PURPOSE:Liver transplantation is the definitive treatment for hepatocellular carcinoma (HCC) in eligible patients with cirrhosis. Bridging liver-directed therapies are critical for maintaining transplant eligibility during long wait times. However, due to the fear of decompensation, many advanced cirrhotic patients are excluded from receiving liver-directed therapies. This prospective pilot clinical trial evaluated the feasibility, safety, and efficacy of stereotactic body radiation therapy (SBRT) as a bridging therapy in an advanced cirrhotic HCC population. METHODS AND MATERIALS:HCC patients with Child-Pugh B8 or worse cirrhosis and eligible for liver transplant were enrolled. SBRT to 40 Gy in 5 fractions was delivered to a single HCC as a bridging strategy. The primary endpoint was the proportion of patients who were transplant eligible up to 1 year following SBRT. Secondary endpoints included disease control per modified Response Evaluation Criteria in Solid Tumors, proportion of patients that proceeded to transplant, incidence of nonclassical radiation-induced liver disease (RILD) within 1 week to 3 months after SBRT, and incidence of liver toxicity per Common Terminology Criteria for Adverse Events v5.0. RESULTS:Between 2019 and 2023, 9 patients with Child-Pugh B8 or worse cirrhosis were enrolled. Median follow-up was 11.2 months with a 22% death rate. Six patients (67%) were transplanted or remained transplant eligible 1 year after SBRT. Three patients (33%) failed to receive a liver transplantation: 2 due to factors unrelated to SBRT or tumor progression, and 1 patient experienced minimal tumor progression outside of Milan criteria. Per modified Response Evaluation Criteria in Solid Tumors, the local control rate was 100% and the incidence of intrahepatic and extrahepatic disease progression was 0%. Within 1 week to 3 months after SBRT, 1 patient (11%) experienced liver toxicity (Common Terminology Criteria for Adverse Events grade 4 acidosis, acute hepatic encephalopathy, and hepatic failure), but there were no instances of nonclassical RILD. CONCLUSIONS:Bridging SBRT in patients with HCC and advanced cirrhosis may safely maintain transplant eligibility without increasing the risk of nonclassical RILD.

AbstractQuantification and detection of circulating tumor DNA (ctDNA) has been used to identify the presence of cancers. Ablative radiation therapy kills tumor cells to reduce tumor burden and it follows that these dying tumor cells could lead to increased ctDNA abundance. We carried out deep, error-corrected sequencing of cell-free DNA collected serially from 12 stage I, and 2 stage II/III non-small cell lung cancer (NSCLC) patients undergoing external-beam radiation treatment (EBRT) after initial diagnosis. We found that ctDNA detection rates decreased at the first blood draw as compared to baseline (43% to 7% of patients). Total ctDNA abundance decreased in 6 patients and increased in 5 patients between those same blood draws, with one patient showing evidence of tumoral heterogeneity. Both patients with stage II/III disease had the largest increases in ctDNA abundance from baseline. Multiple blood draws improved ctDNA detection rates from 43% to 50% with a second blood draw and to 71% with 4 blood draws. Additionally, EGFR mutations were detectable in 6 patients during EBRT that were not detected prior to treatment. Taken together, these results provide an early-stage NSCLC counterpoint to previous work that reported improved ctDNA detection after radiation therapy in more advanced disease.

A 78-year-old man with a history of nonmelanoma skin cancers presented with left-sided upper and lower facial weakness. What is your diagnosis?

INTRODUCTION:For liver stereotactic body radiation therapy (SBRT), the placement of fiducial markers or retained ethiodized oil by transarterial chemoembolisation (TACE) provides a landmark for consistent target localisation. TACE and fiducial markers are invasive procedures that harbour additional risks. We hypothesise that liver SBRT can be accurately delivered without the use of these invasive surrogate markers.METHODS:We retrospectively identified 50 consecutive patients who underwent liver SBRT with respiratory motion management to a single lesion which exhibited retained ethiodized oil per prior TACE delivery. For each SBRT fraction, two manual rigid image registrations were performed by the treating physician. One using the liver contour as a surrogate for the target and second aligning only to the radio-opaque retained ethiodized oil of the treated lesion. The magnitude of the displacement vector between the two registration methods was used to assess the accuracy of target localisation if ethiodized oil was not present.RESULTS:For the 50 patients, a total of 244 analysable cone-beam CTs (CBCTs) were included (six CBCTs excluded due to poor ethiodized oil visualisation). Respiratory motion management techniques consisted of active breathing control for 13 and abdominal compression for 37 patients. Forty-two patients had peripheral lesions and eight had central lesions (<2 cm from left and right portal veins). The average target localisation offset between the two registration methods (i.e. liver contour vs. retained ethiodized oil alignment) for patients with a single peripheral or central liver lesion was 5.8 and 5.3 mm, respectively.CONCLUSIONS:Across all patients, the average change in target position exceeded 5 mm for image registration methods based on the liver contour alone versus the retained ethiodized oil region. This suggests that margins greater than 5 mm may be required for respiratory motion-managed liver SBRT treatments in patients who do not undergo prior TACE or fiducial placement.

Purpose/Objective(s) Liver transplantation (LTX) is the definitive treatment for hepatocellular carcinoma (HCC) in eligible patients with cirrhosis. Bridging liver-directed therapies (LDTs) are critical for maintaining Milan transplant eligibility (one HCC ≤ 5 cm or 2-3 HCCs all ≤ 3 cm) during long wait-times. However, due to the fear of further hepatic decompensation, many patients with advanced cirrhosis are excluded from receiving any LDTs. This prospective pilot study evaluated the feasibility, safety, and efficacy of SBRT as a bridging therapy in an HCC population with advanced cirrhosis. Materials/Methods In this Radiation Oncology Institute (ROI)-funded prospective pilot study, HCC patients with Child-Pugh (CP) B8 or worse cirrhosis who were within Milan transplant criteria and eligible for LTX without prior history of abdominal radiation or Y90 radioembolization and at least 700cc of uninvolved liver were included. SBRT to 40 Gy in 5 fractions was delivered to a single HCC as a bridging strategy (for patients with multi-focal HCC, SBRT was provided to the largest lesion). Previous transarterial chemoembolization (TACE) to the target or non-target lesions was allowed. The primary endpoint was the proportion of patients that were transplant eligible up to 1-year following SBRT. Secondary endpoints included intra- and extra-hepatic disease control, overall survival, proportion of patients that proceeded to transplant, incidence of non-classical radiation-induced liver disease (RILD) within 1 week to 3 months after SBRT (defined as grade 4 AST or ALT elevation, or a ≥ 2-point increase in CP score) and incidence of liver toxicity per CTCAE v5.0. Results Between 2019 and 2023, seven men and two women with baseline liver functions of CP-B8 (7 patients) and CP-B9 (2 patients) were enrolled. Mean baseline bilirubin for all patients was 3.1mg/dL. Three patients had previous TACE. Eight patients had a single HCC while 1 patient had 2 HCCs (largest treated with SBRT). Median follow up was 343 days. With no instances of intra- or extra-hepatic disease progression, there were no patients who were removed from the transplant list due to Milan size or number criteria. Six (66.6%) ultimately received a liver transplantation at a median time of 12 months from study enrollment. Three (33.3%) failed to receive a liver transplantation due to factors unrelated to SBRT or tumor progression; progression of concurrent cardiac comorbidities deeming LTX unsafe, hip fracture and resultant respiratory failure, and poor compliance to LTX protocol. No cases of non-classical RILD were identified and no patients were emergently transplanted due to hepatic decompensation from SBRT. Conclusion Bridging SBRT in patients with HCC and advanced cirrhosis may safely maintain LTX eligibility with no incidence of non-classical RILD. This supports the safety of bridging SBRT in a patient population with limited bridging LDT options. Further research is warranted to validate these findings in larger, multi-center trials.

A man in his 40s presents with back and abdominal pain associated with nausea, vomiting, and flushing; imaging and biopsy findings show a thoracic paraspinal mass with dense cellular infiltrate. What is your diagnosis?

BACKGROUND. Transarterial chemoembolization (TACE) has synergistic properties when combined with ablative therapies for hepatocellular carcinoma (HCC). OBJECTIVE. The purpose of our study was to compare outcomes for inoperable HCC between TACE with percutaneous thermal ablation (TACE-TA) and TACE with stereotactic body radiotherapy (TACE-SBRT) using propensity score-weighted cohorts. METHODS. This retrospective study included 190 patients with a single inoperable HCC treated from 2007 to 2018 by either TACE-SBRT (n = 90) or TACE-TA (n = 100). The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS) and hepatotoxicity (defined as Child-Pugh score elevation of = 2 within 2-6 months after treatment). Fine-Gray competing risk models with propensity score weighting and transplant as the competing risk factor were used to model OS and PFS. RESULTS. The median follow-up time was 48.2 months. Both OS and PFS were significantly higher for TACE-TA (77% and 76%, respectively, at 2 years) than TACE-SBRT (49% and 50%, respectively, at 2 years) in the propensity score-weighted multivariate model (OS: subdistribution hazard ratio [sHR] = 2.70, p < .001; PFS: sHR = 1.71, p = .02). Treatment-related hepatotoxicity occurred in 9% of patients who underwent TACE-TA versus 27% of those who underwent TACE-SBRT (p = .01). For the subset of patients with Barcelona Clinic Liver Cancer A HCC and Child-Pugh A cirrhosis (TACE-SBRT, n = 36 patients; TACE-TA, n = 55 patients), OS (p = .11) and PFS (p = .19) were not significantly different between the two treatment modalities. CONCLUSION. Compared with TACE-SBRT, TACE-TA showed superior OS and PFS, possibly from its lesser hepatotoxicity. The two strategies did not differ in OS and PFS for patients with the earliest-stage HCC and preserved liver function. CLINICAL IMPACT. Across all patients, TACE-TA may be superior to TACE-SBRT for inoperable HCC.

Purpose: The role of MerTK, a member of the Tyro3-Axl-MerTK family of receptor tyrosine kinase, in the immune response to radiation therapy (RT) is unclear. We investigated immune-mediated tumor control after RT in murine models of colorectal and pancreatic adenocarcinoma using MerTK wild-type and knock-out hosts and whether inhibition of MerTK signaling with warfarin could replicate MerTK knock-out phenotypes. Methods and Materials: Wild-type and MerTK(-/-) BALB/c mice were grafted in the flanks with CT26 tumors and treated with computed tomography guided RT. The role of macrophages and CD8 T cells in the response to radiation were demonstrated with cell depletion studies. The role of MerTK in priming immune responses after RT alone and with agonist antibodies to the T cell costimulatory molecule OX40 was evaluated in a Panc02-SIY model antigen system. The effect of warfarin therapy on the in-field and abscopal response to RT was demonstrated in murine models of colorectal adenocarcinoma. The association between warfarin and progression-free survival for patients treated with SABR for early-stage nonsmall cell lung cancer was evaluated in a multi-institutional retrospective study. Results: MerTK(-/-) hosts had better tumor control after RT compared with wild-type mice in a macrophage and CD8 T cell-dependent manner. MerTK(-/- )mice showed increased counts of tumor antigen-specific CD8 T cells in the peripheral blood after tumor-directed RT alone and in combination with agonist anti-OX40. Warfarin therapy phenocopied MerTK(-/-) for single-flank tumors treated with RT and improved abscopal responses for RT combined with anti-CTLA4. Patients on warfarin therapy when treated with SABR for non-small cell lung cancer had higher progression-free survival rates compared with non-warfarin users. Conclusions: MerTK inhibits adaptive immune responses after SABR. Because warfarin inhibits MerTK signaling and phenocopies genetic deletion of MerTK in mice, warfarin therapy may have beneficial effects in combination with SABR and immune therapy in patients with cancer. (C) 2020 Elsevier Inc. All rights reserved.

For patients who undergo liver stereotactic body radiation therapy (SBRT), the placement of fiducial markers or retention of ethiodol delivered by trans-arterial chemoembolization (TACE) provides an accurate landmark for consistent target localization using cone-beam CT (CBCT). However, TACE and fiducial marker placement are invasive procedures that may harbor additional risk. We hypothesize that the delivery of liver SBRT can be safe and accurate without the use of these surrogate markers. In this study, we aim to assess the accuracy of this approach by comparing daily alignment using retained ethiodol within the treated lesion vs. a liver contour surrogate. We retrospectively identified 7 consecutive patients that received TACE prior to 5 fraction SBRT for a single peripheral liver lesion (>2 cm from left and right portal veins). All lesions exhibited retained ethiodol on simulation CT and each CBCT. All patients underwent respiratory motion management using either end-expiratory Active Breathing Coordination (ABC, n = 3) or abdominal compression (n = 4). Liver and retained ethiodol contours were determined on the CT simulation and each daily CBCT. All images and structure sets were exported to a commercial software where rigid image fusion was performed between the planning CT and daily CBCTs. To approximate the positioning of our clinical treatment couch, no roll or yaw was applied during registration. For each fraction, two manual rigid image registrations were performed by the treating physician – once using the liver contour as a surrogate for the target (concentrating on the liver edge(s) closest to the treated liver segment) and once aligning only to the radio-opaque retained ethiodol of the treated lesion. As a figure of merit, the magnitude of the change in vector (i.e., the distance) between the two registration methods was used to assess the target localization if ethiodol were not present. Mean PTV volume was 23.5 cc (range: 5.4cc – 44.5cc). Across all patients, the average change in target localization throughout 5 fraction liver SBRT was 5.8 mm (range: 1 – 15.4 mm) when using the liver contour as surrogate for the target instead of the retained ethiodol region. For patients treated with end-expiratory ABC, average change was 5.7 mm (range: 1.1 – 10.9 mm). For patients treated with abdominal compression, average change was 5.9 mm (range: 1 – 15.4 mm). Across all patients, the average change in target position exceeded 5 mm, for image registration methods based solely on the liver contour versus concentration on retained ethiodol only. Given this, we suggest that greater than standard 5mm PTV margins should be applied when delivering respiratory-managed liver SBRT to peripheral lesions without the assistance of fiducial markers or retained ethiodol.

Abstract Purpose: To determine if the administration of stereotactic body radiation therapy (SBRT) to known tumor masses temporarily elevates levels of circulating tumor DNA (ctDNA) derived from target or distal masses and to identify an optimal period of peak ctDNA enrichment for liquid biopsy. Experimental Design and Procedures: We used deep, whole-exome sequencing (WES) or 100-gene capture with UMI-based error corrected sequencing of cell-free DNA (cfDNA) of individuals undergoing SBRT as standard-of-care (SOC) to determine (a) whether SBRT treatment induces elevated levels of ctDNA in blood plasma as confirmed by biopsy-proven cases, and (b) the optimal window of ctDNA enrichment for sample collection. We collected blood draws every 24-72 hours from each patient prior to and during SBRT treatment (n=20), as well as for two weeks following the final dose (n=3). CfDNA and genomic DNA were isolated from blood plasma and solid tissue biopsies, respectively, and subjected to whole-exome capture and next-generation sequencing with the Illumina HiSeq 2500 platform. Sequencing data were aligned and mutations were called using BWA MEM and Mutect pipelines as previously described (Butler et al., 2019). Genomic DNA extracted from buffy coat was prepared and used as a matched normal in mutation calling. Variant allele frequencies (VAF) of Mutect calls were compared between baseline and post-treatment samples to determine enrichment levels. WES of bulk tumor DNA from pathology-proven cancer patients was used to confirm that the variants identified in the cfDNA sequencing originated in the target tissue. Data Summary: Preliminary data suggest that SBRT induces enrichment of ctDNA in blood plasma by at least 10-fold within 24-96 hours following treatment. When variants identified in separate biopsies of multiple tumors in a single individual were analyzed after SBRT, we found that increases were not uniform among variant clusters, suggesting an abscopal response from nonradiated tumor tissues found elsewhere in the patient. Conclusions: The ability to detect tumor-derived genomic variants in cfDNA has been a major challenge to liquid biopsy applications, particularly in early-stage cancers and recurrence settings. This novel detection strategy, RAMP-Seq, utilizes highly conformational radiation to induce ctDNA enrichment from tumor-cell death, making previously undetectable levels of ctDNA well within the range of standard sequencing and analysis methods. Such an approach has valuable applications from diagnosis of early-stage cancer to genotyping lesions normally inaccessible by a traditional biopsy. Abscopal effects have also been observed, suggesting that induction of ctDNA enrichment by radiating the target lesion can also result in the increase of ctDNA derived from distal lesions. Taken together, these findings offer promising new approaches to both early- and advanced-stage cancer characterization and intervention. This abstract is also being presented as Poster A44. Citation Format: Christopher Boniface, Kathryn Baker, Chris Dieg, Carol Halsey, Ramtin Rahmani, Mark Deffenbach, Charles Thomas, Garth Tormoen, Nima Nabavizadeh, Paul Spellman. Radiation-assisted Amplification Sequencing (RAMP-Seq): Evaluating the use of stereotactic body radiation therapy (SBRT) for enriching circulating tumor DNA in liquid biopsies [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr PR05.

MerTK is a member of the Tyro3-Axl-MerTK (TAM) family of receptors and regulates phagocytosis of dying cells by tumor associated macrophages, ultimately contributing to an immune tolerant tumor microenvironment that subverts adaptive immune control of residual disease. MerTK-/- mice grafted with immunogenic tumors achieve tumor cure following stereotactic ablative radiation (SABR) at higher rates than wild-type mice in a manner dependent upon an intact adaptive immune system. Warfarin is a commonly prescribed anticoagulant that also inhibits MerTK signaling. We hypothesize that warfarin administration at the time of targeted radiotherapy will lead to improved tumor control and promote adaptive immune responses instigated by SABR. BALB/c mice were injected subcutaneously in the flank with 50,000 CT26 cells. Tumors were allowed to grow to 5 mm before treatment with 250 μg anti-CD8α antibodies, warfarin (1.25 mg/L drinking water) and subjected to SABR (12.5 Gy) or no further treatment. Tumors were followed for growth or harvested 4 and 7 days after RT and infiltrating immune cells analyzed by flow cytometry. Disease free survival for patients with early stage (cT1-T3N0) non-small cell lung cancer treated (NSCLC) with SABR at a single institution between 2007 and 2017 was compared between patients on warfarin at the time of treatment. Warfarin treated mice had higher rates of tumor cure following radiation that was abrogated by CD8 depletion, mimicking the phenotype seen in MerTK-/- mice. Warfarin treated mice had higher concentrations of CD45+ infiltrating cells compared to controls. At four days after RT, warfarin treated mice had similar concentrations of CD8+ tumor-infiltrating leukocytes compared to controls, but increased co-expression of CD103. At 7 days after RT, warfarin treated mice had increased concentrations of tumor infiltrating lymphocytes compared to controls. Coexpression of activation markers CD44, PD-1, and loss of CD62L were not different for warfarin treated mice after RT compared to controls. 38 of 251 patients treated with SBRT at a single institution between 2007 and 2017 for early stage NSCLC were on warfarin at the time of SBRT. The 3 year progression free survival in warfarin users was 90.3% and 74.7% for non-warfarin controls (p=0.14). Warfarin promoted adaptive immune control of tumors following targeted radiation in preclinical studies. In a retrospective review, warfarin administration at the time of SABR was associated with a marked but non-statistically significant improvement in regional and distant disease free survival. These data suggest warfarin administration may enhance adaptive immune control of tumors following SABR. Future prospective trials combining warfarin with SABR and immunotherapy with the goal of improving adaptive immune control of residual disease are warranted.

443 Background: To assess the relative efficacy and toxicity associated with TACE+Ablation (Ablation) or TACE+SBRT (SBRT) in a large cohort of patients with unresectable HCC. Methods: Patients with HCC undergoing Ablation or SBRT from 2006-2016 with available follow up were included. Treatment groups were different at baseline regarding tumor stage (BCLC A, B and C: 96%, 4%, 0% (Ablation) vs. 73%, 14% and 13% (SBRT), P < 0.001) and severity of liver disease (CTP A, B, and C: 55%, 45% and 0% (Ablation) vs. 50%, 41%, and 9% (SBRT), P = 0.007). Propensity scores were calculated with age, sex, BCLC stage, CTP class, etiology of liver disease, tumor number, and diameter to balance the cohorts. Average treatment effects on survival with multivariable propensity score-weighted competing risk Cox regression models were evaluated, with BCLC stage, number of treated tumors and liver transplant as additionally controlled variables. Primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS), local tumor control and hepatotoxicity. Treatment-related hepatotoxicity was defined as a two point change in CTP within six months after treatment. Results: 192 subjects were included (101 Ablation, 91 SBRT; median age=60 years, 75% men). Liver disease included HCV (78%), alcohol (35%) and NASH (8%). Liver transplant-adjusted 1- and 2-year OS rates were significantly greater for Ablation vs SBRT (88% vs. 75% and 77% vs. 50%, P<0.001). 1-and 2-year PFS rates were significantly greater for Ablation vs. SBRT (84% vs. 65% and 75% vs. 51%, P < 0.001). 1- and 2- year local tumor control rates were similar with both strategies (99% vs. 91% and 94% vs. 87%, P=0.298). Propensity score-weighted multivariable analysis showed significantly higher OS (sHR: 2.31, P = 0.006) and PFS rates (sHR:1.75, P = 0.008) with Ablation compared to SBRT. Ablation was also associated with lower post-treatment hepatotoxicity compared with SBRT (5% vs. 12%, P = 0.001). Conclusions: TACE+Ablation demonstrated higher OS/PFS and lower post-treatment hepatotoxicity compared with TACE+SBRT. Local disease control up to two years was equivocal, potentially suggesting equipoise for bridge to transplant.

443Background: To assess the relative efficacy and toxicity associated with TACE+Ablation (Ablation) or TACE+SBRT (SBRT) in a large cohort of patients with unresectable HCC. Methods: Patients with HCC undergoing Ablation or SBRT from 2006-2016 with available follow up were included. Treatment groups were different at baseline regarding tumor stage (BCLC A, B and C: 96%, 4%, 0% (Ablation) vs. 73%, 14% and 13% (SBRT), P u003c 0.001) and severity of liver disease (CTP A, B, and C: 55%, 45% and 0% (Ablation) vs. 50%, 41%, and 9% (SBRT), P = 0.007). Propensity scores were calculated with age, sex, BCLC stage, CTP class, etiology of liver disease, tumor number, and diameter to balance the cohorts. Average treatment effects on survival with multivariable propensity score-weighted competing risk Cox regression models were evaluated, with BCLC stage, number of treated tumors and liver transplant as additionally controlled variables. Primary outcome was overall survival (OS). Secondary outcomes were progression-free su...

BACKGROUND:In locally-advanced esophageal cancer (LAEC), providers' concerns regarding eventual surgical candidacy can persuade physicians to defer to definitive doses of 50 Gy or higher preoperatively. We report the successful completion rate of tri-modality therapy (TMT) (documented at the outset) and reasons for TMT non-adherence at a large multi-disciplinary esophageal program.METHODS:LAEC patients diagnosed 2007-2016 from a prospective institutional database were subdivided into CRT/S+ [completed chemoradiation (CRT) and surgery] and CRT/S- (CRT and no subsequent surgery) groups. Chart review provided surgery non-adherence reasons.RESULTS:A total of 283 patients met planned TMT criteria: 164 (58.0%) patients received 50 or 50.4 Gy CRT, 27 patients (9.5%) received greater than 50.4 Gy, and 92 patients received less than 50 Gy (32.5%, only 8 patients received CRT to 41.4 Gy); 221 (78.1%) completed surgery (CRT/S+), while 62 (21.9%) failed to advance to surgery (CRT/S-): 25 of 62 CRT/S- patients (40.3%) evidenced metastatic progression before surgery, 4 (6.5%) were deemed unresectable intraoperatively, 4 (6.5%) expired prior to planned surgery (3 from unknown causes, 1 suicide), 8 (12.9%) experienced significant CRT-related medical decompensation and were withdrawn from surgical consideration, 16 (25.8%) voluntarily declined surgery post-CRT (largely due to long-term quality of life concerns), and 5 (8.1%) failed to advance for unknown reasons. Four of the 16 patients who voluntarily declined surgery after CRT received less than 50 Gy. The 22.2% of CRT/S+ patients achieved pathologic complete response (21.6% for adenocarcinoma and 29.0% for squamous cell carcinoma).CONCLUSIONS:Our institution's 78% surgery completion rate among TMT-indicated patients highlights the benefits of upfront multidisciplinary care. Metastatic disease development most commonly truncated TMT with a low rate failing due to medical decompensation. Given the number of patients who voluntarily declined surgery following CRT, TMT counseling and involvement of a patient advocate are paramount prior to treatment planning.

As non-operative management (NOM) of locally-advanced esophageal (EC) and rectal cancer (RC) is becoming more prevalent, highly sensitive and specific serum biomarkers of treatment response are needed. In this pilot study, we hypothesized that serially monitored patient and tumor-specific mutations in circulating tumor DNA (ctDNA) throughout multi-modality treatment using a novel, highly sensitive quantification method would closely associate with clinical outcomes. Plasma specimens were collected at baseline, through neoadjuvant therapy (NAT), immediately prior to surgery and in follow up. In each patient (n=4 for EC, n=2 for RC), we identified 30-50 tumor-specific mutations from whole exome sequencing using tumor tissue to longitudinally monitor ctDNA in plasma. Using a patient-specific hybrid capture technique (DIDAseq, dual-index degenerate adaptor sequencing - a custom library sequencing approach that significantly reduces polymerase errors), we were able to identify mutant alleles at a frequency of 1 in 10-50k site observations. This variant allele frequency was used to estimate mutant genomes/mL plasma. All patients had detectable ctDNA at baseline. For all but one patient, tumor-specific ctDNA levels showed a marked decrease during NAT. Three of four EC patients underwent esophagectomy, including one whose ctDNA levels became undetectable prior to surgery, with surgical pathology revealing a pathologic complete response (pCR). Another EC patient had low persistent ctDNA levels following CRT with final pathology revealing minimal residual disease. One patient with oligometastatic EC controlled with dual-checkpoint inhibition received CRT prior to esophagectomy as this was the only site of active disease. Throughout CRT, ctDNA levels persistently increased, correlating with radiographic/endoscopic progression and resistance to CRT, with ctDNA levels precipitously dropping following esophagectomy. Shortly after esophagectomy, distant metastatic disease was confirmed with biopsy. Post-hoc analysis of plasma revealed presence of metastasis-specific ctDNA at time-points prior to esophagectomy, representing sub-clinical distant metastatic progression. Two RC patients were treated with NOM consisting of NAC and CRT. Both patients exhibited a clinical complete response and were closely observed rather than proceeding with surgery. CtDNA levels were persistently detectable for both patients; ultimately with local recurrence confirmed on endoscopy 6 and 10 months following NAT. In this pilot study, patient and tumor-specific ctDNA analysis throughout multi-modality therapy for EC and RC was shown to be of practical use in assessment of treatment response, confirming pCR and predicting local recurrences with significant clinical lead times. However, the identification of metastasis-only ctDNA may confound efforts for early detection. Further studies with additional patients are on-going.

To assess the relative efficacy and toxicity associated with TACE+Ablation (Ablation) or TACE+SBRT (SBRT) in a large cohort of patients with unresectable HCC. Patients with HCC undergoing Ablation or SBRT from 2006-2016 with available follow up were included. Treatment groups were different at baseline regarding tumor stage (BCLC A, B and C: 96%, 4%, 0% (Ablation) vs 73%, 14% and 13% (SBRT), P<0.001) and severity of liver disease (CTP A, B and C: 55%, 45% and 0% (Ablation) vs 50%, 41% and 9% (SBRT), P=0.007). Propensity scores were therefore calculated with age, sex, BCLC stage, CTP class, etiology of liver disease, tumor number and diameter to balance the cohorts. Average treatment effects on survival with multivariable propensity score-weighted competing risk Cox regression models were evaluated, with BCLC stage, number of treated tumors and liver transplant as additionally controlled variables. Primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS), local tumor control and hepatotoxicity. Treatment-related hepatotoxicity was defined as a 2 point change in CTP within 6 months after treatment. 192 subjects were included (101 Ablation, 91 SBRT; median age=60 years, 75% men). Liver disease included HCV (78%), alcohol (35%) and NASH (8%). Liver transplant-adjusted 1- and 2-year OS rates were significantly greater for Ablation vs SBRT (88% vs 75% and 77% vs 50%, P<0.001). 1-and 2-year PFS rates were significantly greater for Ablation vs SBRT (84% vs 65% and 75% vs 51%, P<0.001). 1- and 2- year local tumor control rates were similar with both strategies (99% vs 91% and 94% vs 87%, P=0.298). Propensity score-weighted multivariable analysis showed significantly higher OS (sHR: 2.31, P=0.006) and PFS rates (sHR:1.75, P=0.008) with Ablation compared to SBRT. Ablation was also associated with lower post-treatment hepatotoxicity compared with SBRT (5% vs 12%, P=0.001). TACE+Ablation demonstrated higher OS/PFS and lower post-treatment hepatotoxicity compared with TACE+SBRT. Local disease control up to 2-years was equivocal, potentially suggesting equipoise for bridge to transplant.

In locally advanced esophageal cancer, providers' doubts regarding eventual surgical candidacy can affect radiation prescriptions, with many deferring to definitive doses of 50.4 Gy or higher in the preoperative setting. We report the successful completion rate of tri-modality therapy (TMT) and reasons for non-adherence to TMT in patients treated at a large multi-disciplinary esophageal program. We identified locally advanced esophageal cancer patients diagnosed between 2007 and 2016 from a prospective institutional database. Patients indicated for TMT (documentation of planned TMT at the outset) were divided into a CRT/S+ group (documentation of completed surgery) and a CRT/S- group (completion of CRT and no subsequent surgery). Detailed chart review provided reasons for non-adherence to TMT. Two hundred eighty-three patients with documentation of planned TMT prior to CRT were identified. CRT consisted of doses of 50 or 50.4 Gy for 164 patients (57.9%), greater than 50.4 Gy for 27 patients (9.5%), and less than 50 Gy for 92 patients (32.5%, only 8 patients received RT to 41.4 Gy). Concurrent chemotherapy largely consisted of cisplatin/5FU (predominating pre-CROSS trial therapy) or carboplatin/paclitaxel (post-CROSS therapy). Of the TMT-indicated patients, 221 (78.0%) completed surgery after CRT (CRT/S+), while 62 (22.0%) failed to advance to surgery (CRT/S-). Of the 62 CRT/S- patients, 25 (40.3%) had evidence of metastatic progression following CRT (20 identified on imaging, 5 identified intraoperatively), 4 (6.5%) were unresectable intraoperatively, 4 (6.5%) expired prior to planned surgery (3 from unknown causes, 1 committed suicide), 8 (12.9%) experienced significant medical decompensation from CRT and were no longer surgical candidates, 16 (25.8%) voluntarily declined surgery following CRT (largely due to the concerns of long-term quality of life) and 5 (8.1%) failed to advance to surgery for unknown reasons. Four of the 16 patients who voluntarily declined surgery after CRT received RT doses of less than 50 Gy. For the CRT/S+ patients, the pathologic complete response rate was 22.2% (21.6% for adenocarcinoma and 29.0% for squamous cell carcinoma). For the 138 patients with residual disease on pathology, 128 (92.7%) had no tumor at the resection margins (R0). At our institution, a 78% rate of success in completing surgery among patients indicated for TMT highlights the benefits of upfront multi-disciplinary care. As over 25% of our CRT/S- patients declined esophagectomy voluntarily, thorough surgical counseling prior to CRT is essential to avoid under-treatment. For our CRT/S+ patients, pCR and R0 resection rates did not quantitatively improve over the published CROSS trial. In the absence of a demonstration of superiority of radiation doses greater than 41.4 Gy, the robust CROSS regimen should be the standard of care in managing esophageal TMT patients, especially if evaluated upfront in a multi-disciplinary setting.

For hepatocellular carcinoma (HCC), trans-arterial chemoembolization (TACE) has synergistic properties when combined with ablative therapies. We retrospectively compared overall survival (OS) and progression-free survival (PFS) rates of TACE combined with percutaneous thermal ablation (microwave or radiofrequency, T-TA) or TACE combined with stereotactic body radiation therapy (T-SBRT) for patients with HCC at a single institution. From 2006 to 2016, HCC patients received T-TA (n=101) or T-SBRT to 50 Gy in 5 fractions (n=83) to a single tumor. Progression-free survival (PFS) per mRECIST and overall survival (OS) were assessed. Patients were censored at time of orthotopic liver transplantation (OLT). Cox proportional hazards models were used to model PFS and OS using covariates. Baseline demographics are presented in Table 1 (CP=Child-Pugh score, ALBI = albumin-bilirubin score, BCLC = Barcelona Clinic Liver Cancer). T-TA had significantly longer overall survival (log-rank p < 0.0001), with one and two-year OS for T-TA vs. T-SBRT of 86% vs. 73% and 72% vs. 43%, respectively. Baseline CP score, ALBI score, BCLC stage and number of prior TACE treatments were all independently associated with OS. After adjusting for significant covariates, patients treated with T-TA had a lower risk of death than those treated with T-SBRT (hazard ratio (HR) 0.39, 95%CI 0.23 – 0.66). T-TA group had significantly better PFS per mRECIST (log-rank p = 0.031), with one and two-year PFS for T-TA vs. T-SBRT of 78% vs. 59% and 60% vs. 44%, respectively. Only baseline BCLC stage and number of prior TACE treatments were independently associated with PFS. After adjustment, patients treated with T-TA did not have a lower risk of progression than those treated with T-SBRT (HR 0.83, 95%CI 0.47 – 1.44). For patients with CP-A liver function and BCLC stage A HCC, one and two-year OS and PFS for T-TA vs. T-SBRT were not statistically different (one and two-year OS: 92% vs. 91% and 81% vs. 69%, respectively, p = 0.075; one and two-year PFS: 84% vs. 69% and 67% vs. 51%, respectively, p=0.26). In the overall cohort, T-TA showed superior OS but not PFS compared to T-SBRT when adjusted for significant covariates. However, when selecting for patients with the most hepatic reserve and earliest stage HCC (CP-A and BCLC-A), neither OS nor PFS significantly differed. Combination therapy with TACE plus SBRT for early-stage HCC is an effective strategy for patients with preserved liver function. This observed clinical equipoise should be further examined in a randomized trial.Abstract 1043; Table 1T-TAT-SBRTMale69 (68.3%)70 (84.3%)Female32 (31.7%)13 (15.7%)CP-A55 (54.5%)43 (51.8%)CP-B44 (43.6%)34 (41.0%)CP-C2 (2.0%)6 (7.2%)ALBI 115 (14.9%)17 (20.5%)ALBI 266 (65.3%)51 (61.4%)ALBI 320 (19.8%)15 (18.1%)BCLC-A92 (91.1%)58 (69.9%)BCLC-B4 (4.0%)15 (18.1%)BCLC-C0 (0%)4 (4.8%)BCLC-D5 (5.0%)6 (7.2%)OLT14 (13.9%)14 (16.9%)No OLT87 (86.1%)69 (83.1%)≤ 2 TACE99 (98.0%)60 (72.3%)> 2 TACE2 (2.0%)23 (27.7%) Open table in a new tab