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.

Ampullary Adenocarcinoma, Version 1.2023, NCCN Clinical Practice Guidelines in Oncology.

Ampullary cancers refer to tumors originating from the ampulla of Vater (the ampulla, the intraduodenal portion of the bile duct, and the intraduodenal portion of the pancreatic duct), while periampullary cancers may arise from locations encompassing the head of the pancreas, distal bile duct, duodenum, or ampulla of Vater. Ampullary cancers are rare gastrointestinal malignancies, and prognosis varies greatly based on factors such as patient age, TNM classification, differentiation grade, and treatment modality received. Systemic therapy is used in all stages of ampullary cancer, including neoadjuvant therapy, adjuvant therapy, and first-line or subsequent-line therapy for locally advanced, metastatic, and recurrent disease. Radiation therapy may be used in localized ampullary cancer, sometimes in combination with chemotherapy, but there is no high-level evidence to support its utility. Select tumors may be treated surgically. This article describes NCCN recommendations regarding management of ampullary adenocarcinoma.

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.

Neoadjuvant Radiotherapy After (m)FOLFIRINOX for Borderline Resectable Pancreatic Adenocarcinoma: A TAPS Consortium Study.

BACKGROUND: The value of neoadjuvant radiotherapy (RT) after 5-fluorouracil with leucovorin, oxaliplatin, and irinotecan, with or without dose modifications [(m)FOLFIRINOX], for patients with borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC) is uncertain. METHODS: We conducted an international retrospective cohort study including consecutive patients with BR PDAC who received (m)FOLFIRINOX as initial treatment (2012-2019) from the Trans-Atlantic Pancreatic Surgery Consortium. Because the decision to administer RT is made after chemotherapy, patients with metastases or deterioration after (m)FOLFIRINOX or a performance score ≥2 were excluded. Patients who received RT after (m)FOLFIRINOX were matched 1:1 by nearest neighbor propensity scores with patients who did not receive RT. Propensity scores were calculated using sex, age (≤70 vs >70 years), WHO performance score (0 vs 1), tumor size (0-20 vs 21-40 vs >40 mm), tumor location (head/uncinate vs body/tail), number of cycles (1-4 vs 5-8 vs >8), and baseline CA 19-9 level (≤500 vs >500 U/mL). Primary outcome was overall survival (OS) from diagnosis. RESULTS: Of 531 patients who received neoadjuvant (m)FOLFIRINOX for BR PDAC, 424 met inclusion criteria and 300 (70.8%) were propensity score-matched. After matching, median OS was 26.2 months (95% CI, 24.0-38.4) with RT versus 32.8 months (95% CI, 25.3-42.0) without RT (P=.71). RT was associated with a lower resection rate (55.3% vs 72.7%; P=.002). In patients who underwent a resection, RT was associated with a comparable margin-negative resection rate (>1 mm) (70.6% vs 64.8%; P=.51), more node-negative disease (57.3% vs 37.6%; P=.01), and more major pathologic response with <5% tumor viability (24.7% vs 8.3%; P=.006). The OS associated with conventional and stereotactic body RT approaches was similar (median OS, 25.7 vs 26.0 months; P=.92). CONCLUSIONS: In patients with BR PDAC, neoadjuvant RT following (m)FOLFIRINOX was associated with more node-negative disease and better pathologic response in patients who underwent resection, yet no difference in OS was found. Routine use of RT cannot be recommended based on these data.

Intrafractional accuracy and efficiency of a surface imaging system for deep inspiration breath hold during ablative gastrointestinal cancer treatment.

PURPOSE: Beam gating with deep inspiration breath hold (DIBH) usually depends on some external surrogate to infer internal target movement, and the exact internal movement is unknown. In this study, we tracked internal targets and characterized residual motion during DIBH treatment, guided by a surface imaging system, for gastrointestinal cancer. We also report statistics on treatment time. METHODS AND MATERIALS: We included 14 gastrointestinal cancer patients treated with surface imaging-guided DIBH volumetrically modulated arc therapy, each with at least one radiopaque marker implanted near or within the target. They were treated in 25, 15, or 10 fractions. Thirteen patients received treatment for pancreatic cancer, and one underwent separate treatments for two liver metastases. The surface imaging system monitored a three-dimensional surface with ± 3 mm translation and ± 3° rotation threshold. During delivery, a kilovolt image was automatically taken every 20° or 40° gantry rotation, and the internal marker was identified from the image. The displacement and residual motion of the markers were calculated. To analyze the treatment efficiency, the treatment time of each fraction was obtained from the imaging and treatment timestamps in the record and verify system. RESULTS: Although the external surface was monitored and limited to ± 3 mm and ± 3°, significant residual internal target movement was observed in some patients. The range of residual motion was 3-21 mm. The average displacement for this cohort was 0-3 mm. In 19% of the analyzed images, the magnitude of the instantaneous displacement was > 5 mm. The mean treatment time was 17 min with a standard deviation of 4 min. CONCLUSIONS: Precaution is needed when applying surface image guidance for gastrointestinal cancer treatment. Using it as a solo DIBH technique is discouraged when the correlation between internal anatomy and patient surface is limited. Real-time radiographic verification is critical for safe treatments.

Local Control and Survival After Induction Chemotherapy and Ablative Radiation Versus Resection for Pancreatic Ductal Adenocarcinoma With Vascular Involvement.

OBJECTIVE: We sought to compare overall survival (OS) and disease control for patients with localized pancreatic ductal adenocarcinoma (PDAC) treated with ablative dose radiotherapy (A-RT) versus resection. SUMMARY BACKGROUND DATA: Locoregional treatment for PDAC includes resection when possible or palliative RT. A-RT may offer durable tumor control and encouraging survival. METHODS: This was a single-institution retrospective analysis of patients with PDAC treated with induction chemotherapy followed by A-RT [≥98 Gy biologically effective dose (BED) using 15-25 fractions in 3-4.5 Gy/fraction] or pancreatectomy. RESULTS: One hundred and four patients received A-RT (49.8%) and 105 (50.2%) underwent resection. Patients receiving A-RT had larger median tumor size after induction chemotherapy [3.2 cm (undetectable-10.9) vs 2.6 cm (undetectable-10.7), P < 0.001], and were more likely to have celiac or hepatic artery encasement (48.1% vs 11.4%, P <0.001), or superior mesenteric artery encasement (43.3% vs 9.5%, P < 0.001); however, there was no difference in the degree of SMV/PV involvement (P = 0.123). There was no difference in locoregional recurrence/progression at 18-months between A-RT and resection; cumulative incidence was 16% [(95% confidence interval (CI) 10%-24%] versus 21% (95% CI 14%-30%), respectively (P= 0.252). However, patients receiving A-RT had a 19% higher 18-month cumulative incidence of distant recurrence/progression [58% (95% CI 48%-67%) vs 30% (95% CI 30%-49%), P= 0.004]. Median OS from completion of chemotherapy was 20.1 months for A-RT patients (95% CI 16.4-23.1 months) versus 32.9 months (95% CI 29.7-42.3 months) for resected patients (P < 0.001). CONCLUSION: Ablative radiation is a promising new treatment option for PDAC, offering locoregional disease control similar to that associated with resection and encouraging survival.

Pancreatic Adenocarcinoma, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

Pancreatic cancer is the fourth leading cause of cancer-related death among men and women in the United States. A major challenge in treatment remains patients' advanced disease at diagnosis. The NCCN Guidelines for Pancreatic Adenocarcinoma provides recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pancreatic cancer. Although survival rates remain relatively unchanged, newer modalities of treatment, including targeted therapies, provide hope for improving patient outcomes. Sections of the manuscript have been updated to be concordant with the most recent update to the guidelines. This manuscript focuses on the available systemic therapy approaches, specifically the treatment options for locally advanced and metastatic disease.

Accuracy and efficiency of respiratory gating comparable to deep inspiration breath hold for pancreatic cancer treatment.

PURPOSE: Deep inspiration breath hold (DIBH) and respiratory gating (RG) are widely used to reduce movement of target and healthy organs caused by breathing during irradiation. We hypothesized that accuracy and efficiency comparable to DIBH can be achieved with RG for pancreas treatment. METHODS AND MATERIALS: Twenty consecutive patients with pancreatic cancer treated with DIBH (eight) or RG (twelve) volumetric modulated arc therapy during 2017-2019 were included in this study, with radiopaque markers implanted near or in the targets. Seventeen patients received 25 fractions, while the other three received 15 fractions. Only patients who could not tolerate DIBH received RG treatment. While both techniques relied on respiratory signals from external markers, internal target motions were monitored with kV X-ray imaging during treatment. A 3-mm external gating window was used for DIBH treatment; RG treatment was centered on end-expiration with a duty cycle of 40%, corresponding to an external gating window of 2-3 mm. During dose delivery, kV images were automatically taken every 20◦ or 40◦ gantry rotation, from which internal markers were identified. The marker displacement from their initial positions and the residual motion amplitudes were calculated. For the analysis of treatment efficiency, the treatment time of every session was calculated from the motion management waveform files recorded at the treatment console. RESULTS: Within one fraction, the displacement was 0-5 mm for DIBH and 0-6 mm for RG. The average magnitude of displacement for each patient during the entire course of treatment ranged 0-3 mm for both techniques. No statistically significant difference in displacement or residual motion was observed between the two techniques. The average treatment time was 15 min for DIBH and 17 min for RG, with no statistical significance. CONCLUSIONS: The accuracy and efficiency were comparable between RG and DIBH treatment for pancreas irradiation. RG is a feasible alternative strategy to DIBH.

Marital Status and Overall Survival in Patients with Resectable Pancreatic Cancer: Results of an Ancillary Analysis of NRG Oncology/RTOG 9704.

BACKGROUND: Several registry-based analyses suggested a survival advantage for married versus single patients with pancreatic cancer. The mechanisms underlying the association of marital status and survival are likely multiple and complex and, therefore, may be obscured in analyses generated from large population-based databases. The goal of this research was to characterize this potential association of marital status with outcomes in patients with resected pancreatic cancer who underwent combined modality adjuvant therapy on a prospective clinical trial. MATERIALS AND METHODS: This is an ancillary analysis of 367 patients with known marital status treated on NRG Oncology/RTOG 97-04. Survival analysis was performed using the Kaplan-Meier method and compared using the log-rank test. Multivariate analysis was performed using the Cox proportional hazards regression model. RESULTS: Of 367 patients, 271 (74%) were married or partnered and 96 (26%) were single. Married or partnered patients were more likely to be male. There was no association between marital status and overall survival (OS) or disease-free survival (DFS) on univariate (hazard ratio [HR], 1.09 and 1.01, respectively) or multivariate analyses (HR, 1.05 and 0.98, respectively). Married or partnered male patients did not have improved survival compared with female or single patients. CONCLUSION: Ancillary analysis of data from NRG Oncology/RTOG 97-04 demonstrated no association between marital and/or partner status and OS or DFS in patients with resected pancreatic cancer who received adjuvant postoperative chemotherapy followed by concurrent external beam radiation therapy and chemotherapy. Clinical trial identification number. NCT00003216. IMPLICATIONS FOR PRACTICE: Several population-based studies have shown an epidemiological link between marital status and survival in patients with pancreatic cancer. A better understanding of this association could offer an opportunity to improve outcomes through psychosocial interventions designed to mitigate the negative effects of not being married. Based on the results of this analysis, patients who have undergone a resection and are receiving adjuvant therapy on a clinical trial are unlikely to benefit from such interventions. Further efforts to study the association between marital status and survival should be focused on less selected subgroups of patients with pancreatic cancer.

Intrafraction tumor motion during deep inspiration breath hold pancreatic cancer treatment.

PURPOSE: Beam gating with deep inspiration breath hold (DIBH) has been widely used for motion management in radiotherapy. Normally it relies on some external surrogate for estimating the internal target motion, while the exact internal motion is unknown. In this study, we used the intrafraction motion review (IMR) application to directly track an internal target and characterized the residual motion during DIBH treatment for pancreatic cancer patients through their full treatment courses. METHODS AND MATERIALS: Eight patients with pancreatic cancer treated with DIBH volumetric modulated arc therapy in 2017 and 2018 were selected for this study, each with some radiopaque markers (fiducial or surgical clips) implanted near or inside the target. The Varian Real-time Position Management (RPM) system was used to monitor the breath hold, represented by the anterior-posterior displacement of an external surrogate, namely reflective markers mounted on a plastic block placed on the patient's abdomen. Before each treatment, a cone beam computed tomography (CBCT) scan under DIBH was acquired for patient setup. For scan and treatment, the breath hold reported by RPM had to lie within a 3 mm window. IMR kV images were taken every 20° or 40° gantry rotation during dose delivery, resulting in over 5000 images for the cohort. The internal markers were manually identified in the IMR images. The residual motion amplitudes of the markers as well as the displacement from their initial positions located in the setup CBCT images were analyzed. RESULTS: Even though the external markers indicated that the respiratory motion was within 3 mm in DIBH treatment, significant residual internal target motion was observed for some patients. The range of average motion was from 3.4 to 7.9 mm, with standard deviation ranging from 1.2 to 3.5 mm. For all patients, the target residual motions seemed to be random with mean positions around their initial setup positions. Therefore, the absolute target displacement relative to the initial position was small during DIBH treatment, with the mean and the standard deviation 0.6 and 2.9 mm, respectively. CONCLUSIONS: Internal target motion may differ from external surrogate motion in DIBH treatment. Radiographic verification of target position at the beginning and during each fraction is necessary for precise RT delivery. IMR can serve as a useful tool to directly monitor the internal target motion.

Stereotactic body radiation vs. intensity-modulated radiation for unresectable pancreatic cancer.

BACKGROUND: Stereotactic body radiation therapy (SBRT) is an emerging treatment option for unresectable pancreatic cancer, and is postulated to be more effective and less toxic than conventionally fractionated intensity modulated radiation therapy (IMRT). MATERIAL AND METHODS: We retrospectively reviewed unresectable stage I-III pancreatic adenocarcinoma treated from 2008 to 2016 at our institution with SBRT (five fractions, 30-33 Gy) or IMRT (25-28 fractions, 45-56 Gy with concurrent chemotherapy). Groups were compared with respect to overall survival (OS), local and distant failure, and toxicity. Log-rank test and Cox proportional hazards regression model, and competing risks methods were used for univariate and multivariate analysis. RESULTS: SBRT patients (n = 44) were older than IMRT (n = 226) patients; otherwise there was no significant difference in baseline characteristics. There was no significant difference in OS or local or distant failure. There was no significant difference in rates of subsequent resection (IMRT =17%, SBRT =7%, p = .11). IMRT was associated with more acute grade 2+ gastrointestinal toxicity, grade 2+ fatigue, and grade 3+ hematologic toxicity (p = .008, p < .0001, p = .001, respectively). CONCLUSIONS: In this analysis, SBRT achieves similar disease control outcomes as IMRT, with less acute toxicity. This suggests SBRT is an attractive technique for pancreatic radiotherapy because of improved convenience and tolerability with equivalent efficacy. However, the lack of observed advantages in disease control with this moderate-dose SBRT regimen may suggest a role for increasing SBRT dose, if this can be accomplished without significant increase in toxicity.

Distance to the anal verge is associated with pathologic complete response to neoadjuvant therapy in locally advanced rectal cancer.

BACKGROUND AND OBJECTIVES: Achieving a pathologic complete response (pCR) after neoadjuvant therapy has been associated with better prognosis in rectal cancer patients. The objective of this study was to investigate the relationship between distance to the anal verge (DTAV) and pCR. METHODS: Review of a prospectively maintained database of patients with locally advanced rectal cancer who received neoadjuvant treatment was completed. Uni- and multivariate analysis assessed the association between DTAV and pCR after neoadjuvant therapy. RESULTS: Of 827 included patients, 20% had a pCR. We found that pCR rates were 11% for tumors <4 cm, 24% for tumors 4-6 cm, 30% for tumors at 6-8 cm, 17% for tumors 8-10 cm, and 14% for tumors >10 cm from the anal verge (P = 0.002). Multivariate analysis also showed a strong association between DTAV and pCR (P = 0.008). The bimodal distribution of pCR resulted in a lower odds ratio of pCR for tumors <4 and >8 cm from the anal verge. CONCLUSIONS: Patients with low tumors (<4 cm) and higher tumors (>8 cm), were less likely to have a pCR. Further investigation is warranted to determine if these observations are related to tumor biology or possibly differences in radiation technique. J. Surg. Oncol. 2016;114:637-641. © 2016 Wiley Periodicals, Inc.

Neoadjuvant radiotherapy use in locally advanced rectal cancer at NCCN member institutions.

Based on randomized data, neoadjuvant chemoradiotherapy has been incorporated into the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for stage II-III rectal cancer. Factors associated with nonadherence to evidence-based guidelines for neoadjuvant radiotherapy (RT) were examined at dedicated cancer centers. The prospective NCCN Oncology Outcomes Database for Colorectal Cancers was queried for patients with stage II-III rectal cancer who underwent a transabdominal surgical resection between September 2005 and June 2012. Multivariable logistic regression was used to identify factors associated with omission of RT. Among 1199 identified patients, 1119 (93%) received neoadjuvant RT, 51 (4%) did not receive RT, and 29 (2%) received adjuvant RT. Among 51 patients not receiving RT, only 19 (37%) were referred and evaluated by a radiation oncologist. On multivariable analysis, clinical factors associated with not receiving RT included a history of prior pelvic RT (adjusted odds ratio [aOR], 23.9; P=.0003), ECOG performance status of 2 or greater (aOR, 11.1; P=.01), tumor distance from the anal verge greater than 10 cm (aOR, 5.4; P=.009), age at diagnosis of 75 years or older (aOR, 4.43; P=.002), body mass index of 25 to 30 kg/m(2) and less than 25 kg/m(2) (aOR, 5.22 and 4.23, respectively; P=.03), and clinical stage II (aOR, 2.27; P=.02). No significant change was seen in RT use according to diagnosis year, nor was any correlation seen with distance to the nearest RT facility. Concordance with NCCN Guidelines for neoadjuvant RT is high among NCCN Member Institutions. After adjusting for clinical characteristics that increase the risk for RT toxicity, including history of pelvic RT and high comorbidity burden/low functional status, the authors found that non-obese patients of advanced age or those with more favorable clinical features were more likely to not receive RT.

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.

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.

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.

Progressively refined deep joint registration segmentation (ProRSeg) of gastrointestinal organs at risk: Application to MRI and cone-beam CT.

BACKGROUND: Adaptive radiation treatment (ART) for locally advanced pancreatic cancer (LAPC) requires consistently accurate segmentation of the extremely mobile gastrointestinal (GI) organs at risk (OAR) including the stomach, duodenum, large and small bowel. Also, due to lack of sufficiently accurate and fast deformable image registration (DIR), accumulated dose to the GI OARs is currently only approximated, further limiting the ability to more precisely adapt treatments. PURPOSE: Develop a 3-D Progressively refined joint Registration-Segmentation (ProRSeg) deep network to deformably align and segment treatment fraction magnetic resonance images (MRI)s, then evaluate segmentation accuracy, registration consistency, and feasibility for OAR dose accumulation. METHOD: ProRSeg was trained using five-fold cross-validation with 110 T2-weighted MRI acquired at five treatment fractions from 10 different patients, taking care that same patient scans were not placed in training and testing folds. Segmentation accuracy was measured using Dice similarity coefficient (DSC) and Hausdorff distance at 95th percentile (HD95). Registration consistency was measured using coefficient of variation (CV) in displacement of OARs. Statistical comparison to other deep learning and iterative registration methods were done using the Kruskal-Wallis test, followed by pair-wise comparisons with Bonferroni correction applied for multiple testing. Ablation tests and accuracy comparisons against multiple methods were done. Finally, applicability of ProRSeg to segment cone-beam CT (CBCT) scans was evaluated on a publicly available dataset of 80 scans using five-fold cross-validation. RESULTS: ProRSeg processed 3D volumes (128 × 192 × 128) in 3 s on a NVIDIA Tesla V100 GPU. It's segmentations were significantly more accurate ( p < 0.001 $p<0.001$ ) than compared methods, achieving a DSC of 0.94 ±0.02 for liver, 0.88±0.04 for large bowel, 0.78±0.03 for small bowel and 0.82±0.04 for stomach-duodenum from MRI. ProRSeg achieved a DSC of 0.72±0.01 for small bowel and 0.76±0.03 for stomach-duodenum from public CBCT dataset. ProRSeg registrations resulted in the lowest CV in displacement (stomach-duodenum C V x $CV_{x}$ : 0.75%, C V y $CV_{y}$ : 0.73%, and C V z $CV_{z}$ : 0.81%; small bowel C V x $CV_{x}$ : 0.80%, C V y $CV_{y}$ : 0.80%, and C V z $CV_{z}$ : 0.68%; large bowel C V x $CV_{x}$ : 0.71%, C V y $CV_{y}$ : 0.81%, and C V z $CV_{z}$ : 0.75%). ProRSeg based dose accumulation accounting for intra-fraction (pre-treatment to post-treatment MRI scan) and inter-fraction motion showed that the organ dose constraints were violated in four patients for stomach-duodenum and for three patients for small bowel. Study limitations include lack of independent testing and ground truth phantom datasets to measure dose accumulation accuracy. CONCLUSIONS: ProRSeg produced more accurate and consistent GI OARs segmentation and DIR of MRI and CBCTs compared to multiple methods. Preliminary results indicates feasibility for OAR dose accumulation using ProRSeg.

Phase 1 Dose Escalation Study of SBRT Using 3 Fractions for Locally Advanced Pancreatic Cancer.

PURPOSE: The optimal dose and fractionation of stereotactic body radiation therapy (SBRT) for locally advanced pancreatic cancer (LAPC) have not been defined. Single-fraction SBRT was associated with more gastrointestinal toxicity, so 5-fraction regimens have become more commonly employed. We aimed to determine the safety and maximally tolerated dose of 3-fraction SBRT for LAPC. METHODS AND MATERIALS: Two parallel phase 1 dose escalation trials were conducted from 2016 to 2019 at Memorial Sloan Kettering Cancer Center and University of Colorado. Patients with histologically confirmed LAPC without distant progression after at least 2 months of induction chemotherapy were eligible. Patients received 3-fraction linear accelerator-based SBRT at 3 dose levels, 27, 30, and 33 Gy, following a modified 3+3 design. Dose-limiting toxicity, defined as grade ≥3 gastrointestinal toxicity within 90 days, was scored by National Cancer Institute Common Terminology Criteria for Adverse Events, version 4. The secondary endpoints included cumulative incidence of local failure (LF) and distant metastasis (DM), as well as progression-free and overall survival PFS and OS, respectively, toxicity, and quality of life (QoL) using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and the pancreatic cancer-specific QLQ-PAN26 questionnaire. RESULTS: Twenty-four consecutive patients were enrolled (27 Gy: 9, 30 Gy: 8, 33 Gy: 7). The median (range) age was 67 (52-79) years, and 12 (50%) had a head/uncinate tumor location, with a median tumor size of 3.8 (1.1-11) cm and CA19-9 of 60 (1-4880) U/mL. All received chemotherapy for a median of 4 (1.4-10) months. There were no grade ≥3 toxicities. Two-year rates (95% confidence interval) of LF, DM, PFS, and OS were 31.7% (8.6%-54.8%), 70.2% (49.7%-90.8%), 20.8% (4.6%-37.1%), and 29.2% (11.0%-47.4%), respectively. Three- and 6-month QoL assessment showed no detriment. CONCLUSIONS: For select patients with LAPC, dose escalation to 33 Gy in 3 fractions resulted in no dose-limiting toxicities, no detriments to QoL, and disease outcomes comparable with conventional RT. Further exploration of SBRT schemes to maximize tumor control while enabling efficient integration with systemic therapy is warranted.

Abbreviated course of radiation therapy with concurrent temozolomide for high-grade glioma in patients of advanced age or poor functional status.

Elderly or frail patients with high-grade gliomas (HGG) can be effectively treated with an abbreviated course of radiation therapy (RT) consisting of 40 Gy in 15 fractions. Concurrent temozolomide (TMZ) improves survival in non-elderly patients with glioblastoma treated with standard schedule of 60 Gy in 30 fractions. We describe our institutional experience of combining abbreviated RT with concurrent TMZ for treatment of HGG. Between 1/1/2004 and 2/5/2010 31 patients were treated. Survival was estimated with the Kaplan-Meier method. Toxicity was scored according to CTCAE 3.0. Median age was 66 years (range 32-90), and 17 patients had Karnofsky performance score <70. At the time of analysis, 30 patients (98 %) had died, with a followup of 14 months in the surviving patient. Median survival was 11 months (range 1-20), and 41 % of patients were alive at 12 months. Thirty patients (97 %) had a decreased corticosteroid requirement after completion of therapy. Only one new hospitalization for worsening neurologic status was required during therapy. Grade 3-4 hematologic toxicity occurred in 11 patients. Abbreviated RT with concurrent TMZ provides a clinical benefit, is safe and tolerable in patients of advanced age or poor functional status.

Automatic stent recognition using perceptual attention U-net for quantitative intrafraction motion monitoring in pancreatic cancer radiotherapy.

PURPOSE: Stent has often been used as an internal surrogate to monitor intrafraction tumor motion during pancreatic cancer radiotherapy. Based on the stent contours generated from planning CT images, the current intrafraction motion review (IMR) system on Varian TrueBeam only provides a tool to verify the stent motion visually but lacks quantitative information. The purpose of this study is to develop an automatic stent recognition method for quantitative intrafraction tumor motion monitoring in pancreatic cancer treatment. METHODS: A total of 535 IMR images from 14 pancreatic cancer patients were retrospectively selected in this study, with the manual contour of the stent on each image serving as the ground truth. We developed a deep learning-based approach that integrates two mechanisms that focus on the features of the segmentation target. The objective attention modeling was integrated into the U-net framework to deal with the optimization difficulties when training a deep network with 2D IMR images and limited training data. A perceptual loss was combined with the binary cross-entropy loss and a Dice loss for supervision. The deep neural network was trained to capture more contextual information to predict binary stent masks. A random-split test was performed, with images of ten patients (71%, 380 images) randomly selected for training, whereas the rest of four patients (29%, 155 images) were used for testing. Sevenfold cross-validation of the proposed PAUnet on the 14 patients was performed for further evaluation. RESULTS: Our stent segmentation results were compared with the manually segmented contours. For the random-split test, the trained model achieved a mean (±standard deviation) stent Dice similarity coefficient (DSC), 95% Hausdorff distance (HD95), the center-of-mass distance (CMD), and volume difference V o l d i f f $Vo{l_{diff}}$ were 0.96 (±0.01), 1.01 (±0.55) mm, 0.66 (±0.46) mm, and 3.07% (±2.37%), respectively. The sevenfold cross-validation of the proposed PAUnet had the mean (±standard deviation) of 0.96 (±0.02), 0.72 (±0.49) mm, 0.85 (±0.96) mm, and 3.47% (±3.27%) for the DSC, HD95, CMD, and V o l d i f f $Vo{l_{diff}}$ . CONCLUSION: We developed a novel deep learning-based approach to automatically segment the stent from IMR images, demonstrated its clinical feasibility, and validated its accuracy compared to manual segmentation. The proposed technique could be a useful tool for quantitative intrafraction motion monitoring in pancreatic cancer radiotherapy.