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For patients with oligometastatic colorectal cancer (CRC), aggressive local therapy of isolated metastases, particularly in the liver, has been associated with long-term progression-free and overall survival (OS) primarily based on retrospective evidence. However, in patients with limited metastatic CRC that is deemed inoperable or those with additional disease outside of the liver or lungs, the role of local ablative therapies, including microwave ablation (MWA) and stereotactic body radiation therapy (SBRT), to render patients disease free is less clear. Further, despite the long history of treating oligometastatic CRC with local therapy, which is provider biased and not evidence based, questions remain regarding the benefit of extending the paradigm of metastatic directed therapy to patients with more extensive disease. This trial seeks to use a pragmatic multimodality approach that mirrors the current clinical dilemma. This study is designed to evaluate the safety and efficacy of adding total ablative therapy (TAT) of all sites of disease to standard of care systemic treatment in those with limited metastatic CRC. A022101/NRG-GI009 is a National Clinical Trials Network randomized phase III study planned to enroll 364 patients with newly diagnosed metastatic CRC (BRAF wild-type, microsatellite stable) with ≤4 sites of metastatic disease on baseline imaging. Liver-only metastatic disease is not permitted, and lesions must be amenable to any combination of surgical resection, MWA, and/or SBRT with SBRT required for at least 1 lesion. Patients receive first-line systemic therapy for 16-26 weeks and are then randomized 1:1, stratified by number of metastatic organ sites (1-2 vs. 3-4), timing of metastatic disease diagnosis (de novo vs. secondary), and presence of metastatic disease outside the liver/lungs in at least 1 site. Patients in Arm 1 will receive TAT consisting of treatment of all metastatic sites with SBRT ± MWA ± surgical resection followed by standard of care systemic therapy. Patients in Arm 2 will continue with standard of care systemic therapy alone. The primary endpoint is OS. Secondary endpoints include event-free survival, treatment-related toxicities, and local recurrence with exploratory biomarker analyses. The study needs 346 evaluable patients combined in the 2 arms to demonstrate an improvement in OS with a hazard ratio of 0.7 to provide 80% power with a one-sided alpha of 5%. The trial utilizes a group sequential design with two interim analyses (25% and 50% of events) for futility. The trial activated in January 2023 and recruitment is ongoing. TBD TBD [ABSTRACT FROM AUTHOR]

Ablative RT (A-RT) has been shown to safely provide favorable local progression-free and overall survival (OS) in pts with liver cancers. Concerns have been raised regarding the safety of A-RT in pts with large liver tumors and in those with prior liver directed therapies. In this work, we assess response and toxicities associated with A-RT to liver metastases (LM). We identified 121 pts treated with A-RT to LM between 2017–2022. We assessed toxicities using CTCAE V5.0. Early radiographic response was measured by a dedicated liver radiologist using RECIST 1.1. Patients with scores of 1, 2, or 3 (complete response (CR), partial response, and stable disease respectively) were grouped as responders. Median age was 64 yrs (range = 25-93), with 63 (52%) males and 58 (48%) females. 63 (48%) pts had large tumors (defined as combined gross tumor volume (GTV) > 33cc equivalent to > 4cm diameter), and 25 (21%) pts had a GTV/liver volume ratio > 10%. Most pts (96%) had prior liver directed therapies. 70 (58%) pts had colorectal primaries. Median follow-up and OS were 14 and 19 months respectively. Median BED was 120Gy (range = 96-225) delivered using SBRT (1-5 fx) or fractionated A-RT (up to 25 fx). Median total GTV volume was 29 cc (range = 1-1,863). In correspondence with the RT plan, a median of 1,137 cc (range = 478-2,472) of liver minus GTV were spared and mean liver minus GTV dose was exceeded in 17 (13%) pts by a median of 6% (range = 0.4-36). For all pts, GTV coverage was excellent (median D95 and V100 of 102% and 99.8% respectively). 90% of pts responded to A-RT at 1st follow-up (median 60 days) and 98% at 2nd follow-up (median 128 days). Zero and six pts had a CR at 1st and 2nd follow-ups respectively. On univariable analysis, histology, prior liver-directed therapies and dosimetric parameters were not significant predictors of response to A-RT. While GTV volume was significantly associated with response at 1st follow-up (p = 0.024), this lost significance at 2nd follow-up (p = 0.13). A-RT to large liver lesions was not associated with more toxicity. No acute grade 4-5 toxicities were noted. Most common acute toxicity was grade 1 fatigue in 72 pts (62%). Long-term toxicities are shown in table 1. Liver function measured using albumin, LFTs, bilirubin and INR levels at 3- and 6-months post RT compared to respective baselines was maintained. A-RT to LM is safe even in heavily pretreated pts and in patients with large liver tumor volumes. A-RT is associated with an excellent early radiographic response. This response is slightly slow, with more responders noted at 18 weeks vs 8 weeks. Additional local control data will be available at the time of the meeting. [ABSTRACT FROM AUTHOR]

To report the results of a multi-center phase II trial of using proton re-irradiation (re-RT) for previously irradiated recurrent head/neck cancer (HNC). Recurrent HNC patients who received >/= 40 Gy of prior head/neck radiation were enrolled. Patients received fractionated re-RT (F-Re-RT to 70 Gy) or QUAD Shot re-RT (QS-Re-RT, 4 cycles to 59.2 Gy) at physician discretion. The primary endpoints (Clopper-Pearson Confidence Intervals method) were to determine the 12-months, 6-months locoregional recurrence-free (LRRF) rates for F-Re-RT and QS-Re-RT, respectively. Secondary endpoints were to determine: overall survival (OS), progression-free survival (PFS) [both estimated using the Kaplan-Meier method]; distant metastasis (DM), locoregional recurrence (LRR) rates [both calculated from using the Cumulative Incidence Function with death as a competing event]. Patient reported outcomes (PROs) included EORTC QLQ-HN35, PRO-CTCAE, Skindex-16, OMWQ-HM mucositis, EQ-5D. Median follow-up was calculated using the Reverse Kaplan-Meier method. From July 2017 to November 2022, 88 patients were enrolled (85 analyzable): F-Re-RT (n = 57) versus QS-Re-RT (n = 28). F-Re-RT patients were young with better performance status versus QS-Re-RT patients. Median follow-up was 35 months (all patients); F-Re-RT (38 months); QS-Re-RT (23 months). The 1-year LRRF rate for F-Re-RT was 71% (90% CI = 59%, 81%); 6-month LRRF rate for QS-Re-RT was 76% (90% CI = 58%, 89%) [See table for treatment factors, other endpoints] 36% of the patients had acute grade 3-4 toxicities, most notably dermatitis, dysphagia, dysgeusia. Late grade 3 complications were 20% (see the Table below). Nine patients had grade 4 and 3 had grade 5 complications. The Baseline, 1-year post re-RT mean score of EORTC QLQ-HN35 for F-Re-RT versus QS-Re-RT were 31.05 to 39.09 versus 35.43 to 14.85. Other PROs will be presented at the meeting. In this largest and first multi-center phase II trial for recurrent HNC patients, proton therapy achieved remarkable locoregional control and survival. Although long-term survivors (> 5 years) were observed which compares very favorably to other treatment modalities, especially when multiple therapies were done prior to re-RT with proton, these patients remain at risk for late complications. [ABSTRACT FROM AUTHOR]

The CivaSheet® is a novel device consisting of unidirectionally shielded Pd-103 sources embedded in a polymer sheet. This facilitates intraoperative placement of permanent brachytherapy seeds in a surgical tumor bed, while minimizing radiation dose to structures overlying the bed. No clinical trial data is yet published for this device. We prospectively investigated its feasibility as an alternative to standard intraoperative radiation therapy (IORT) for pelvic tumors. The CivaSheet® is a novel device consisting of unidirectionally shielded Pd-103 sources embedded in a polymer sheet. This facilitates intraoperative placement of permanent brachytherapy seeds in a surgical tumor bed, while minimizing radiation dose to structures overlying the bed. No clinical trial data is yet published for this device. We prospectively investigated its feasibility as an alternative to standard intraoperative radiation therapy (IORT) for pelvic tumors. Ten patients (pts) were enrolled and underwent surgery. Eight patients successfully underwent CivaSheet implantation, exceeding the primary feasibility endpoint. Eight pts had colorectal, one had appendiceal, and one had urothelial cancer. All but three pts received prior EBRT (45-50.4Gy). The two feasibility exclusions were technically unfavorable for CivaSheet based on intraoperative assessment of tumor bed configuration and underwent standard IORT. All CivaSheet pts were treated to the pelvic sidewall or presacral space. Median prescription dose was 100Gy (range = 91.1-100Gy) to 5mm depth, and median area treated was 40cm2 (range = 16-75cm2). Median follow-up from date of implant was 25 months. One pt had a marginal recurrence 3 months following implant, and 1 pt recurred at implant site after 13 months. ½-year OS was 75%/63%, and ½-year LC was 86%/69%. One pt died 2 weeks after surgery from cardiopulmonary arrest, unrelated to the device. No pts had device-related Grade 4-5 AEs. One pt developed temporary grade 3 bowel obstruction 18 months after with unclear relationship to CivaSheet, as well as wound dehiscence at a location separate from CivaSheet. No other grade 3+ AEs related to CivaSheet were observed. Post-implant stability was satisfactory in all pts, based on serial CT scans up to 12 months post-implantation. This is the first clinical trial of CivaSheet and demonstrated that it is a feasible and promising technique for IORT in pelvic malignancies. Because of several unique and potentially advantageous characteristics compared to standard IORT, this supports further prospective study of CivaSheet as a means to prevent local recurrence in concert with surgical resection. [ABSTRACT FROM AUTHOR]

Anti-programmed cell death protein 1/programmed death-ligand 1 (anti-PD-[L]1) immunotherapy promotes systemic anti-tumor immunity through expanding neoantigen-specific CD8+ T cells, but it is less effective in patients with liver metastases. Nearly 20% of non-small cell lung cancer (NSCLC) patients develop liver metastases, and these patients are characterized by fewer and less active effector T cells. Preclinical work investigating this phenomenon has shown that liver metastases cause systemic immunosuppression through siphoning neoantigen-specific CD8+ T cells from systemic circulation with subsequent macrophage-mediated intrahepatic death. Preclinical models have shown that liver metastasis-directed radiotherapy can reverse this systemic immunosuppression and sensitize tumors to anti-PD-(L)1 therapy; however, it is unknown whether liver metastasis-directed stereotactic ablative radiotherapy (L-SABR) can sensitize tumors to anti-PD-(L)1 in human NSCLC. This trial is designed to determine if L-SABR, when added to first-line standard-of-care anti-PD-(L)1-based immunotherapy +/- chemotherapy, can improve median progression-free survival (PFS) in patients with metastatic NSCLC involving the liver. The HAMMER-NSCLC Trial is a randomized phase II study planned to enroll 68 patients with newly diagnosed metastatic NSCLC – without known targetable EGFR, ALK, BRAF, or ROS1 alterations – involving the liver and at least one extrahepatic site. Patients will be randomized 1:1 to standard-of-care anti-PD-(L)1 immunotherapy +/- platinum-based chemotherapy (Arm 1) or standard-of-care treatment plus L-SABR (Arm 2). Patients can be enrolled and randomized up to the start of cycle 3 of immunotherapy. For patients in Arm 2, it is preferred that L-SABR be completed prior to initiating standard-of-care anti-PD-(L)1 therapy. L-SABR must be completed prior to the 3rd cycle of anti-PD-(L)1 or within 45 days of anti-PD-(L)1 therapy initiation, whichever is sooner. The primary endpoint is PFS. Secondary endpoints include the safety and tolerability of L-SABR when added to standard-of-care anti-PD-(L)1 immunotherapy, overall survival, and hepatic progression. Correlative objectives include characterizing how L-SABR remodels the liver tumor immune microenvironment and comprehensively profiling how L-SABR remodels the systemic T cell response. The study needs 68 patients combined in the two arms to demonstrate an improvement in PFS with a hazard ratio of 0.6 to provide 80% power with a one-sided alpha of 10%. Pending full accrual. Pending full accrual. The HAMMER-NSCLC Trial (NCT05657873) was activated on 12/9/2022 and recruitment is ongoing. [ABSTRACT FROM AUTHOR]