (TARE) for colorectal liver metastases (CLMs). MATERIALS AND METHODS: This prospective pilot study assessed 12 patients with 13 CLMs through positron emission tomography (PET)/computed tomography (CT)-guided biopsies before, immediately after TARE (T0), and 3 weeks after TARE (T3). Subsequent sampling from the same location was enabled by fiducial placement. Biopsy samples were evaluated with hematoxylin and eosin, TUNEL, Ki67, OxPhos, caspase-3 (CC3), and pH2AX antibodies. Proliferation changes (Ki67) and double-strand DNA breaks (DSBs) were evaluated quantitatively. TAD was calculated on post-TARE PET/CT scan of the biopsy needle location at T0 and T3. RESULTS: Median TAD at 3 weeks after TARE was 162 Gy (interquartile range (IQR), 92-211 Gy). DSBs decreased significantly from T0 (median, 77%; IQR, 75%-100%) to T3 (median, 14%; IQR, 0%-54%; P = .028). A decrease in Ki67 was also documented (median, 73%; IQR, 70%-80% at T0 vs median, 41%; IQR, 0%-66% at T3; P = .046). There was a strong positive correlation between TAD and DSBs at T0 (r[9] = 0.68) and a strong negative correlation at T3 (r[10] = -0.855; P = .042 and P = .002, respectively). There was a strong negative correlation between TAD and Ki67 at both T0 (r[9] = -0.733; P = .025) and T3 (r[10] = -0.681; P = .030). Tumors that exhibited caspase-3 activation (8/13, 62%) at either T0 or T3 time point were more likely to develop progression (7/8 [88%] vs 1/5 [20%]; P = .015). CONCLUSIONS: Post-TARE biopsy can be used to assess TAD and histopathologic changes. Significant decreases in DSBs and proliferation index were noted after TARE. Post-TARE CC3 activation deserves further exploration.

MR signature matching (MRSIGMA) implementation for true real-time free-breathing volumetric imaging with sub-200 ms latency on an MR-Linac.

PURPOSE: Develop a true real-time implementation of MR signature matching (MRSIGMA) for free-breathing 3D MRI with sub-200 ms latency on the Elekta Unity 1.5T MR-Linac. METHODS: MRSIGMA was implemented on an external computer with a network connection to the MR-Linac. Stack-of-stars with partial kz sampling was used to accelerate data acquisition and ReconSocket was employed for simultaneous data transmission. Movienet network computed the 4D MRI motion dictionary and correlation analysis was used for signature matching. A programmable 4D MRI phantom was utilized to evaluate MRSIGMA with respect to a ground-truth translational motion reference. In vivo validation was performed on patients with pancreatic cancer, where 15 patients were employed to train Movienet and 7 patients to test the real-time implementation of MRSIGMA. Dice coefficients between real-time MRSIGMA and a retrospectively computed 4D reference were used to evaluate motion tracking performance. RESULTS: Motion dictionary was computed in under 5 s. Signature acquisition and matching presented 173 ms latency on the phantom and 193 ms on patients. MRSIGMA presented a mean error of 1.3-1.6 mm for all phantom experiments, which was below the 2 mm acquisition resolution along the motion direction. The Dice coefficient over time between MRSIGMA and reference contours was 0.88 ± 0.02 (GTV), 0.87 ± 0.02(duodenum-stomach), and 0.78 ± 0.02(small bowel), demonstrating high motion tracking performance for both tumor and organs at risk. CONCLUSION: The real-time implementation of MRSIGMA enabled true real-time free-breathing 3D MRI with sub-200 ms imaging latency on a clinical MR-Linac system, which can be used for treatment monitoring, adaptive radiotherapy and dose accumulation mapping in tumors affected by respiratory motion.

Oncologic Outcomes of Salvage Abdominoperineal Resection for Anal Squamous Cell Carcinoma Initially Managed with Chemoradiation.

Background: Abdominoperineal resection (APR) has been advocated for persistent or recurrent disease after failure of chemoradiation (CRT) for anal squamous cell cancer (SCC). Treatment with salvage APR can potentially achieve a cure. This study aimed to analyze oncological outcomes for salvage APR in a recent time period at a comprehensive cancer center. Methods: A retrospective review of all patients who underwent APR for biopsy-proven persistent or recurrent anal SCC between 1 January 2007 and 31 December 2020 was performed. Patients with stage IV disease at the time of initial diagnosis and patients with missing data were excluded. Univariate analysis was used with a chi-square test for categorical variables, and non-parametric tests were used for continuous variables. Kaplan-Meier survival analysis was performed to evaluate disease-specific (DSS), post-APR local recurrence-free (RFS), and disease-free survival (DFS). Results: A total of 96 patients were included in the analysis: 39 (41%) with persistent disease and 57 (59%) with recurrent SCC after chemoradiation had been completed. The median follow-up was 22 months (IQR 11-47). Forty-nine patients (51%) underwent extended APR and/or pelvic exenteration. Eight (8%) patients developed local recurrence, 30 (31%) developed local and distant recurrences, and 16 (17%) developed distant recurrences alone. The 3-year DSS, post-APR local recurrence-free survival, and disease-free survival were 53.8% (95% CI 43.5-66.5%), 54.5% (95% CI 44.4-66.8%), and 26.8% (95% CI 18.6-38.7%), respectively. In multivariate logistic regression analysis, positive microscopic margin (OR 10.0, 95% CI 2.16-46.12, p = 0.003), positive nodes in the surgical specimen (OR 9.19, 95% CI 1.99-42.52, p = 0.005), and lymphovascular invasion (OR 2.61 95% CI 1.05-6.51, p = 0.04) were associated with recurrence of disease. Gender, indication for APR (recurrent vs. persistent disease), HIV status, extent of surgery, or type of reconstruction did not influence survival outcomes. Twenty patients had targeted tumor-sequencing data available. Nine patients had PIK3CA mutations, seven of whom experienced a recurrence. Conclusions: Salvage APR for anal SCC after failed CRT was associated with poor disease-specific survival and low recurrence-free survival. Anal SCC patients undergoing salvage APR should be counseled that microscopic positive margins, positive lymph nodes, or the presence of lymphovascular invasion in the APR specimen are prognosticators for disease relapse. Our results accentuate the necessity for additional treatment strategies for the ongoing treatment challenge of persistent or recurrent anal SCC after failed CRT.

Extramammary Paget Disease. Part II. Evidence-based Approach to Management.

Extramammary Paget disease is a rare cutaneous malignancy that most commonly affects the genitals, perianal area, and axilla of elderly patients. Delays in care often lead to high levels of disease burden for patients. Thus, evidence-based recommendations are paramount in mitigating morbidity and mortality for this unique patient population. This 2-part continuing medical education series provides a complete picture of extramammary Paget disease. Part 2 of this continuing medical education series focuses on the complex management of extramammary Paget disease including surgical and non-invasive therapies, as well as novel approaches for advanced disease.

Radiomodulating Properties of Superparamagnetic Iron Oxide Nanoparticle (SPION) Agent Ferumoxytol on Human Monocytes: Implications for MRI-Guided Liver Radiotherapy.

Superparamagnetic iron oxide nanoparticles (SPION) have attracted great attention not only for therapeutic applications but also as an alternative magnetic resonance imaging (MRI) contrast agent that helps visualize liver tumors during MRI-guided stereotactic body radiotherapy (SBRT). SPION can provide functional imaging of liver parenchyma based upon its uptake by the hepatic resident macrophages or Kupffer cells with a relative enhancement of malignant tumors that lack Kupffer cells. However, the radiomodulating properties of SPION on liver macrophages are not known. Utilizing human monocytic THP-1 undifferentiated and differentiated cells, we characterized the effect of ferumoxytol (Feraheme®), a carbohydrate-coated ultrasmall SPION agent at clinically relevant concentration and therapeutically relevant doses of gamma radiation on cultured cells in vitro. We showed that ferumoxytol affected both monocytes and macrophages, increased the resistance of monocytes to radiation-induced cell death and inhibition of cell activity, and supported the anti-inflammatory phenotype of human macrophages under radiation. Its effect on human cells depended on the duration of SPION uptake and was radiation dose-dependent. The results of this pilot study support a strong mechanism-based optimization of SPION-enhanced MRI-guided liver SBRT for primary and metastatic liver tumors, especially in patients with liver cirrhosis awaiting a liver transplant.

The bioequivalence study design recommendations for immediate-release solid oral dosage forms in the international pharmaceutical regulators programme participating regulators and organisations: differences and commonalities.

Bioequivalence (BE) studies are considered the standard for demonstrating that the performance of a generic drug product in the human body is sufficiently similar to that of its comparator product. The objective of this article is to describe the recommendations from participating Bioequivalence Working Group for Generics (BEWGG) members of the International Pharmaceutical Regulators Programme (IPRP) regarding the conduct and acceptance criteria for BE studies of immediate release solid oral dosage forms. A survey was conducted among BEWGG members regarding their BE recommendations and requirements related to study subjects, study design, sample size, single or multiple dose administration, study conditions (fasting or fed), analyte to be measured, selection of product strength, drug content, handling of endogenous substances, BE acceptance criteria, and additional design aspects. All members prefer conducting single dose cross-over designed studies in healthy subjects with a minimum of 12 subjects and utilizing the parent drug data to assess BE. However, differences emerged among the members when the drug's pharmacokinetics and pharmacodynamics become more complex, such that the study design (e.g., fasting versus fed conditions) and BE acceptance criteria (e.g., highly variable drugs, narrow therapeutic index drugs) may be affected. The survey results and discussions were shared with the ICH M13 Expert Working Group (EWG) and played an important role in identifying and analyzing gaps during the harmonization process. The draft ICH M13A guideline developed by the M13 EWG was endorsed by ICH on 20 December 2022, under Step 2.

Comparison between pelvic MRI, CT, and PET/CT in baseline staging and radiation planning of anal squamous cell carcinoma.

PURPOSE: To investigate the differences in baseline staging of anal squamous cell carcinoma based on CT, MRI, and PET/CT, and the resultant impact on the radiation plan. METHODS: This retrospective study included consecutive patients with anal squamous cell carcinoma who underwent baseline pelvic MRI, CT, and PET/CT (all examinations within 3 weeks of each other) from January 2010 to April 2020. CTs, MRIs, and PET/CTs were re-interpreted by three separate radiologists. Several imaging features were assessed; tumor stage was determined based on the eight edition of the American Joint Committee on Cancer (AJCC) staging manual; and T (tumor), N (node), and M (metastasis) categories were determined based on National Comprehensive Cancer Network (NCCN) guidelines. Radiologist assessments were then randomly presented to a radiation oncologist who formulated the radiation plan in a blinded fashion. RESULTS: Across 28 patients (median age, 62 years [range, 31-78], T-category classification was significantly different on PET/CT compared to MRI and CT (p = 0.037 and 0.031, respectively). PET/CT staged a higher proportion of patients with T1/T2 disease (16/28, 57%) compared to MRI (11/28, 39%) and CT (10/28, 36%). MRI staged a higher proportion of patients with T3/T4 disease (14/28, 50%) compared to CT (12/28, 43%) and PET/CT (11/28, 39%). However, there was no significant difference between the three imaging modalities in terms of either N-category, AJCC staging, or NCCN TNM group classification, or in treatment planning. CONCLUSION: Our exploratory study showed that MRI demonstrated a higher proportion of T3/T4 tumors, while PET/CT demonstrated more T1/T2 tumors; however, MRI, CT, and PET/CT did not show any significant differences in AJCC and TNM group categories, nor was there any significant difference in treatment doses between them when assessed independently by an experienced radiation oncologist.

Radiation Therapy for Colorectal Liver Metastasis: The Effect of Radiation Therapy Dose and Chemotherapy on Local Control and Survival.

Purpose: Colorectal liver metastases (CLMs) represent a radioresistant histology. We aimed to investigate CLM radiation therapy (RT) outcomes and explore the association with treatment parameters. Methods and Materials: This retrospective analysis of CLM treated with RT at Memorial Sloan Kettering Cancer Center used Kaplan-Meier analysis to estimate freedom from local progression (FFLP), hepatic progression-free, progression-free, and overall survival (OS). Cox proportional hazards regression was used to evaluate association with clinical factors. Dose-response relationship was further evaluated using a mechanistic tumor control probability (TCP) model. Results: Ninety patients with 122 evaluable CLMs treated 2006 to 2019 with a variety of RT fractionation schemes with a median biologically effective dose (α/ß = 10; BED10) of 97.9 Gy (range, 43.2-187.5 Gy) were included. Median lesion size was 3.5 cm (0.7-11.8 cm). Eighty-seven patients (97%) received prior systemic therapy, and 73 patients (81%) received prior liver-directed therapy. At a median follow-up of 26.4 months, rates of FFLP and OS were 62% (95% CI, 53%-72%) and 75% (66%-84%) at 1 year and 42% (95% CI, 32%-55%) and 44% (95% CI, 34%-57%) at 2 years, respectively. BED10 below 96 Gy and receipt of ≥3 lines of chemotherapy were associated with worse FFLP (hazard ratio [HR], 2.69; 95% CI, 1.54-4.68; P < .001 and HR, 2.67; 95% CI, 1.50-4.74; P < .001, respectively) and OS (HR, 2.35; 95% CI, 1.35-4.09; P = .002 and HR, 4.70; 95% CI, 2.37-9.31; P < .001) on univariate analyses, which remained significant or marginally significant on multivariate analyses. A mechanistic Tumor Control Probability (TCP) model showed a higher 2-Gy equivalent dose needed for local control in patients who had been exposed to ≥ 3 lines of chemotherapy versus 0 to 2 (250 ± 29 vs 185 ± 77 Gy for 70% TCP). Conclusions: In a large single-institution series of heavily pretreated patients with CLM undergoing liver RT, low BED10 and multiple prior lines of systemic therapy were associated with lower local control and OS. These results support continued dose escalation efforts for patients with CLM.

Daily Vaginal Dilator Use During Radiation for Women With Squamous Cell Carcinoma of the Anus: Vaginal Wall Dosimetry and Patient-Reported Sexual Function.

PURPOSE: At our institution, we treat patients with a daily vaginal dilator (VD) during chemoradiation (CRT) for squamous cell carcinoma of the anus (SCCA). We evaluated compliance with daily VD use, radiation dose to the vaginal wall (VW), and anterior vaginal wall (AVW), and patient-reported long-term sexual function. METHODS AND MATERIALS: We included women with SCCA who received definitive, intensity-modulated radiation therapy-based CRT. Women who were alive without evidence of disease received a patient-reported outcome survey, which included the Female Sexual Function Index (FSFI). We identified factors associated with FSFI, such as radiation dose to the VW and AVW using linear regression models and used Youden index analysis to estimate a dose cutoff to predict sexual dysfunction. RESULTS: Three hundred thirty-nine consecutively treated women were included in the analysis; 285 (84.1%) were treated with a daily VD. Of 184 women alive without disease, 90 patients (49%) completed the FSFI, and 51 (56.7%) were sexually active with valid FSFI scores. All received therapy with a daily VD. Forty-one women (80%) had sexual dysfunction. Univariate analysis showed higher dose to 50% (D50%) of the AVW correlated with worse FSFI (ß -.262; P = .043), worse desire FSFI subscore (ß -.056; P = .003), and worse pain FSFI subscore (ß -.084; P = .009). Younger age correlated with worse pain FSFI subscale (ß .067; P = .026). Age (ß .070; P = .013) and AVW D50% (ß -.087; P = .009) were significant on multivariable analysis. AVW D50% >48 Gy predicted increased risk of sexual dysfunction. CONCLUSIONS: Daily VD use is safe and well tolerated during CRT for SCCA. Using a VD during treatment to displace the AVW may reduce the risk for sexual dysfunction. Limiting the AVW D50% <48 Gy may further reduce the risk but additional data are needed to validate this constraint.

Movienet: Deep space-time-coil reconstruction network without k-space data consistency for fast motion-resolved 4D MRI.

PURPOSE: To develop a novel deep learning approach for 4D-MRI reconstruction, named Movienet, which exploits space-time-coil correlations and motion preservation instead of k-space data consistency, to accelerate the acquisition of golden-angle radial data and enable subsecond reconstruction times in dynamic MRI. METHODS: Movienet uses a U-net architecture with modified residual learning blocks that operate entirely in the image domain to remove aliasing artifacts and reconstruct an unaliased motion-resolved 4D image. Motion preservation is enforced by sorting the input image and reference for training in a linear motion order from expiration to inspiration. The input image was collected with a lower scan time than the reference XD-GRASP image used for training. Movienet is demonstrated for motion-resolved 4D MRI and motion-resistant 3D MRI of abdominal tumors on a therapeutic 1.5T MR-Linac (1.5-fold acquisition acceleration) and diagnostic 3T MRI scanners (2-fold and 2.25-fold acquisition acceleration for 4D and 3D, respectively). Image quality was evaluated quantitatively and qualitatively by expert clinical readers. RESULTS: The reconstruction time of Movienet was 0.69 s (4 motion states) and 0.75 s (10 motion states), which is substantially lower than iterative XD-GRASP and unrolled reconstruction networks. Movienet enables faster acquisition than XD-GRASP with similar overall image quality and improved suppression of streaking artifacts. CONCLUSION: Movienet accelerates data acquisition with respect to compressed sensing and reconstructs 4D images in less than 1 s, which would enable an efficient implementation of 4D MRI in a clinical setting for fast motion-resistant 3D anatomical imaging or motion-resolved 4D imaging.

Analysis of Radiation Therapy Quality Assurance in NRG Oncology RTOG 0848.

PURPOSE: NRG/Radiation Therapy Oncology Group 0848 is a 2-step randomized trial to evaluate the benefit of the addition of concurrent fluoropyrimidine and radiation therapy (RT) after adjuvant chemotherapy (second step) for patients with resected pancreatic head adenocarcinoma. Real-time quality assurance (QA) was performed on each patient who underwent RT. This analysis aims to evaluate adherence to protocol-specified contouring and treatment planning and to report the types and frequencies of deviations requiring revisions. METHODS AND MATERIALS: In addition to a web-based contouring atlas, the protocol outlined step-by-step instructions for generating the clinical treatment volume through the creation of specific regions of interest. The planning target volume was a uniform 0.5 cm clinical treatment volume expansion. One of 2 radiation oncology study chairs independently reviewed each plan. Plans with unacceptable deviations were returned for revision and resubmitted until approved. Treatment started after final approval of the RT plan. RESULTS: From 2014 to 2018, 354 patients were enrolled in the second randomization. Of these, 160 patients received RT and were included in the QA analysis. Resubmissions were more common for patients planned with 3-dimensional conformal RT (43%) than with intensity modulated RT (31%). In total, at least 1 resubmission of the treatment plan was required for 33% of patients. Among patients requiring resubmission, most only needed 1 resubmission (87%). The most common reasons for resubmission were unacceptable deviations with respect to the preoperative gross target volume (60.7%) and the pancreaticojejunostomy (47.5%). CONCLUSION: One-third of patients required resubmission to meet protocol compliance criteria, demonstrating the continued need for expending resources on real-time, pretreatment QA in trials evaluating the use of RT, particularly for pancreas cancer. Rigorous QA is critically important for clinical trials involving RT to ensure that the true effect of RT is assessed. Moreover, RT QA serves as an educational process through providing feedback from specialists to practicing radiation oncologists on best practices.

Anal Adenocarcinoma Treated in the Era of Total Neoadjuvant Therapy and Nonoperative Management.

BACKGROUND: Anal adenocarcinoma bears a treatment strategy unique to other anal cancers. OBJECTIVE: This study aimed to describe oncologic outcomes of total neoadjuvant therapy followed by watch-and-wait approach for anal adenocarcinoma. DESIGN: Retrospective analysis. SETTINGS: This study was conducted at a comprehensive cancer center. PATIENTS: Patients with anal adenocarcinoma treated between 2004 and 2019 were selected. INTERVENTIONS: Fifty-four patients received neoadjuvant therapy and were divided into 2 groups according to their treatment strategy: total neoadjuvant therapy versus single neoadjuvant modality therapy. MAIN OUTCOME MEASURES: Organ preservation, tumor regrowth, local failure, distant metastasis rates, recurrence-free survival, and overall survival. RESULTS: This study included 70 patients with anal adenocarcinoma. Fifty-four patients (77%) received neoadjuvant therapy, of whom 30 (42%) received total neoadjuvant therapy and 24 (34%) received single neoadjuvant modality. Twenty-three (33%) patients achieved complete clinical response and were managed by watch-and-wait approach. The proportion of patients able to continue to watch-and-wait approach was higher after receiving total neoadjuvant therapy (60%) compared with single neoadjuvant modality therapy (20%; p = 0.004). A tumor regrowth rate of 22% was observed in the total neoadjuvant therapy group. The 5-year overall survival rate was 70% (95% CI, 59%-83%), including 61% (95% CI, 42%-88%) for the total neoadjuvant therapy and 65% (95% CI, 48%-88%) for the single neoadjuvant modality groups. Colostomy was avoided in 50% of patients who received total neoadjuvant therapy and 83% of watch-and-wait patients. Five-year recurrence-free survival rates of 55% (95% CI, 39%-79%) and 30% (95% CI, 15%-58%) were observed in the total neoadjuvant therapy and single neoadjuvant modality groups. LIMITATIONS: Retrospective nature. CONCLUSIONS: This is the first report in the literature describing the safety and feasibility of nonoperative management for anal adenocarcinoma. Anal adenocarcinoma treated with total neoadjuvant therapy and nonoperative management achieve regrowth rates comparable to those observed in rectal cancer, with oncologic outcomes similar to those of traditional treatment strategies. See Video Abstract . ADENOCARCINOMA ANAL TRATADO EN LA ERA DE LA TERAPIA NEOADYUVANTE TOTAL Y EL TRATAMIENTO NO QUIRRGICO: ANTECEDENTES:El adenocarcinoma anal conlleva una estrategia de tratamiento único para otros cánceres anales.OBJETIVO:Describir los resultados oncológicos de la terapia neoadyuvante total seguida de observar y esperar en adenocarcinoma anal.DISEÑO:Análisis retrospectivo.AJUSTE:Este estudio se llevó a cabo en un centro oncológico integral.PACIENTES:Se seleccionaron pacientes con adenocarcinoma anal tratados entre 2004-2019.INTERVENCIONES:Cincuenta y cuatro pacientes recibieron terapia neoadyuvante y se dividieron en dos grupos según su estrategia de tratamiento: terapia neoadyuvante total versus terapia de modalidad neoadyuvante única.PRINCIPALES MEDIDAS DE RESULTADO:Preservación de órganos, recurrencia tumoral, falla local, tasas de metástasis a distancia, libre de recurrencia y supervivencia general.RESULTADOS:El estudio incluyó a 70 pacientes con adenocarcinoma anal. Cincuenta y cuatro pacientes (77%) recibieron terapia neoadyuvante, de los cuales 30 (42%) recibieron terapia neoadyuvante total y 24 (34%) recibieron modalidad neoadyuvante única. Veintitrés (33%) pacientes presentaron una respuesta clínica completa y fueron tratados con vigilancia y espera. La proporción de pacientes capaces de continuar en observar y esperar fue mayor después de recibir terapia neoadyuvante total (60%) en comparación con la terapia de modalidad neoadyuvante única (20%) ( p = 0,004). Se observó una tasa de recurrencia tumoral del 22% en el grupo de terapia neoadyuvante total. La tasa de supervivencia general a 5 años fue del 70% (IC95% 59%-83 %), incluido el 61% (IC95% 42%-88%) para la terapia neoadyuvante total y el 65% (IC95% 48%-88%) para grupos de modalidad neoadyuvante única. Se evitó la colostomía en el 50% de los pacientes que recibieron terapia neoadyuvante total y el 83% de los pacientes en observar y esperar. Se observaron tasas de supervivencia libre de recurrencia a cinco años del 55% (IC95% 39%-79%) y del 30% (IC95% 15%-58%) en los grupos de terapia neoadyuvante total y modalidad neoadyuvante única, respectivamente.LIMITACIONES:Diseño retrospectivo.CONCLUSIONES:Este es el primer informe en la literatura que describe la seguridad y viabilidad del tratamiento no quirúrgico del adenocarcinoma anal. El adenocarcinoma anal tratado con terapia neoadyuvante total y manejo no quirúrgico logra tasas de recurrencia comparables a las observadas en el cáncer de recto, con resultados oncológicos similares a las estrategias de tratamientos tradicionales. (Traducción-Dr. Fidel Ruiz Healy ).

Radiation and Immune Checkpoint Inhibitors: Combination Therapy for Treatment of Hepatocellular Carcinoma.

The liver tumor immune microenvironment has been thought to possess a critical role in the development and progression of hepatocellular carcinoma (HCC). Despite the approval of immune checkpoint inhibitors (ICIs), such as programmed cell death receptor 1 (PD-1)/programmed cell death ligand 1 (PD-L1) and cytotoxic T lymphocyte associated protein 4 (CTLA-4) inhibitors, for several types of cancers, including HCC, liver metastases have shown evidence of resistance or poor response to immunotherapies. Radiation therapy (RT) has displayed evidence of immunosuppressive effects through the upregulation of immune checkpoint molecules post-treatment. However, it was revealed that the limitations of ICIs can be overcome through the use of RT, as it can reshape the liver immune microenvironment. Moreover, ICIs are able to overcome the RT-induced inhibitory signals, effectively restoring anti-tumor activity. Owing to the synergetic effect believed to arise from the combination of ICIs with RT, several clinical trials are currently ongoing to assess the efficacy and safety of this treatment for patients with HCC.

Real-time 4D MRI using MR signature matching (MRSIGMA) on a 1.5T MR-Linac system.

Objective. To develop real-time 4D MRI using MR signature matching (MRSIGMA) for volumetric motion imaging in patients with pancreatic cancer on a 1.5T MR-Linac system.Approach. Two consecutive MRI scans with 3D golden-angle radial stack-of-stars acquisitions were performed on ten patients with inoperable pancreatic cancer. The complete first scan (905 angles) was used to compute a 4D motion dictionary including ten pairs of 3D motion images and signatures. The second scan was used for real-time imaging, where each angle (275 ms) was processed separately to match it to one of the dictionary entries. The complete second scan was also used to compute a 4D reference to assess motion tracking performance.Dicecoefficients of the gross tumor volume (GTV) and two organs-at-risk (duodenum-stomach and small bowel) were calculated between signature matching and reference. In addition, volume changes, displacements, center of mass shifts, andDicescores over time were calculated to characterize motion.Main results. Total imaging latency of MRSIGMA (acquisition + matching) was less than 300 ms. TheDicecoefficients were 0.87 ± 0.06 (GTV), 0.86 ± 0.05 (duodenum-stomach), and 0.85 ± 0.05 (small bowel), which indicate high accuracy (high mean value) and low uncertainty (low standard deviation) of MRSIGMA for real-time motion tracking. The center of mass shift was 3.1 ± 2.0 mm (GTV), 5.3 ± 3.0 mm (duodenum-stomach), and 3.4 ± 1.5 mm (small bowel). TheDicescores over time (0.97 ± [0.01-0.03]) were similarly high for MRSIGMA and reference scans in all the three contours.Significance. This work demonstrates the feasibility of real-time 4D MRI using MRSIGMA for volumetric motion tracking on a 1.5T MR-Linac system. The high accuracy and low uncertainty of real-time MRSIGMA is an essential step towards continuous treatment adaptation of tumors affected by real-time respiratory motion and could ultimately improve treatment safety by optimizing ablative dose delivery near gastrointestinal organs.

Definitive Liver Radiotherapy for Intrahepatic Cholangiocarcinoma with Extrahepatic Metastases.

Introduction: Tumor-related liver failure (TRLF) is the most common cause of death in patients with intrahepatic cholangiocarcinoma (ICC). Though we previously showed that liver radiotherapy (L-RT) for locally advanced ICC is associated with less frequent TRLF and longer overall survival (OS), the role of L-RT for patients with extrahepatic metastatic disease (M1) remains undefined. We sought to compare outcomes for M1 ICC patients treated with and without L-RT. Methods: We reviewed ICC patients that found to have M1 disease at initial diagnosis at a single institution between 2010 and 2021 who received L-RT, matching them with an institutional cohort by propensity score and a National Cancer Database (NCDB) cohort by frequency technique. The median biologically effective dose was 97.5 Gy (interquartile range 80.5-97.9 Gy) for L-RT. Patients treated with other local therapies or supportive care alone were excluded. We analyzed survival with Cox proportional hazard modeling. Results: We identified 61 patients who received L-RT and 220 who received chemotherapy alone. At median follow-up of 11 months after diagnosis, median OS was 9 months (95% confidence interval [CI] 8-11) and 21 months (CI: 17-26) for patients receiving chemotherapy alone and L-RT, respectively. TRLF was the cause of death more often in the patients who received chemotherapy alone compared to those who received L-RT (82% vs. 47%; p = 0.001). On multivariable propensity score-matched analysis, associations with lower risk of death included duration of upfront chemotherapy (hazard ratio [HR] 0.82; p = 0.005) and receipt of L-RT (HR: 0.40; p = 0.002). The median OS from diagnosis for NCDB chemotherapy alone cohort was shorter than that of the institutional L-RT cohort (9 vs. 22 months; p < 0.001). Conclusion: For M1 ICC, L-RT associated with a lower rate of death due to TRLF and longer OS versus those treated with chemotherapy alone. Prospective studies of L-RT in this setting are warranted.