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To systematically review all dosimetric studies investigating the impact of deep inspiration breath hold (DIBH) compared with free breathing (FB) in mediastinal lymphoma patients treated with proton therapy as compared to IMRT (intensity-modulated radiation therapy)-DIBH.We conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline using the PubMed database to identify studies of mediastinal lymphoma patients with dosimetric comparisons of proton-FB and/or proton-DIBH with IMRT-DIBH. Parameters included mean heart (MHD), lung (MLD), and breast (MBD) doses, among other parameters. Case reports were excluded. Absolute differences in mean doses 1 Gy between comparators were considered to be clinically meaningful.As of April 2021, eight studies fit these criteria (n = 8), with the following comparisons: proton-FB vs IMRT-DIBH (n = 5), proton-DIBH vs proton-FB (n = 5), and proton-DIBH vs IMRT-DIBH (n = 8). When comparing proton-FB with IMRT-DIBH in 5 studies, MHD was reduced with proton-FB in 2 studies, was similar (1 Gy difference) in 2 studies, and increased in 1 study. On the other hand, MLD and MBD were reduced with proton-FB in 3 and 4 studies, respectively. When comparing proton-DIBH with proton-FB, MHD and MLD were reduced with proton DIBH in 4 and 3 studies, respectively, while MBD remained similar. Compared with IMRT-DIBH in 8 studies, proton-DIBH reduced the MHD in 7 studies and was similar in 1 study. Furthermore, MLD and MBD were reduced with proton-DIBH in 8 and 6 studies respectively. Integral dose was similar between proton-FB and proton-DIBH, and both were substantially lower than IMRT-DIBH.Accounting for heart, lung, breast, and integral dose, proton therapy (FB or DIBH) was superior to IMRT-DIBH. Proton-DIBH can lower dose to the lungs and heart even further compared with proton-FB, depending on disease location in the mediastinum, and organ-sparing and target coverage priorities.

Allogeneic hematopoietic cell transplantation (alloHCT) is indicated for patients with intermediate-risk or high-risk myelofibrosis (MF) and remains the sole potential cure. Reduced-intensity conditioning (RIC) is commonly used because of older patient age, comorbidities, and a high incidence of transplantation-related mortality. Patients with MF are at increased risk of graft failure (GF), which is more common with RIC regimens, and is associated with shortened overall survival (OS). Owing to the high rate of GF with conventional fludarabine (Flu) and busulfan (Bu) RIC, we added low-dose total body irradiation (TBI; 200 cGy) for patients with MF. We retrospectively compared alloHCT outcomes in adult patients with MF who received RIC with Flu/Bu/TBI and those who received RIC with Flu/Bu. The primary endpoint was the incidence of GF. Secondary endpoints included time to engraftment, acute and chronic graft-versus-host disease (GVHD), hepatic sinusoidal obstruction syndrome (SOS), nonrelapse mortality, overall response rate, progression-free survival, and OS. Of 33 patients who underwent alloHCT, 8 received Flu/Bu RIC and 25 received Flu/Bu/TBI RIC. GF occurred in 50% of the Flu/Bu recipients (all secondary GF) and in 4% of the Flu/Bu/TBI recipients (1 case of primary GF; relative risk, .08; 95% confidence interval [CI], .01 to .62; P = .0016). GF incidence was similar with related or unrelated donors and in patients who did and did not receive Janus-associated kinase inhibitors prior to alloHCT. Molecular remission and donor chimerism ≥99% were significantly more common with Flu/Bu/TBI. No significant differences in acute GVHD, chronic GVHD, or time to engraftment were observed. SOS occurred in none of the 8 patients who received Flu/Bu and in 6 of the 25 patients who received Flu/Bu/TBI, but this difference did not reach statistical significance. Progression or relapse at 1 year was less common with Flu/Bu/TBI (0% versus 63%; P.001). The median OS was 49 months for Flu/Bu/TBI recipients and 30.8 months for Flu/Bu recipients (hazard ratio, .98; 95% CI, .33 to 2.88; P = .97). Flu/Bu/TBI resulted in a significant reduction in GF and a significant improvement in the frequency of molecular remission and full donor chimerism compared with Flu/Bu. The addition of low-dose TBI to Flu/Bu successfully mitigates against GF in patients with MF without increased rates of complications.

Supplementary Figures 1-2 from Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and paclitaxel have cooperative in vivo effects against glioblastoma multiforme cells

sTable 1 shows radiation characteristics of Group A, B, and C. sTable 2 shows characteristics of CART-BCMA cells during manufacturing and at peak expansion in vivo in Group A, B, and C. sTable 3 shows details of radiation received after CART-BCMA therapy. sFigure 1 shows soluble BCMA serum levels before cyclophosphamide lymphodepletion on Day -3. sFigure 2 shows that prior radiation exposure is not associated with the level of CART-BCMA cells in vivo at peak expansion. sFigure 3 shows radiation was not associated with the level of persistent CART-BCMA cells in peripheral blood at Day 28. sFigure 4 shows level of CART-BCMA cells at peak expansion and Day 28 correlated with clinical response, and within responders, receipt of prior radiation was not associated with differences in CART=BCMA levels.

Purpose:B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cells (CART-BCMA) are a promising treatment for relapsed/refractory multiple myeloma (r/rMM). We evaluated the safety and feasibility of bridging radiation (RT) in subjects treated on a phase I trial of CART-BCMA.Experimental Design:Twenty-five r/rMM subjects were treated in three cohorts with two doses of CART-BCMA cells ± cyclophosphamide. We retrospectively analyzed toxicity, response, and CART manufacturing data based on RT receipt.Results:Thirteen subjects received no RT 18–35). Group C had qualitatively lower rates of grade 4 (G4) hematologic toxicities (25%) versus A (61.5%) and B (62.5%). G3–4 neurotoxicity occurred in 7.7%, 25%, and 25% in Group A, B, and C, respectively. G3–4 cytokine release syndrome was observed in 38.5%, 25%, and 25% in Group A, B, and C, respectively. Partial response or better was observed in 54%, 38%, and 50% of Group A, B, and C, respectively. RT administered P = 0.002) and P = 0.069) before apheresis was associated with lower in vitro proliferation during manufacturing; however, in vivo CART-BCMA expansion appeared similar across groups.Conclusions:Bridging-RT appeared safe and feasible with CART-BCMA therapy in our r/rMM patients, though larger future studies are needed to draw definitive conclusions.

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) in conjunction with microtubule-targeting agents may be a promising novel anticancer treatment strategy. In vitro studies have suggested that relatively low concentrations of TRAIL enhance the lethality of paclitaxel (Taxol) against human cancer cells. The increased efficacy may be due to the triggering of caspase activation, resulting in mitotic checkpoint abrogation and catastrophe. We show here that wild-type p53 protects cells from caspase-dependent death induced by this therapeutic combination in vitro. We have now also developed an imaging-based model system to test the in vivo efficacy of combined TRAIL and Taxol, in which tumor growth and treatment response can be monitored noninvasively and in real-time. We further utilize bioluminescence, F18-fluorodeoxyglucose-positron emission tomography, and microscale computed tomography imaging to confirm the effects of combined treatment on tumors. These studies together provide the first in vivo confirmation that combined TRAIL plus paclitaxel results in better tumor control compared with either TRAIL or paclitaxel alone, and with no discernable increased normal tissue toxicity in the mouse. Interestingly, the in vivo antitumor response elicited by combined treatment was not affected by the p53 status of the tumor cells. These preclinical observations together suggest the therapeutic potential of combining TRAIL plus paclitaxel in cancer treatment, and support further preclinical and future clinical testing. [Mol Cancer Ther 2009;8(12):3285–95]

Supplementary Figures 1-3 from Cell Cycle–Dependent and Schedule-Dependent Antitumor Effects of Sorafenib Combined with Radiation

Supplementary Materials and Figure Legends 1-3 from Cell Cycle–Dependent and Schedule-Dependent Antitumor Effects of Sorafenib Combined with Radiation

The antineoplastic drug sorafenib (BAY 43-9006) is a multikinase inhibitor that targets the serine-threonine kinase B-Raf as well as several tyrosine kinases. Given the numerous molecular targets of sorafenib, there are several potential anticancer mechanisms of action, including induction of apoptosis, cytostasis, and antiangiogenesis. We observed that sorafenib has broad activity in viability assays in several human tumor cell lines but selectively induces apoptosis in only some lines. Sorafenib was found to decrease Mcl-1 levels in most cell lines tested, but this decrease did not correlate with apoptotic sensitivity. Sorafenib slows cell cycle progression and prevents irradiated cells from reaching and accumulating at G2-M. In synchronized cells, sorafenib causes a reversible G1 delay, which is associated with decreased levels of cyclin D1, Rb, and phosphorylation of Rb. Although sorafenib does not affect intrinsic radiosensitivity using in vitro colony formation assays, it significantly reduces colony size. In HCT116 xenograft tumor growth delay experiments in mice, sorafenib alters radiation response in a schedule-dependent manner. Radiation treatment followed sequentially by sorafenib was found to be associated with the greatest tumor growth delay. This study establishes a foundation for clinical testing of sequential fractionated radiation followed by sorafenib in gastrointestinal and other malignancies. [Cancer Res 2007;67(19):9443–54]

The role of radiation therapy (RT) varies across hematologic malignancies (HM). Radiation oncology (RO) resident comfort with specific aspects of HM patient management is unknown. The International Lymphoma RO Group (ILROG) assessed resident HM training opportunities and interest in an HM away elective. RO residents (PGY2-5) in the Association of Residents in RO (ARRO) database (n = 572) were emailed an anonymous, web-based survey in January 2019 including binary, Likert-type scale (1 = not at all, 5 = extremely, reported as median [interquartile range]), and multiple-choice questions. Of 134 resident respondents (23%), 86 (64%) were PGY4/5 residents and 36 (27%) were in larger programs (≥ 13 residents). Residents reported having specialized HM faculty (112, 84%) and a dedicated HM rotation (95, 71%). Residents reported “moderate” preparedness to advocate for RT in multidisciplinary conferences (3 [2–3]); make HM-related clinical decisions (3 [2–4]); and critique treatment planning (3 [2–4]). They reported feeling “moderately” to “quite” prepared to contour HM cases (3.5 [3–4]) and “quite” prepared to utilize the PET-CT five-point scale (4 [3–5]). Overall, residents reported feeling “moderately” prepared to treat HM patients (3 [2–3]); 24 residents (23%) felt “quite” or “extremely” prepared. Sixty-six residents (49%) were potentially interested in an HM away elective, commonly to increase comfort with treating HM patients (65%). Therefore, HM training is an important component of RO residency, yet a minority of surveyed trainees felt quite or extremely well prepared to treat HM patients. Programs should explore alternative and additional educational opportunities to increase resident comfort with treating HM patients. Supplementary Information The online version contains supplementary material available at 10.1007/s13187-021-02098-9.

Recent improvements in chemoimmunotherapies, targeted agents, hematopoietic stem cell transplants, and cellular therapies have revolutionized treatment paradigms for patients with diffuse large B-cell lymphoma (DLBCL). Even in the relapsed or refractory setting, contemporary treatment options are delivered with curative intent and can lead to lasting remissions. Although such therapies have improved overall outcomes, they have increasingly led to a wide variety of presentations of recurrent tumors in need of palliation. Here, we review the use of radiotherapy (RT) in the palliation of DLBCL. We draw particular attention to the evolving role for hypofractionated RT and low-dose RT for DLBCL. We review the available literature on these topics and focus on commonly encountered clinical scenarios.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Historically, radiation therapy (RT) served as the primary treatment modality for patients with localized disease. While still an option for select patients who are not candidates for systemic therapy, RT is currently used most frequently as a consolidation treatment after chemoimmunotherapy. Consolidation RT is most commonly recommended after an abbreviated course of systemic therapy in patients who have bulky disease or multiple risk factors, or in the setting of a partial response. Consolidation RT is also appropriate in some patients with advanced DLBCL, including those presenting with bulky disease (≥7.5 cm). While many patients achieve sustained remissions after first-line therapy, up to 50% of patients with DLBCL will eventually relapse. The most common salvage options include second-line chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) and chimeric antigen receptor (CAR) T-cell therapy. RT can be used in both settings to optimize clinical outcomes. This includes consolidation RT in patients with localized presentations or bulky disease in the setting of ASCT and bridging RT in select patients undergoing CAR T-cell therapy. RT is also a valuable modality in any patient with symptomatic disease requiring palliation.

Purpose Primary mediastinal B cell lymphoma (PMBCL) is a highly curable subtype of non-Hodgkin lymphoma that is diagnosed predominantly in adolescents and young adults. Consequently, long-term treatment-related morbidity is critical to consider when devising treatment strategies that include different chemoimmunotherapy strategies with or without radiation therapy. Furthermore, adaptive approaches using the end-of-chemotherapy (EOC) positron emission tomography (PET)/computed tomography (CT) scanning may help to determine which patients may benefit from additional therapies. We aimed to develop evidence-based guidelines for treating these patients. Methods and Materials We conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline using the PubMed database. The ARS expert committee, composed of radiation oncologists, hematologists, and pediatric oncologists, developed consensus guidelines using the modified Delphi framework. Results Nine studies met the full criteria for inclusion based on reporting outcomes on patients with primary mediastinal B cell lymphoma with EOC PET/CT response scored with the 5-point Deauville scale. These studies formed the evidence for these guidelines in managing patients with PMBCL according to the EOC PET response, including after a 5-point Deauville scale of 1 to 3, 4, or 5, and for patients with relapsed and refractory disease. The expert group also developed guidance on radiation simulation, treatment planning, and plan evaluation based on expert opinion. Conclusions Various treatment approaches exist in the management of PMBCL, including different chemoimmunotherapy regimens, the use of consolidative radiation therapy, and adaptive approaches based on EOC PET/CT response. These guidelines can be used by practitioners to provide appropriate treatment according to different disease scenarios.

The effects of thoracic radiation therapy (RT) on physical functioning and quality of life (QoL) are incompletely defined. We determined the associations between thoracic RT dose volume metrics, physical activity, and QoL in patients with cancer.Participants with breast cancer, lung cancer, or mediastinal lymphoma treated with radiation with or without chemotherapy were enrolled in a prospective, longitudinal cohort study. Data were collected pre-RT, immediately post-RT, and 5 to 9 months post-RT. At each timepoint, self-reported physical activity was assessed via the Godin-Shephard Leisure-Time Physical Activity Questionnaire, and QoL metrics were assessed via Functional Assessment of Chronic Illness Therapy Fatigue and Dyspnea Scales. Multivariable adjusted linear regression models were stratified by breast cancer alone and lung cancer and lymphoma combined.One hundred thirty participants were included in the study. In breast cancer (n = 80), each 1-Gy increase in mean heart dose was associated with worse Functional Assessment of Chronic Illness Therapy Fatigue scores (-1.0; 95% confidence interval [CI], -1.9 to -0.2; P = .021); similar associations were observed between V5 and fatigue (-2.5; 95% CI, -4.4 to -0.6; P = .010 for each 10% increase in V5). In lung cancer and lymphoma (n = 50), each 10% increase in V5 was associated with decreased physical activity (Godin-Shephard Leisure-Time Physical Activity Questionnaire score -2.3; 95% CI, -4.3 to -0.4; P = .017). Although the associations between baseline levels of physical activity and fatigue and dyspnea were of borderline significance in breast cancer alone (P.10), increased physical activity over time was associated with improvements in fatigue and dyspnea across all cancer types (P.05 for all).Higher cardiac RT dose was associated with worse fatigue and physical activity across breast cancer, lung cancer, and mediastinal lymphoma. Longitudinal increases in physical activity were associated with concurrent improvements in QoL measures. Strategies to increase physical activity and decrease cardiac RT dose may improve physical functioning and QoL for patients with cancer.

PURPOSE: Physical activity is associated with decreased hospitalization during cancer treatment. We hypothesize that activity data can help identify and triage high-risk patients with GI cancer undergoing concurrent chemoradiation. MATERIALS AND METHODS: This prospective study randomly assigned patients to activity monitoring versus observation. In the intervention arm, a 20% decrease in daily steps or 20% increase in heart rate triggered triage visits to provide supportive care, medication changes, and escalation of care. In the observation group, activity data were recorded but not monitored. The primary objective was to show a 20% increase in triage visits in the intervention group. Secondary objectives were estimating the rates of emergency department (ED) visits and hospitalizations. Crude and adjusted odds ratios were computed using logistic regression modeling. RESULTS: There were 22 patients in the intervention and 18 in the observation group. Baseline patient and treatment characteristics were similar. The primary objective was met, with 3.4 more triage visits in the intervention group than in the observation group (95% CI, 2.10 to 5.50; P < .0001). Twenty-six (65.0%) patients required at least one triage visit, with a higher rate in the intervention arm compared with that in the observation arm (86.4% v 38.9%; odds ratio, 9.95; 95% CI, 2.13 to 46.56; P = .004). There was no statistically significant difference in ED visit (9.1% v 22.2%; P = .38) or hospitalization (4.5% v 16.7%; P = .31). CONCLUSION: It is feasible to use activity data to trigger triage visits for symptom management. Further studies are investigating whether automated activity monitoring can assist with early outpatient management to decrease ED visits and hospitalizations.

We conducted a phase I/II multicenter trial using six cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for treatment of patients with CD30-positive B-cell lymphomas. Thirty-one patients were evaluable for toxicity and 29 for efficacy including 22 with primary mediastinal B-cell lymphoma, five with diffuse large B-cell lymphoma, and two with gray zone lymphoma. There were no treatmentrelated deaths; 32% of patients had non-hematologic grade 3/4 toxicities. The overall response rate was 100% (95% confidence interval [95% CI]: 88-100) with 86% (95% CI: 68-96) of patients achieving complete response at the end of systemic treatment. Consolidative radiation following end-of-treatment response assessment was permissible and used in 52% of all patients including 59% of the patients with primary mediastinal B-cell lymphoma. With a median follow-up of 30 months, the 2- year progression-free survival and overall survival rates were 85% (95% CI: 66-94) and 100%, respectively. In the cohort with primary mediastinal B-cell lymphoma, the 2-year progression-free survival rate was 86% (95% CI: 62-95). In summary, BV-R-CHP with or without consolidative radiation is a feasible and active frontline regimen for CD30-positive Bcell lymphomas (ClinicalTrials.gov identifier: NCT01994850).

Background: Radiotherapy (RT) is part of the standard of care management of most gastrointestinal (GI) cancers. Even with advanced RT, systemic therapy, and surgical techniques, locoregional recurrences or second primary cancers can still occur within previously irradiated fields, which can present challenges in delivering effective and safe treatment. Options for reirradiation are often limited, but given the favorable dosimetric aspects of proton-beam RT, it may provide an effective and safe re-irradiation option for patients with recurrent or second primary GI cancers. Methods: We conducted a systematic review as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement protocol, assessing for reports of proton-beam reirradiation for recurrent or second primary GI cancers, primarily via PubMed. From the initial 373 articles identified, 7 articles were ultimately included in the analysis. Results: The 7 included studies reported on proton-beam re-irradiation for the following disease sites: esophageal (n=2), pancreas (n=1), liver (n=2), rectal (n=1), and anal (n=1). Study sizes varied from as few as 1 to as many as 83 patients. Across studies, in patients who presented with tumor-related symptoms, palliation (stability/improvement) was achieved in 80–100% of the cases. Local control rates, with variable follow-up, ranged from 36–100%. All median overall survival values, when reported, were greater than 1 year. Across both liver studies, there were no cases of radiation-induced liver disease (RILD) from proton-beam re-irradiation. Across all studies, there were 2 acute (esophagopleural fistula in esophageal cancer, small bowel perforation in pancreatic cancer) and 1 late (esophageal ulcer in esophageal cancer) grade 5 toxicities, all favored to be due to progressive disease, rather than proton-beam re-irradiation. Two studies (1 esophageal, 1 rectal) generated comparison photon plans. One found that proton therapy reduced mean heart and lung doses, spinal cord dose, and lung V5Gy as compared to photon treatment, while resulting in higher lung V20Gy and V30Gy. The other found that protons decreased bowel V10Gy, V20Gy, and the dose to 200 and 150 cc of bowel, as compared to photons. Conclusions: Based upon the published experiences, proton-beam re-irradiation for recurrent or second primary GI cancers appears effective for palliation, with good disease-control, limited toxicity, favorable dosimetry, and overall compares well with published non-proton-beam experiences. Given short follow-up, additional studies are warranted to determine if dosimetric advantages from proton therapy will translate into comparative toxicity benefits.

Sinus histiocytosis with massive lymphadenopathy (Rosai Dorfman Disease [RDD]), is a rare, benign but clinically heterogeneous histiocytic disorder. Our aims were to analyze the clinical characteristics of the disease and explore the outcomes of patients with RDD followed at our institution. Between January 2000 and February 2019, there were 15 patients with a pathologically confirmed diagnosis of RDD. Median age at diagnosis was 48 years old (range 26-78). The majority (87%

Background Total skin electron therapy (TSET) utilizes high-energy electrons to treat malignancies on the entire body surface. The otherwise invisible radiation beam can be observed via the optical Cherenkov photons emitted from interactions between the high-energy electron beam and tissue. Methods and materials With a time-gated intensified camera system, the Cherenkov emission can be used to evaluate the dose uniformity on the surface of the patient in real time. Fifteen patients undergoing TSET in various conditions (whole body and half body) were imaged and analyzed. Each patient was monitored during TSET via in vivo detectors (IVD) in nine locations. For accurate Cherenkov imaging, a comparison between IVD and Cherenkov profiles was conducted using a polyvinyl chloride board to establish the perspective corrections. Results and discussion With proper corrections developed in this study including the perspective and inverse square corrections, the Cherenkov imaging provided two-dimensional maps proportional to dose and projected on patient skin. The results of ratio between chest and umbilicus points were in good agreement with in vivo point dose measurements, with a standard deviation of 2.4% compared to OSLD measurements. Conclusions Cherenkov imaging is a viable tool for validating patient-specific dose distributions during TSET.

Purpose: This study evaluates the toxicity and tumor response with concurrent nab-paclitaxel chemoradiotherapy (CRT) compared with standard (5-fluorouracil or gemcitabine) CRT. Materials and Methods: Fifty patients with borderline resectable or unresectable pancreatic adenocarcinoma from 2014 to 2017 were divided into 2 groups: concurrent nab-paclitaxel (100 to 125 mg/m2 weekly) CRT (median: 2.1 Gy fraction size and 52.5 Gy total) or standard CRT (median: 1.8 Gy fraction size, 54.5 Gy total). The primary endpoint was toxicity, and secondary endpoints were local failure and conversion to resectability. Comparisons were made using rank-sum or Fisher exact test and multivariable competing risk regression for the cumulative incidence of local failure. Results: There were 28 patients in the nab-paclitaxel CRT group and 22 in the standard CRT group; 88% had the unresectable disease. The median follow-up was 18 months. The median duration of chemotherapy before concurrent CRT was 1.9 and 2.3 months in the nab-paclitaxel and standard CRT groups (P=0.337), and radiotherapy dose was 52.5 Gy (range, 52.5 to 59.4 Gy) and 54.5 Gy (range, 45.0 to 59.4 Gy), respectively. There were no statistically significant grade ≥2 toxicities. The nab-paclitaxel CRT group experienced a nonstatistically significant lower incidence of local failure (hazard ratio=0.91, 95% confidence interval: 0.27-3.03, P=0.536). More patients in the nab-paclitaxel CRT group proceeded to surgery (9/28 compared with 3/22 in the standard CRT, P=0.186); of which 6 (25%) in the nab-paclitaxel CRT and 2 (10%) in the standard CRT groups were initially unresectable. Conclusions: Nab-paclitaxel CRT had similar toxicity compared with standard CRT in the treatment of borderline resectable or unresectable pancreatic cancer. Its use was associated with an arithmetically lower cumulative incidence of local failure and an arithmetically higher conversion to resectability, both of which were not statistically significant.

PurposeRadiation therapy (RT) with doses ranging from 24 Gray (Gy) to 40 Gy is a proven treatment modality for indolent orbital adnexal lymphoma (IOAL), but recently the use of low dose RT (LDRT, defined as 2 Gy x 2 fractions) has become a notable alternative. However, limited data exists comparing outcomes following LDRT to moderate-dose RT (MDRT, RT dose 4 – 36 Gy). We present a single institution retrospective analysis comparing outcomes of patients with IOALs following LDRT or MDRT.MethodsA total of 36 patients treated with 38 consecutive courses of RT were identified; LDRT was delivered for 14 courses and MDRT for 24 courses. Overall response rates (ORR) were recorded according to Deauville or RECIST criteria with a response characterized as a complete response (CR) or partial response. Local control (LC), orbital control (OC), and overall survival (OS) rates were estimated with the Kaplan-Meier method. RT toxicity was graded per CTCAEv5 and compared with the Fisher’s exact test.ResultsMedian follow-up time was 29 months (m) (range, 4-129m), and median MDRT dose used was 24 Gy (range 21-36 Gy). Overall response rates (ORR) were 100% (CR 50%) and 87.5% (CR 58.3%) following LDRT and MDRT, respectively. OS at 2 years was 100% and 95% for the LDRT and MDRT groups, respectively (p=0.36). LC rates at 2 years was 100% for both LDRT and MDRT groups and at 4 years was 100% and 89% for the LDRT and MDRT groups, respectively (p=0.56). The 4-year OC rate (including both ipsilateral and contralateral relapses) was 80% and 85% for the LDRT and MDRT groups, respectively (p=0.79). No patient required treatment with RT to a previously irradiated orbit. Acute toxicities were reported following 6 LDRT courses compared to 20 MDRT courses (p=.014). No Grade 3 or higher acute toxicities occurred in either group. Late toxicities were reported following 2 LDRT courses compared to 10 MDRT courses (p=0.147).ConclusionsLDRT produced similar ORR, LC, OC, and OS rates compared to MDRT with fewer acute and minimal late toxicities reported. Future multi-center studies with larger patient numbers are warranted to show significant associations.

Background and aim This study quantifies how changes in healthcare utilization and delivery during the first months of the COVID-19 pandemic have altered the presentation, treatment, and management of patients with gastrointestinal (GI) malignancies within an academic health system. Methods and results Patients diagnosed with a GI malignancy (ICD10: C15-C26) who received medical care within the health system during the observation period (first 44 weeks of 2019 and 2020) were identified for a retrospective cohort study. Deidentified patient encounter parameters were collected for this observation period and separated into pre-pandemic (weeks 1-10) and early pandemic (weeks 11-20) study periods. Difference-in-difference analyses adjusted for week-specific and year-specific effects quantified the impact of the COVID-19 pandemic on care delivery between pre-pandemic and early pandemic study periods in 2020. Across all GI malignancies, the COVID-19 pandemic has been associated with a significant decline in the number of patients with new patient visits (NPVs) (p = 1.2 × 10-4 ), Radiology encounters (p = 1.9 × 10-7 ), Surgery encounters (p = 1.6 × 10-3 ), Radiation Oncology encounters (p = 4.1 × 10-3 ), and infusion visits (6.1 × 10-5 ). Subgroup analyses revealed cancer-specific variations in changes to delivery. Patients with colorectal cancer (CRC) had the most significant decrease in NPVs (p = 7.1 × 10-5 ), which was significantly associated with a concomitant decrease in colonoscopies performed during the early pandemic period (r2 = 0.722, p = 2.1 × 10-10 ). Conclusions The COVID-19 pandemic has been associated with significant disruptions to care delivery. While these effects were appreciated broadly across GI malignancies, CRC, diagnosed and managed by periodic screening, has been affected most acutely.

Gingival myeloid sarcoma (MS) refractory to induction chemotherapy is a rare clinical entity and can be treated with palliative radiation therapy (RT). However, there are few previously published reports of RT approaches for the treatment of gingival MS. We present a single institution retrospective observational study of adult patients treated with palliative RT for chemotherapy refractory gingival MS. A total of six patients diagnosed with gingival MS in the setting of relapsed or refractory acute myeloid leukemia treated with palliative RT were identified, with a median age of 66 (range 52–77). Patients were treated with radiation doses ranging from 5 to 20 Gy in 2–10 fractions. Two patients had adequate follow-up time to assess treatment response. One patient who was simulated with PET/CT experienced a local complete response, while the other patient required retreatment 2 months after initial treatment and experienced an eventual local partial response. Three patients experienced radiation mucositis, with one patient experiencing grade 5 toxicity attributed to concomitant treatment with the radiosensitizer hydroxyurea. We believe that this study can provide a practical reference point for other clinicians given the rarity of gingival MS requiring palliative radiation therapy as a clinical entity.

PURPOSE/OBJECTIVE(S) Orbital low grade non-Hodgkin Lymphomas (LGNHLs) are a common tumor of the ocular adnexa. Courses of low-dose radiotherapy (LDRT), previously defined as 2 Gray (Gy) x 2 fractions, have resulted in excellent short-term outcomes for orbital LGNHLs. Recent data, however, suggests that higher doses are associated with improvements in response rates and progression free survival. RT is a proven treatment modality for this entity, but no prior data exists comparing outcomes following LDRT to moderate-dose RT (MDRT, RT dose > 4 Gy). Herein, we compare outcomes including overall response rates (ORR), local control (LC) and overall survival (OS) for patients treated with LDRT vs MDRT. MATERIALS/METHODS We reviewed 38 consecutive courses of RT for 36 patients treated for orbital LGNHL at a single institution. Bilateral disease was present in 15 patients. Nine patients had advanced stage disease or secondary orbital lymphoma following systemic dissemination. Indolent histologies included marginal zone lymphoma (20 patients), follicular lymphoma (11 patients), and mantle cell lymphoma (MCL, 5 patients). ORR were recorded according to Deauville or RECIST criteria with a response characterized as a complete response (CR) or partial response. Time to orbital recurrence (TTOR) and OS were estimated with the Kaplan-Meier (KM) method from start of RT to event or last follow-up. Univariate and multivariate Cox regression analysis was performed for characteristics associated with the studied outcomes. RT toxicity was graded per CTCAEv5. RESULTS Median follow-up time for all patients was 29 months (m) (range, 4-129m) and median MDRT dose used was 24 Gy (range 21-36 Gy) in 1.5-2 Gy fractions. LDRT was delivered for 14 courses and MDRT for 24 courses. Advanced stage (odds ratio (OR) 7, P = 0.021) and year of RT ≥2016 (OR 24, P = 0.008) were associated with increased use of LDRT as compared to MDRT. Acute grade 1 (G1) and G2 RT toxicities occurred following 22 (58%) and 5 (13%) courses, respectively. No ≥G3 acute toxicities occurred. Late toxicities included 6 patients with G1 dry eye (4 MDRT, 2 LDRT), 3 patients with G2 dry eye (3 MDRT) and one patient with a G1 cataract (1 MDRT). ORR were 100% (CR 50%) and 87.5% (CR 58.3%) following LDRT and MDRT, respectively. No evaluated characteristics, including the use of LDRT, were significantly associated with inferior ORR, TTOR or OS. LC at 2 years was 100% and 95% for the LDRT and MDRT groups, respectively. CONCLUSION RT for orbital LGNHL is associated with excellent outcomes in terms of response rates and local control. Due to the exquisite radiosensitivity of orbital LGNHL, LDRT produces similar response rates and TTOR as compared to more protracted RT courses. Present data suggests that LDRT should be considered for patients with orbital LGNHL; however, further multi-center studies with larger patient numbers are warranted to show significant associations.

Purpose/objective(s) Radiotherapy is curative for the majority of patients with IOAL. Some reports suggest inferior outcomes for bilateral IOAL, leading to uncertainty regarding optimal management for this presentation. This retrospective, international study evaluated long-term outcomes of bilateral IOAL treated with radiotherapy alone, with the current analysis limited to synchronous presentations (defined as ≤90 days between diagnoses). Materials/methods Ninety patients with bilateral synchronous IOAL were treated with radiotherapy to both orbits at 13 centers. Overall (OS), progression-free survival (PFS), freedom from local (FFLF) and freedom from distant (FFDF) failure were measured from the commencement of treatment of the second orbit. The study met local institutional review board requirements. Results The median age at diagnosis was 55 years (range 15-83), with 47% males. Histology was marginal zone lymphoma in 90% and disease was conjunctival in 65% of orbits. Sixty-three percent had bilateral conjunctival disease. The radiotherapy dose (per orbit) was 20-25.2 Gy for 46%, 27-30.6 Gy for 33%, 33-40 Gy for 8% and 13% had 4 Gy. Radiotherapy was given to the whole orbit for 62% of orbits, conjunctiva only for 29% and other partial orbit for 9%. Median follow-up was 6.6 years. The 10-year OS and PFS were 99% (95% CI: 92-100) and 73% (95% CI: 60-82), respectively. Ten-year FFLF and FFDF were 88% (95% CI: 78-94) and 83% (95% CI: 70-91), respectively. PFS was lower for the 33 patients with one or both orbits having non-conjunctival disease (HR 3.7 (1.4-9.3), P = 0.004). Three-year FFLP was 91% (95% CI: 81-95) for orbits receiving ≥ 20 Gy and 61% (95% CI: 27-84) after 4Gy (P Conclusion In this large, multicenter experience, patients with bilateral, synchronous IOAL treated with radiotherapy alone appeared to have outcomes comparable to historical series of unilateral disease. These results would suggest bilateral IOAL can be considered a localized process and support the use of curative intent radiotherapy in this setting.

Purpose/objective(s) Painful osteolytic bone lesions are common in patients with multiple myeloma (MM). Radiotherapy (RT) is effective in providing pain relief from MM bone lesions in over 80% of patients. There is no consensus as to the most effective dose or fractionation for palliation. Shorter courses of RT are not only more convenient for patients and their families, but they also have less impact on timing of systemic therapies. There is precedent for using 2 Gy x 2 for palliation of lymphomas, which have similar radiosensitivity to myeloma. The primary objective is to determine whether treatment with 2 Gy x 2 to painful myeloma bone lesions achieves patient-reported pain reduction comparable to historical controls at 4 weeks. Secondary objectives will assess QOL endpoints, use of analgesia and time to pain relief, and duration of pain relief. Materials/methods Patients who consent to participation will complete quality of life and pain questionnaires (Brief Pain Index, EORTC QLQ-BM22, and EORTC QLQ-C30) prior to treatment and at 2,4,8 weeks and 6 months following treatment. Pain response, as defined by the international consensus on palliative RT for bone metastases, will be measured based on BPI and daily oral morphine equivalent. Reirradiation at standard dose can be considered at ≥4 weeks following initial treatment for indeterminate pain response or pain progression. Cytogenetics and International Myeloma Working Group risk stratification and response criteria are recorded, when available, but are not required for patient participation. Results This trial, supported by ILROG, has opened at 7 institutions with one more in process of opening. Prior to COVID, accrual was 1.5 patients per month. Since COVID, enrollment has been at 0.7 patients per month. A total of 18 patients have been accrued. The median age of patients accrued is 65.5 years with 7/18 female patients. Fourteen patients are Caucasian. Twelve patients have an ECOG performance score of 1-2. Thirteen patients had pain response captured at 4 weeks following RT. Of the 5 patients that did not complete questionnaires at 4 weeks post-RT, 2 expired, 1 was lost to follow-up, 1 had a missed evaluation and 1 had pain progression). The most common site of treatment was the shoulder (4/18). Conclusion This ongoing prospective trial in palliation of multiple myeloma bone lesions is feasible and able to accrue at multiple institutions and will provide valuable information as to the role of low-dose RT in this population.

CD19-targeted chimeric antigen receptor (CAR) T cells have transformed the treatment of patients with relapsed or refractory CD19-positive hematologic malignancies. However, a significant subset of these patients either fails to respond or eventually relapses. Moreover, patients who are candidates for CART-19 therapy often have symptomatic disease that requires some form of treatment to support them during the manufacture period. An ideal bridging therapy would simultaneously both (1) sensitize the tumor to CART-19 attack to increase antitumor control and (2) debulk the disease during manufacture. Radiotherapy (RT) is an established curative and palliative cancer treatment regimen, with approximately half of cancer patients with solid tumors receiving RT some time during their disease. Several reports have underscored the existence of threshold doses (and regimens) that are able to switch on different damage programs that profoundly affect responses to therapy by eliciting potent immune modulatory effects, prompting immunologically mediated tumor cell death. These effects have been attributed to multiple pathways, including the activation of the cGMP-cAMP Synthetase (cGAS), Stimulator of Interferon Genes (STING) pathway with Type I Interferons expression, and tumor associated antigen (TAA) cross priming with anti-tumor CD8+ T cell elicitation, ultimately inducing “abscopal” effects. By virtue of the immunomodulatory effects of RT, we hypothesize that RT could serve as a successful bridging strategy for CAR T-cell therapy. To investigate this hypothesis we established the A20 Lymphoma CART-19 therapy mouse model in our lab and use it to perform preliminaries experiments. A20 cells were implanted into both flanks of the animals. Mimicking human immune adjuvant dose used in our institute for RT bridging, 20 days after the A20 challenge we RT treated one of the two tumors using a dose of 8Gy divided in two fractions of 4Gy each. Twenty-four hours later 1x10ep6 CART-19 cells were infused intravenously. While the effects of RT in combination with CART-19 have similar impact on the tumor growth of the irradiated mass a significant increase of the antitumor effects of the single therapy was observed on the non-irradiated tumor. FACS studies demonstrated heavy leukocytes infiltration with increased presence of infused CART-19 as well indigenous T cells. To investigate possible molecular mechanisms involved in the increased effects on the non-irradiated tumor, we perform a qPCR array and observed increased expression of genes linked to cross priming, including IFN type I and Batf3. A20 cells express the ectopic retroviral antigen gp70 with well characterized AH1 immune-dominant epitope. AH1 tetramer staining on infiltrating T cells demonstrated increase staining in tumor from mice treated with the combination. Overall these results suggest RT may serve as optimal debulking and adjuvant bridging therapy for CAR-T cells therapy. Citation Format: Nektarios Kostopoulos, Costanitnos Koumeins, John P. Plastaras, Stephen J. Schuster, Andrea Facciabene. Radiation therapy for bridging and improving CAR-T cells therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3449.

Purpose Convolutional neural networks (CNN) have greatly improved medical image segmentation. A robust model requires training data can represent the entire dataset. One of the differing characteristics comes from variability in patient positioning (prone or supine) for radiotherapy. In this study, we investigated the effect of position orientation on segmentation using CNN. Methods Data of 100 patients (50 in supine and 50 in prone) with rectal cancer were collected for this study. We designed three sets of experiments for comparison: (a) segmentation using the model trained with data from the same orientation; (b) segmentation using the model trained with data from the opposite orientation; (c) segmentation using the model trained with data from both orientations. We performed fivefold cross‐validation. The performance was evaluated on segmentation of the clinical target volume (CTV), bladder, and femurs with Dice similarity coefficient (DSC) and Hausdorff distance (HD). Results Compared with models trained on cases positioned in the same orientation, the models trained with cases positioned in the opposite orientation performed significantly worse (P 0.05). The average DSC values were 0.74 vs 0.84, 0.85 vs 0.88, and 0.91 vs 0.91 for CTV, bladder, and femurs, respectively. The corresponding HD values (mm) were 16.6 vs 14.6, 8.4 vs 8.1, and 6.3 vs 6.3, respectively. The models trained with data from both orientations have comparable accuracy (P > 0.05), with average DSC of 0.84, 0.88, and 0.91 and HD of 14.4, 8.1, and 6.3, respectively. Conclusions Orientation affects the accuracy for CTV and bladder, but has negligible effect on the femurs. The model trained from data combining both orientations performs as well as a model trained with data from the same orientation for all the organs. These observations can offer guidance on the choice of training data for accurate segmentation.

Among adult lymphoma survivors, radiation treatment techniques that increase the excess radiation dose to organs at risk (OARs) put patients at risk for increased side effects, especially late toxicities. Minimizing radiation to OARs in adults patients with Hodgkin and non-Hodgkin lymphomas involving the mediastinum is the deciding factor for the choice of treatment modality. Proton therapy may help to reduce the radiation dose to the OARs and reduce toxicities, especially the risks for cardiac morbidity and second cancers. Because proton therapy may have some disadvantages, identifying the patients and the circumstances that may benefit the most from proton therapy is important. We present modern guidelines to identify adult lymphoma patients who may derive the greatest benefit from proton therapy, along with an analysis of the advantages and disadvantages of proton treatment.

Total Skin Electron Therapy (TSET) utilizes high-energy electrons to treat cancers on the entire body surface. The otherwise invisible radiation beam can be observed via the optical Cherenkov photons emitted from interaction between the high-energy electron beam and tissue. Cherenkov emission can be used to evaluate the dose uniformity on the surface of the patient in real-time using a time-gated intensified camera system. Each patient was monitored during TSET by in-vivo detectors (IVD) as well as Scintillators. Patients undergoing TSET in various conditions (whole body and half body) were imaged and analyzed. A rigorous methodology for converting Cherenkov intensity to surface dose as products of correction factors, including camera vignette correction factor, incident radiation correction factor, and tissue optical properties correction factor. A comprehensive study has been carried out by inspecting various positions on the patients such as vertex, chest, perineum, shins, and foot relative to the umbilicus point (the prescription point).

Purpose: B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cells (CART-BCMA) are a promising treatment for relapsed/refractory multiple myeloma (r/rMM). We evaluated the safety and feasibility of bridging radiation (RT) in subjects treated on a phase I trial of CART-BCMA. Experimental Design: Twenty-five r/rMM subjects were treated in three cohorts with two doses of CART-BCMA cells ± cyclophosphamide. We retrospectively analyzed toxicity, response, and CART manufacturing data based on RT receipt. Results: Thirteen subjects received no RT Conclusions: Bridging-RT appeared safe and feasible with CART-BCMA therapy in our r/rMM patients, though larger future studies are needed to draw definitive conclusions.