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We report our experience with 3 strategies for treating hilar and extrahepatic cholangiocarcinoma (CCA) including chemoradiotherapy: neoadjuvant chemoradiotherapy (nCRT) and orthotopic liver transplant, surgical resection and adjuvant chemoradiotherapy (aCRT), and definitive chemoradiotherapy (dCRT).We included patients treated from 1998 through 2019. Kaplan-Meier estimates, log-rank testing, and univariate/multivariate Cox models were used to assess outcomes (local progression-free survival, disease-free survival, and overall survival).Sixty-five patients (nCRT, n=20; aCRT, n=16; dCRT, n=29) met inclusion criteria [median (range) age 65 years (27-84 years)]. Median posttreatment follow-up was 19.1 months (0.8-164.8 months) for all patients and 38.6, 24.3, and 9.0 months for the nCRT, aCRT, and dCRT groups, respectively. At 3 and 5 years, overall survival was 78% and 59% for the nCRT group; 47% and 35%, aCRT group; and 11% and 0%, dCRT group. Compared with the dCRT group, the nCRT group (hazard ratio =0.13, 95% CI: 0.05-0.33) and the aCRT group (hazard ratio =0.29, 95% CI: 0.14-0.64) had significantly improved overall survival (P0.001). The 5-year local progression-free survival (50% nCRTOutcomes for patients with extrahepatic CCA were superior for those who underwent nCRT/orthotopic liver transplant or postsurgical aCRT than for patients treated with dCRT. The excellent outcomes after nCRT/orthotopic liver transplant provide additional independent data supporting the validity of this strategy. The poor survival of patients treated with dCRT highlights a need for better therapies when surgery is not possible.

Analyze the pattern of disease failure after anti-CD19-directed chimeric antigen receptor T-cell therapy (CART) for non-Hodgkin lymphoma, assess the local control rate of bridging radiotherapy (bRT) and characterize in-field recurrences.We retrospectively reviewed 120 patients with NHL who received CART between 2018 and 2020. Baseline characteristics and treatment outcomes were compared between patients who received bRT and those who did not (noRT).Of the 118 patients included, 14 (12%) received bRT, while 104 (88%) did not. bRT group had more localized and extranodal disease. bRT was delivered with a median dose of 20 Gy (range: 15-36) in 5 fractions (range: 3-24). Pattern of failure analysis revealed that progression involving pre-existing sites was the predominant pattern of failure in both the bRT and noRT groups (86% and 88%, respectively). Median duration of response was 128 days (range: 25-547) for bRT group and 93 days (range: 22-965) for noRT group (p = 0.78). In the bRT group, only 2/15 sites irradiated had infield recurrence and where characterized by bulky disease, SUVMajority of progressions after CART infusion involve pre-existing sites. Bridging RT prior to CART provides excellent in-field local control and durable response. Patients with bulky disease, SUV

The optimal approach to incorporate radiotherapy (RT) in conjunction with CAR T-cell Therapy (CART) for relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (bNHL) remains unclear. This study documents the RT local control rate among patients who received bridging radiotherapy (BRT) prior to CART and compares it to those who received salvage radiotherapy (SRT) post CART. It further reports on a promising way to utilize SRT for post CART disease, and identifies predictors for RT in-field recurrence.We retrospectively reviewed 83 patients with r/r bNHL who received CART and RT, either as BRT pre-CART infusion (n=35) or as SRT post-CART infusion (n=48), between 2018 and 2021. RT was defined as comprehensive (compRT) - treated all sites of active disease - or focal (focRT). Limited disease was defined as disease amenable to compRT, involving5 active disease sites.At time of RT, patients who received BRT prior to CART had bulkier disease sites (median diameter 8.7cm vs. 5.5cm; p=0.01) and were treated to significantly lower doses (median equivalent 2 Gy dose 23.3Gy vs. 34.5Gy, p=0.002), compared to SRT post CART. Among 124 total irradiated sites identified, 8/59 (13%) bridged-sites and 21/65 (32%) salvaged-sites experienced in-field recurrence translating to 1-year local control rate (LC) of 84% and 62%, respectively (p=0.009). Patients with limited post-CART disease (n=37) who received compSRT (n=26) had better overall survival (51% vs. 12%; p=0.028), freedom from subsequent progression (31% vs. 0%; p0.001) and freedom from subsequent event (19% vs. 0%; p=0.011) compared to patients with limited disease who received focSRT (n=11).BRT followed by CART appears to be associated with improved LC compared to SRT in r/r bNHL. Nonetheless, SRT offers a promising salvage intervention for limited (5 sites) relapsed post-CART disease if given comprehensively.

Purpose To compare the dosimetric performances of small-spot three-dimensional (3D) and four-dimensional (4D) robustly optimized intensity-modulated proton (IMPT) plans in the presence of uncertainties and interplay effect simultaneously for distal esophageal carcinoma. Method and materials Thirteen (13) patients were selected and re-planned with small-spot ( σ ~ 2-6 mm) 3D and 4D robust optimization in IMPT, respectively. The internal clinical target volumes (CTVhigh3d , CTVlow3d ) were used in 3D robust optimization. Different CTVs (CTVhigh4d , CTVlow4d ) were generated by subtracting an inner margin of the motion amplitudes in three cardinal directions from the internal CTVs and used in 4D robust optimization. All patients were prescribed the same dose to CTVs (50 Gy[RBE] for CTVhigh3d /CTVhigh4d and 45 Gy[RBE] for CTVlow3d /CTVlow4d ). Dose-volume histogram (DVH) indices were calculated to assess plan quality. Comprehensive plan robustness evaluations that consisted of 300 perturbed scenarios (10 different motion patterns to consider irregular motion (sampled from a Gaussian distribution) and 30 different uncertainties scenarios (sampled from a 4D uniform distribution) combined), were performed to quantify robustness to uncertainties and interplay effect simultaneously. Wilcoxon signed-rank test was used for statistical analysis. Results Compared to 3D robustly optimized plans, 4D robustly optimized plans had statistically improved target coverage and better sparing of lungs and heart (heart Dmean , P = 0.001; heart V30Gy[RBE] , P = 0.001) in the nominal scenario. 4D robustly optimized plans had better robustness in target dose coverage (CTVhigh4d V100% , P = 0.002) and the protection of lungs and heart (heart Dmean , P = 0.001; heart V30Gy[RBE] , P = 0.001) when uncertainties and interplay effect were considered simultaneously. Conclusions Even with small spots in IMPT, 4D robust optimization outperformed 3D robust optimization in terms of normal tissue protection and robustness to uncertainties and interplay effect simultaneously. Our findings support the use of 4D robust optimization to treat distal esophageal carcinoma with small spots in IMPT.

We report long-term outcomes from our phase 1 dose-escalation study to determine the maximum tolerated dose of single-fraction liver SABR pooled with our subsequent single institutional experience with patients treated postprotocol at the highest dose level (40 Gy) established from the phase 1 study.Patients with liver metastases from solid tumors located outside of the central liver zone were treated with single-fraction SABR on a phase 1 dose escalation trial. At least 700 cc of normal liver had to receive9.1 Gy. Seven patients with 10 liver metastases received the initial prescription dose of 35 Gy, and dose was then escalated to 40 Gy for 7 more patients with 7 liver metastases. An additional 19 postprotocol patients with 22 liver metastases were treated to 40 Gy in a single fraction. Patients were followed for toxicity and underwent serial imaging to assess local control.Median imaging follow-up for the combined cohort (n = 33, 39 lesions) was 25.9 months; 38.9 months for protocol patients and 20.2 months for postprotocol patients. Median lesion size was 2.0 cm (range, 0.5-5.0 cm). There were no dose-limiting toxicities observed for protocol patients, and only 3 grade 2 toxicities were observed in the entire cohort, with no grade ≥3 toxicities attributable to treatment. Four-year actuarial local control of irradiated lesions in the entire cohort was 96.6%, 100% in the protocol group and 92.9% in the subsequent patients. Two-year overall survival for all treated patients was 82.0%.For selected patients with liver metastases, single-fraction SABR at doses of 35 and 40 Gy was safe and well-tolerated, and shows excellent local control with long-term follow-up; results in subsequent patients treated with single-fraction SABR doses of 40 Gy confirmed our earlier results.

Purpose Our purpose was to determine the effect of chemoradiotherapy (CRT) on patient-reported quality of life (QOL) for patients with intact pancreas cancer. Methods and Materials We reviewed a prospective QOL registry for patients with intact, clinically localized pancreatic ductal adenocarcinoma treated with CRT between June 2015 and November 2018. QOL was assessed pre-CRT (immediately before CRT, after neoadjuvant chemotherapy) and at the completion of CRT with the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) and its component parts: FACT-General (FACT-G) and hepatobiliary cancer subscore (HCS). A minimally important difference from pre-CRT was defined as ≥ 6, 5, and 8 points for FACT-G, HCS, and FACT-Hep, respectively. Results Of 157 patients who underwent CRT, 100 completed both pre- and post-CRT surveys and were included in the primary analysis. Median age at diagnosis was 65 years (range, 23-90). National Comprehensive Cancer Network resectability status was resectable (3%), borderline resectable (40%), or locally advanced (57%). Folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) (75%) or gemcitabine and nab-paclitaxel (42%) were given for a median of 6 cycles (range, 0-42) before CRT. Radiation therapy techniques included 3-dimensional conformal (22%), intensity modulated photon (55%), and intensity modulated proton (23%) radiation therapy to a median dose of 50 Gy (range, 36-62.5). Concurrent chemotherapy was most commonly capecitabine (82%). Sixty-three patients (63%) had surgery after CRT. The mean decline in FACT-G, HCS subscale, and FACT-Hep from pre- to post-CRT was 3.5 (standard deviation [SD], 13.7), 1.7 (SD 7.8), and 5.2 (SD 19.4), respectively. Each of these changes were statistically significant, but did not meet the minimally important difference threshold. Pancreatic head tumor location was associated with decline in FACT-Hep. Nausea was the toxicity with the greatest increase from pre- to post-CRT by both physician-assessment and patient-reported QOL. Conclusions For patients with intact pancreatic adenocarcinoma, modern CRT is well tolerated with minimal decline in QOL during treatment.

Purpose To compare the dosimetric performances of intensity-modulated proton therapy (IMPT) plans generated with two different beam angle configurations (the Right-Left oblique posterior beams and the Superior-Inferior oblique posterior beams) for the treatment of distal esophageal carcinoma in the presence of uncertainties and interplay effect. Methods and materials Twenty patients' IMPT plans were retrospectively selected, with 10 patients treated with the R-L oblique posterior beams (Group R-L) and the other 10 patients treated with the S-I oblique posterior beams (Group S-I). Patients in both groups were matched by their clinical target volumes (CTVs-high and low dose levels) and respiratory motion amplitudes. Dose-volume-histogram (DVH) indices were used to assess plan quality. DVH bandwidth was calculated to evaluate plan robustness. Interplay effect was quantified using four-dimensional (4D) dynamic dose calculation with random respiratory starting phase of each fraction. Normal tissue complication probability (NTCP) for heart, liver, and lung was calculated, respectively, to estimate the clinical outcomes. Wilcoxon signed-rank test was used for statistical comparison between the two groups. Results Compared with plans in Group R-L, plans in Group S-I resulted in significantly lower liver Dmean and lung V30Gy[RBE] with slightly higher but clinically acceptable spinal cord Dmax . Similar plan robustness was observed between the two groups. When interplay effect was considered, plans in Group S-I performed statistically better for heart Dmean and V30Gy[RBE] , lung Dmean and V5Gy[RBE] , and liver Dmean , with slightly increased but clinically acceptable spinal cord Dmax . NTCP for liver was significantly better in Group S-I. Conclusions IMPT plans in Group S-I have better sparing of liver, heart, and lungs at the slight cost of spinal cord maximum dose protection, and are more interplay-effect resilient compared to IMPT plans in Group R-L. Our study supports the routine use of the S-I oblique posterior beams for the treatments of distal esophageal carcinoma.

Purpose Optimal clinical target volume (CTV) for inguinal lymph node irradiation in anal cancer remains uncertain. This study documents the location of radiographically involved inguinal lymph nodes and proposes guidelines for CTV delineation. Materials and Methods Patients with anal canal squamous cell carcinoma with inguinal lymph node metastases were identified. Criteria for lymph node involvement included: >15 mm short axis or suspicious morphology on CT or MRI, increased avidity on 18-FDG-PET, or positive biopsy. Distances from center of involved nodes to femoral vessels and inferior pubic symphysis were measured. Results Forty patients with 79 inguinal lymph nodes were included. Relative to right femoral vessels, nodes were located: 12:00 (n = 6); 1:00 (n = 28); 2:00 (n = 35), 3:00 (n = 5); 4:00 (n = 1); 10:00 (n = 1); 11:00 (n = 3). No nodes were identified lateral or posterior to vessels. Published AGITG guidelines covered 68% of nodes anteriorly and 85% medially. Margins from nearest femoral vessel to cover 95% of nodes were 30 mm anteriorly and 26 mm medially. Inferior margin to cover 95% of nodes was 14 mm below inferior pubic symphysis. Proposed borders include cranial, where external iliac vessels leave bony pelvis; caudal, 14 mm below inferior pubic symphysis; posterior, posterior border of femoral vessels; lateral, lateral border of femoral vessels; anterior, 30 mm margin on femoral vessels and medial, 26 mm margin on femoral vessels, including radiographically suspicious nodes. Conclusions Published guidelines for inguinal CTV in anal cancer may result in inadequate coverage of high risk areas. Updated guidelines based on this study ensure coverage of at-risk areas.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Since the relapse rate of DLBCL to frontline chemoimmunotherapy and salvage autologous hematopoietic cell transplant is high, CD19-directed chimeric antigen receptor (CAR) T-cell therapy was adopted. Given the time interval needed for CAR T cells to be manufactured (3-5 weeks) and the aggressiveness of these relapsed/refractory lymphomas, some patients do not make it to the CAR T-cell infusion phase. This calls for a bridging therapy to control, debulk, and sensitize the disease during this period. Radiation therapy can serve this purpose and has shown promising results in some studies. Proton therapy, compared to standard radiation therapy, in some locations, can reduce the radiation dose to the organs at risk, which may lead to fewer side effects for patients with lymphomas. Thus, we hypothesize that proton therapy may serve as a promising bridging strategy to CAR T-cell therapy for some patients.

Cutaneous B cell pseudolymphoma (CBPL), or cutaneous lymphoid hyperplasia, is the most common pseudolymphoma. It typically responds well to local treatment and follows a benign course. Herein, we describe the unique case of a patient with CBPL that was refractory to a variety of treatments, with subsequent response to rituximab followed by methotrexate. This case explores the complex interplay of T and B lymphocytes, and the potential role of perifollicular T cells in treatment resistant CBPL. Further, it describes the additive therapeutic effect of rituximab and methotrexate to target both B cell and T cell populations in CBPL, a strategy already employed in a number of other conditions.

Plasmablastic lymphoma (PBL) is a rare subtype of large B-cell lymphoma most commonly seen in immunocompromised patients, particularly in those with HIV infection. In these patients, PBL often affects the oral mucosa.1 Other immunocompromised states, including immunosuppression for organ transplant and immunosenescence, have been linked to PBL.1 Epstein-Barr virus (EBV) reactivation is thought to be a major driver of PBL.1 PBL is characterized histologically by an absence of B- and T-cell markers and expression of plasma cell markers CD38 and CD138. The median overall survival of HIV-positive and HIV-negative patients with PBL is 15 months and 9 months, respectively.1 Some patients with PBL present with primary cutaneous disease (pcPBL), defined as no systemic involvement. These patients have a unique clinical presentation and an indolent course. We report the first case of iatrogenic pcPBL secondary to romidepsin therapy for primary cutaneous peripheral T-cell lymphoma not otherwise specified (pcPTCL-NOS).

Background Guidelines to provide recommendations about driving restrictions for patients with brain metastases are lacking. We aim to determine whether clinical neurologic examination is sufficient to predict suitability to drive in these patients by comparison with an occupational therapy driving assessment (OTDA). Methods We prospectively evaluated the concordance between neurology assessment of suitability to drive (pass/fail) and OTDA in 41 individuals with brain metastases. Neuro-oncology evaluation included an interview and neurological examination. Participants subsequently underwent OTDA during which a battery of objective measures of visual, cognitive, and motor skills related to driving was administered. Results The mean age of patients who failed OTDA was age 68.9 years vs 59.3 years in the group members who passed (P = .0046). The sensitivity of the neurology assessment to predict driving fitness compared with OTDA was 16.1% and the specificity 90%. The 31 patients who failed OTDA were more likely to fail Vision Coach, Montreal Cognitive Assessment, and Trail Making B tests. Conclusions There was poor association between the assessment of suitability to drive by neurologists and the outcome of the OTDA in patients with brain metastases. Subtle deficits that may impair the ability to drive safely may not be evident on neurologic examination. The positive predictive value was high to predict OTDA failure. Age could be a factor affecting OTDA performance. The results raise questions about the choice of assessments in making recommendations about driving fitness in people with brain metastases. OTDA should be strongly considered in patients with brain metastases who wish to continue driving.

Background Esophageal carcinoma is the eighth most common cancer in the world. Volumetric-modulated arc therapy (VMAT) is widely used to treat distal esophageal carcinoma due to high conformality to the target and good sparing of organs at risk (OAR). It is not clear if small-spot intensity-modulated proton therapy (IMPT) demonstrates a dosimetric advantage over VMAT. In this study, we compared dosimetric performance of VMAT and small-spot IMPT for distal esophageal carcinoma in terms of plan quality, plan robustness, and interplay effects. Methods 35 distal esophageal carcinoma patients were retrospectively reviewed; 19 patients received small-spot IMPT and the remaining 16 of them received VMAT. Both plans were generated by delivering prescription doses to clinical target volumes (CTVs) on phase-averaged 4D-CT's. The dose-volume-histogram (DVH) band method was used to quantify plan robustness. Software was developed to evaluate interplay effects with randomized starting phases for each field per fraction. DVH indices were compared using Wilcoxon rank-sum test. For fair comparison, all the treatment plans were normalized to have the same CTVhigh D95% in the nominal scenario relative to the prescription dose. Results In the nominal scenario, small-spot IMPT delivered statistically significantly lower liver Dmean and V30Gy[RBE] , lung Dmean , heart Dmean compared with VMAT. CTVhigh dose homogeneity and protection of other OARs were comparable between the two treatments. In terms of plan robustness, the IMPT and VMAT plans were comparable for kidney V18Gy[RBE] , liver V30Gy[RBE] , stomach V45Gy[RBE] , lung Dmean , V5Gy[RBE] , and V20Gy[RBE] , cord Dmax and D 0.03 c m 3 , liver Dmean , heart V20Gy[RBE] , and V30Gy[RBE] , but IMPT was significantly worse for CTVhigh D95% , D 2 c m 3 , and D5% -D95% , CTVlow D95% , heart Dmean , and V40Gy[RBE] , requiring careful and experienced adjustments during the planning process and robustness considerations. The small-spot IMPT plans still met the standard clinical requirements after interplay effects were considered. Conclusions Small-spot IMPT decreases doses to heart, liver, and total lung compared to VMAT as well as achieves clinically acceptable plan robustness. Our study supports the use of small-spot IMPT for the treatment of distal esophageal carcinoma.

OPINION STATEMENT Choice of therapy in mycosis fungoides is based on both patient- and lymphoma-specific factors, such as disease characteristics, comorbidities, symptoms and effect on quality of life, potential associated toxicities of therapy, response and tolerance to prior lines of therapy, and convenience and practicality. Generally, we sequence therapies from least toxic, targeted, nonimmunosuppressive to more toxic, immunosuppressive and from single agent to multiple agents, as necessary. If more toxic, immunosuppressive agents are required to alleviate disease burden or symptoms, we generally use them just long enough to control the disease, then transition to a maintenance regimen with less toxic, less immunosuppressive agents.

Purpose/Objective(s) Metastasis-directed radiotherapy (RT) may improve disease free and overall survival (OS) in select patients with lung metastases (LM). Long-term toxicity and cancer outcome data in patients with LM treated with ablative RT is limited, particularly in patients treated concurrently with novel systemic therapies. This is a retrospective, multi-hospital analysis of ablative RT for LM. Materials/Methods From 2015-2020, 343 LM-directed ablative RT treatment courses were delivered in 301 patients. Second primary lung cancers and non-parenchymal lesions were excluded. Medical records were reviewed retrospectively, and local progression (LP) was determined by evaluation of serial CT and/or PET scans. Univariate associations of clinical and radiographic parameters with clinical outcomes were evaluated using Cox proportional hazard models. Acute and late adverse events (AEs) were defined using CTCAE v.4.0. Results Median age was 64 years with 51% of patients being female. Median lesion size was 1.6 cm (range 0.3-9.4 cm). Seventy-four (22%) courses involved treatment of > 1 LM. Most common primary tumor histologies included melanoma (18%), colorectal adenocarcinoma (15%), urothelial/renal cell carcinoma (11%), and sarcoma (9%). Median physical dose was 5000 cGy. Median number of fractions delivered was 5, and 27 (8%) courses were > 5 fractions. Concurrent systemic therapies included immuno-, targeted, hormone, and cytotoxic therapy in 16%, 8%, 2%, and 1% of courses, respectively. Treatment to prior lung LM included surgery, RT, and ablation in 25%, 22%, and 2% of courses, respectively. With a median follow-up of 2.8 years, median and 5-year estimated OS were 3.0 years and 43% (95% confidence interval [CI] 34-52%), respectively. Factors associated with shorter OS included larger lesion size (P 2 LM (P = 0.016; HR 1.6), and > 5 fraction treatment (P = 0.024; HR 2.0). Fifteen patients experienced LP with a 5-year estimated cumulative incidence of 5.7% (95% CI 3.4-9.3%). Factors associated with increased risk of LP included larger lesion size (P = 0.004; HR 1.4 per cm), > 5 fraction treatment (P = 0.040; HR 3.8), and colorectal histology (P = 0.011; HR 3.9). Acute and late grade 2-3 AEs were 13% and 5%, respectively. There were no grade 4+ AEs. Increased toxicity was associated with larger size (P = 0.007; odds ratio 1.3 per cm) but not concurrent systemic therapy (P = 0.546) or prior treatment to other LM (P = 0.694). Conclusion These data confirm the efficacy and safety of ablative RT for LM in well-selected patients. 5-year OS and LP were 43% and 6%, respectively. AEs were infrequent, even in the setting of 24% of courses delivered concurrently with systemic therapy and 40% of courses delivered subsequent to other local therapies for LM. Given the excellent OS, these data are suggestive of improved local control as a factor for improved OS.

BACKGROUND: Previous reports suggest that intact SMAD4 expression is associated with a locally aggressive pancreas cancer phenotype. The objectives of this work were to determine the frequency of intact SMAD4 and its association with patterns of recurrence in patients with upfront resected pancreas cancer receiving adjuvant therapy. METHODS: A tissue microarray was constructed using resected specimens from patients who underwent upfront surgery and adjuvant gemcitabine with no neoadjuvant treatment for pancreas cancer. SMAD4 expression was determined by immunohistochemical staining. Associations of SMAD4 expression and clinicopathologic parameters with clinical outcomes were evaluated using Cox proportional hazard models. RESULTS: One hundred twenty-seven patients were included with a median follow up of 5.7 years. Most patients had stage ≥ pT3 tumors (75%) and pN1 (68%). All patients received adjuvant gemcitabine, and 79% of patients received adjuvant chemoradiotherapy. Ten (8%) patients had intact SMAD4 expression. Grade was the only clinicopathologic parameter statistically associated with SMAD4 expression (P=0.05). Median overall survival was 2.1 years. On univariate analysis, SMAD4 expression was associated with increased locoregional recurrence (hazard ratio 7.0, P

7556 Background: The majority of R/R NHL progressions after CART involve pre-existing sites, suggesting a promising role for bridging radiotherapy (bRT). We assessed the local control rate of disease sites bridged with radiotherapy prior to CART and identified predictors of in-field recurrence. Methods: We retrospectively reviewed 35 patients with aggressive B-cell NHL who received bRT between leukapheresis and CART infusion between 2018 and 2021 at a multi-site single institution. bRT local control rate (LC), calculated based on the total number of irradiated sites, was defined from bRT end date. Progression-free survival (PFS) and overall-survival (OS) were defined from the date of CART infusion. In-field recurrence was defined as disease relapse occurring within the radiation planning target volume. Kaplan-Meier plots and cox regression modeling were used to estimate the desired output. Results: Median age of the cohort at time of CART infusion was 59 (range 19-73). The median equivalent 2 Gy dose (EQD2) administered was 23.3 Gy (range 4-41 Gy). The median time from end of bRT to CART infusion was 14 days (range 6-42). Five (14%) patients also received bridging chemotherapy with bRT. Among the 34 evaluable patients, 30 (88%) achieved an objective response (59% complete response and 29% partial response). At a median follow-up of 12 months, 1-year PFS was 48% and 1-year OS was 72%. No progression occurred beyond 240 days. On review of treatment plans and pre-treatment PET/CT scans, 59 sites were identified that received bRT prior to CART infusion. The median size and SUVmax of the irradiated sites were 8.7cm (range 1.5-22) and 13 (range 4-46), respectively. Of the 59 irradiated sites, 8 sites (13.6%) in 7 patients had in-field local recurrence, translating to 1-year LC of 84%. No in-field recurrence occurred beyond 180 days. Moreover, no local recurrence occurred in patients who received radiation to all known sites of active disease to EQD2> 30 Gy (n = 4 patients); these patients remained in remission except for 1 who experienced progression outside the bRT field. On univariate analysis, triple hit lymphoma (THL) (OR 22.8, 95% CI: 3.8-138.3; p < 0.001), tumor size (OR 1.25, 95% CI: 1.1-1.4; p < 0.001), specifically ≥ 9cm (OR 9.4, CI: 1.2-77.3; p = 0.036) and SUVmax (OR 1.1, CI: 1.02-1.15; p = 0.008), specifically ≥ 20 (OR 5.6, CI: 1.3-23.7; p = 0.018), were significantly associated with increased risk of in-field recurrence. On multivariate analysis, THL (OR 32.9, CI: 3.2-336.0; p = 0.03) and tumor size (OR 1.3, CI: 1.1-1.6; p = 0.01) retained significant association with in-field recurrence. Conclusions: Bridging radiotherapy prior to CART provides excellent and durable in-field local control for R/R B-cell NHL. Patients with triple hit histology and bulky disease are likely at higher risk of in-field recurrence and may benefit from higher doses of bRT.

Purpose To compare dosimetric performance of volumetric-modulated arc therapy (VMAT) and small-spot intensity-modulated proton therapy for stage III non-small-cell lung cancer (NSCLC). Methods and materials A total of 24 NSCLC patients were retrospectively reviewed; 12 patients received intensity-modulated proton therapy (IMPT) and the remaining 12 received VMAT. Both plans were generated by delivering prescription doses to clinical target volumes (CTV) on averaged 4D-CTs. The dose-volume-histograms (DVH) band method was used to quantify plan robustness. Software was developed to evaluate interplay effects with randomized starting phases of each field per fraction. DVH indices were compared using Wilcoxon rank sum test. Results Compared with VMAT, IMPT delivered significantly lower cord Dmax , heart Dmean , and lung V5 Gy[ RBE ] with comparable CTV dose homogeneity, and protection of other OARs. In terms of plan robustness, the IMPT plans were statistically better than VMAT plans in heart Dmean , but were statistically worse in CTV dose coverage, cord Dmax , lung Dmean , and V5 Gy[ RBE ] . Other DVH indices were comparable. The IMPT plans still met the standard clinical requirements with interplay effects considered. Conclusions Small-spot IMPT improves cord, heart, and lung sparing compared to VMAT and achieves clinically acceptable plan robustness at least for the patients included in this study with motion amplitude less than 11 mm. Our study supports the usage of IMPT to treat some lung cancer patients.

Objective To examine disease control and survival after stereotactic body radiotherapy (SBRT) for medically inoperable, early-stage non–small cell lung cancer (NSCLC) and determine associations of pretreatment 18 F-fluorodeoxyglucose–positron emission tomography (FDG-PET) maximum standardized uptake values (SUVmax), biologically effective dose, and mediastinal staging with disease control and survival outcomes. Patients and Methods We retrospectively reviewed the cases of consecutive patients with FDG-PET–staged, medically inoperable NSCLC treated with SBRT at our institution between January 1, 2008, and August 4, 2014. Cumulative incidences of recurrence were estimated, accounting for the competing risk of death. Associations of SUVmax, biologically effective dose, and mediastinal staging with outcomes were evaluated using Cox proportional hazards regression models. Results Among 282 patients, 2-year cumulative incidences of recurrence were 4.9% (95% CI, 2.6%-8.3%) for local, 9.8% (95% CI, 6.3%-14.2%) for nodal, 10.8% (95% CI, 7.0%-15.5%) for ipsilateral lung, 6.0% (3.3%-9.8%) for contralateral lung, 9.7% (95% CI, 6.3%-14.0%) for distant recurrence, and 26.1% (95% CI, 20.4%-32.0%) for any recurrence. The 2-year overall survival was 70.4% (95% CI, 64.5%-76.8%), and the 2-year disease-free survival was 51.2% (95% CI, 44.9%-58.5%). Risk of any recurrence was significantly higher for patients with higher SUVmax (hazard ratio [per each doubling], 1.29 [95% CI, 1.05-1.59]; P =.02). A similar association with SUVmax was observed when considering the composite outcome of any recurrence or death (hazard ratio, 1.23 [95% CI, 1.05-1.44]; P =.01). The SUVmax was not significantly associated with other outcomes ( P ≥0.69). Two-year cumulative incidences of local recurrence for patients receiving 48 Gy in 4 fractions, 54 Gy in 3 fractions, or 50 Gy in 5 fractions were 1.7% (95% CI, 0.3%-5.6%), 3.7% (95% CI, 0.7%-11.4%), and 15.3% (95% CI, 5.9%-28.9%), respectively ( P =.02); this difference was independent of lesion size ( P =.02). Conclusion Disease control was excellent for patients who received SBRT for early-stage NSCLC, and this series represents the largest single-institution experience from the United States on SBRT for early-stage inoperable NSCLC. Higher pretreatment FDG-PET SUVmax was associated with increased risk of any recurrence, and the 50 Gy in 5 fractions dose prescription was associated with increased risk of local recurrence.

Purpose/Objective(s) Anti-CD19-directed chimeric antigen receptor T-cell therapy (CART) is a new treatment option for patients with relapsed and/or refractory non-Hodgkin lymphoma (NHL). We reviewed the outcomes of patients receiving CART and the potential role of bridging radiation therapy (bRT) in reducing local recurrences. Materials/Methods Following IRB approval, we retrospectively reviewed 120 patients with NHL who received CART between 2018 and 2020 at a multi-site single institution. Baseline clinical and treatment characteristics were compared between patients who received bRT (≤30 days prior to CART or after leukapheresis) and those who did not using chi-square and Fisher's exact tests. Overall-survival (OS) and progression-free survival (PFS) were defined from date of CART infusion and estimated by Kaplan-Meier curves. Response rate was based on the post-CART PET scan with the best attained response. Results Of 120 patients who received CART, 2 (1.7%) died soon after CART infusion from infection. Of the 118 remaining patients (88% diffuse large B-cell, 7.5% high-grade B-cell, 2.5% mantle cell, 2% primary mediastinal B-cell), 14 (12%) received bRT, while 104 (88%) did not (noRT). There were no significant differences in the baseline clinicopathological characteristics between the two groups. bRT was delivered with a median dose of 20 Gy (range 15-36) in 5 fractions (range: 3-24). No grade 2+ radiation-related toxicities were noted. Median time between end of bRT and the CART infusion was 19 days (range: 8-38). Rates of grade > 2 ICANS (21% vs 16%; P = .70) and CRS (7% vs 2%; P = .32) were not significantly different between bRT and noRT, respectively. Median follow-up was 7 months (range: 1-31). There were 42 (36%) deaths: 31 due to progression, 9 due to infection and 2 of unknown causes. The 6-month and 1-year OS were 67% and 67% for the bRT, and 76% and 63% for the noRT groups, respectively (P = .96). The median time to CART failure for the cohort was 78 days (range: 22-627). The 6-month and 1-year PFS were 47% and 47% for the bRT, and 47% and 42% for the noRT groups, respectively (P = .73). Median time to achieve the best response on PET scan was 30 days (range 22-382). Sixty patients (51%) achieved complete remission to CART, 7 (50%) in the bRT group and 53 (51%) in the noRT group, while 40 (34%) achieved partial remission, 5 (36%) in the bRT group and 35 (34%) in the noRT group (P = .97). For the entire cohort, pattern of failure analysis revealed that progression in pre-existing sites alone or in combination with new sites was the predominant site of failure in the bRT and noRT groups (86% and 88%, respectively). However, 71.4% of progressions in the bRT group occurred outside the RT field (n = 5), compared to 28.6% (n = 2) inside the RT field. Conclusion Bridging RT prior to CAR T-cell infusion is well tolerated and appears to provide excellent in-field local control. Large prospective studies evaluating the value of integrating bRT with CAR T-cell therapy are needed.

Purpose Concurrent chemoradiation therapy is a curative treatment for squamous cell carcinoma of the anus, but patients can suffer from significant treatment-related toxicities. This study was undertaken to determine whether intensity modulated proton therapy (IMPT) is associated with less acute toxicity than intensity modulated radiation therapy (IMRT) using photons. Materials and Methods We performed a multi-institutional retrospective study comparing toxicity and oncologic outcomes of IMRT versus IMPT. Patients with stage I-IV (for positive infrarenal para-aortic or common iliac nodes only) squamous cell carcinoma of the anus, as defined by the American Joint Committee on Cancer's AJCC Staging Manual, eighth edition, were included. Patients with nonsquamous histology or mixed IMPT and IMRT treatment courses were excluded. Acute nonhematologic toxicities, per the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 4, were recorded prospectively at all sites. Acute and late toxicities, dose metrics, and oncologic outcomes were compared between IMRT and IMPT using univariable and multivariable statistical methods. To improve the robustness of our analysis, we also analyzed the data using propensity score weighting methods. Results A total of 208 patients were treated with either IMPT (58 patients) or IMRT (150 patients). Of the 208 total patients, 13% had stage I disease, 36% stage II, 50% stage III, and 1% stage IV. IMPT reduced the volume of normal tissue receiving low-dose radiation but not high-dose radiation to bladder and bowel. There was no significant difference between treatment groups in overall grade 3 or greater acute toxicity (IMRT, 68%; IMPT, 67%; P = .96) or 2-year overall grade 3 or greater late toxicity (IMRT, 3.5%; IMPT, 1.8%; P = .88). There was no significant difference in 2-year progression-free survival (hazard ratio, 0.8; 95% CI, 0.3-2.0). Conclusions Despite reducing the volume of normal tissue receiving low-dose radiation, IMPT was not associated with decreased grade 3 or greater acute toxicity as measured by CTCAE. Additional follow-up is needed to assess whether important differences arise in late toxicities and if further prospective evaluation is warranted.

Purpose: This study compares reduced (

Purpose Our purpose was to assess the safety and efficacy of intensity modulated proton therapy (IMPT) for the treatment of hepatocellular carcinoma (HCC). Methods and Materials A retrospective review was conducted on all patients who were treated with IMPT for HCC with curative intent from June 2015 to December 2018. All patients had fiducials placed before treatment. Inverse treatment planning used robust optimization with 2 to 3 beams. The majority of patients were treated in 15 fractions (n = 30, 81%, 52.5-67.5 Gy, relative biological effectiveness), whereas the remainder were treated in 5 fractions (n = 7, 19%, 37.5-50 Gy, relative biological effectiveness). Daily image guidance consisted of orthogonal kilovoltage x-rays and use of a 6° of freedom robotic couch. Outcomes (local control, progression free survival, and overall survival) were determined using Kaplan-Meier methods. Results Thirty-seven patients were included. The median follow-up for living patients was 21 months (Q1-Q3, 17-30 months). Pretreatment Child-Pugh score was A5-6 in 70% of patients and B7-9 in 30% of patients. Nineteen patients had prior liver directed therapy for HCC before IMPT. Eight patients (22%) required a replan during treatment, most commonly due to inadequate clinical target volume coverage. One patient (3%) experienced a grade 3 acute toxicity (pain) with no recorded grade 4 or 5 toxicities. An increase in Child-Pugh score by ≥ 2 within 3 months of treatment was observed in 6 patients (16%). At 1 year, local control was 94%, intrahepatic control was 54%, progression free survival was 35%, and overall survival was 78%. Conclusions IMPT is safe and feasible for treatment of HCC.

165 Background: Distant metastases are common in primary esophageal cancer, but data conflict regarding the rates of brain metastases (BM) ranging from 0% to 13%. We sought to investigate whether the incidence of BM from esophageal malignancies is increasing in the modern era. Methods: After IRB approval, a single institution retrospective review identified 583 patients (pts) treated between 1/1997 and 1/2016 for stage I-IV cancer of the esophagus/esophagogastric junction with at least 3 months follow-up. Data collected included demographic information, primary diagnosis date and staging, histologic subtype, treatment regimens for primary and BM, date of BM diagnosis, status of neurologic symptoms and extracranial disease at BM diagnosis, and date of death. Data were analyzed by Fischer’s exact test and Kaplan-Meier analysis. Results: The overall cohort was comprised of 495 pts (85%) with adenocarcinoma and 82 pts (14%) with squamous cell carcinoma. 492 pts (84%) were male; the median age was 68 years (range 26-90). BM were identified in 22 pts (3.8%) with a median latency of 11 months from the primary diagnosis. Of the pts with BM, the primary histology was adenocarcinoma in 21 pts and squamous cell carcinoma in 1 pt ( P = 0.3). BM developed in 12 pts who were initially treated for locally advanced disease and in 10 pts who presented with distant metastases. Diagnosis of BM was at the time of initial presentation in 4 of these 10 stage IV pts. A solitary BM was identified in 9 pts. Initial treatments of BM were surgical resection followed by stereotactic radiosurgery (SRS; n = 5); surgical resection followed by whole brain radiotherapy (WBRT; n = 1); WBRT alone (n = 13); SRS alone (n = 3). Overall survival (OS) following diagnosis of BM was 18% at 1 year with a median of 4 months. OS was superior for pts who had surgical resection as initial treatment of BM compared to pts treated with WBRT or SRS alone (1-year OS 67 vs. 0%; median OS 13.5 vs. 3 months; P = 0.003). Conclusions: The incidence of BM is low in esophageal cancer with no statistically significant increased rate of BM developing in patients with adenocarcinoma compared with squamous cell carcinoma. Outcomes were poor overall for pts who developed BM, but pts who were appropriate for neurosurgical resection had improved survival.

The purpose of this study was to compare Functional Assessment of Cancer Therapy-Esophagus (FACT-E) questionnaire changes during proton (PRT) or photon (XRT) chemoradiation therapy (CRT) for esophageal cancer (EC).We reviewed patients enrolled in a prospective registry who received preoperative or definitive CRT for EC. Patients completed the FACT-E before CRT and during the last week of CRT. Analysis of variance testing was used to assess associations between patient and treatment characteristics and FACT-E score changes.One hundred twenty-five patients completed a baseline and posttreatment FACT-E; 63 received XRT and 62 received PRT. The mean age was 65 years; the PRT group was older (68 vs 64 years, P = .0063). The following characteristics were similar between cohorts: 83% male, 78% adenocarcinoma, and 89% stage II-III. The radiation therapy prescription dose was higher in the PRT group (≥50 Gy in 94% vs 67%, P .0001), whereas the median clinical target volume was smaller in the PRT group (553 vs 668 cmFor patients receiving CRT for EC, PRT was associated with less decline in FACT-E scores compared with XRT.

To examine, in a prospective fashion, the utilization and efficacy of adjuvant radiation therapy (RT) in patients with resected desmoplastic melanoma (DM). Adult patients with resected, margin‐negative, and nonmetastatic DM were eligible for this single‐arm prospective phase II study. Patients were to receive postoperative RT, 30 Gy in five fractions, to the operative bed with 2‐ to 3‐cm margins (depending on the tumor location). Nodal basin RT was not allowed. The primary study endpoint was the 2‐year local recurrence rate (LRR). Secondary endpoints included the incidence of regional and distant metastatic disease, progression‐free survival, overall survival (OS), and treatment‐related toxicity. Twenty patients with a single de novo DM lesion meeting trial eligibility criteria were enrolled and treated. The 2‐year LRR was 10%, with two patients demonstrating a LR within 2 years of completion of protocol therapy. No regional or distant failures occurred. OS at 2 and 5 years was 95 and 77%, respectively. There were no grade 3 or higher acute or late adverse events that were related to the protocol therapy. Adjuvant RT after wide local excision (WLE) for DM is efficacious and well tolerated. It should be considered for DM patients after margin‐negative WLE. Additional study is needed to further refine low‐risk patient populations that can potentially have adjuvant RT omitted as part of the treatment plan.

Background:Case reports suggest photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) is an effective treatment for refractory mycosis fungoides (MF). No prospective trials have examined the use of ALA-PDT in MF. Objective:We aimed to assess the efficacy of ALA-PDT in refractory MF. Methods:This was a prospective study at Mayo Clinic in Scottsdale, Arizona in patients ≥ 18 years with plaque-stage treatment-refractory MF. Monthly sessions of ALA with blue light PDT were administered for up to six months. Responses were measured by Composite Assessment of Index Lesion Severity (CAILS) and Physician Global Assessment (PGA). Ad hoc analysis with modified CAILS (mCAILS) was performed, eliminating hyperpigmentation from scoring. Results:Eleven patients (30 total lesions) were treated. Six patients completed the trial per protocol. Objective response rates were 36.4% by PGA (10.9-69.2%), 18.2% by CAILS (2.3-51.8%), and 36.4% by mCAILS (10.9-69.2%). Limitations:Five patients did not complete all six PDT cycles per protocol, possibly accounting for reduced efficacy. Conclusion:ALA-PDT with blue light irradiation was moderately effective and well tolerated in refractory plaque stage MF. Lower response rates compared to similar trials may be partially explained by utilization of strict lesional assessment criteria and other variations in methodology. Disclosures Mangold: MiRagen:Research Funding;Sun Pharma:Research Funding;Elorac:Research Funding;Kirin:Membership on an entity's Board of Directors or advisory committees;Solagenix:Research Funding. OffLabel Disclosure: Photodynamic therapy is a two-step therapy in which a drug that acts as a photosensitizer is administered to target a diseased tissue, followed by illumination with visible light to activate the drug and destroy the target tissue. PDT has been used to treat internal cancers as well as treatment of cancer and precancer of the skin.