Liver stereotactic body radiation therapy without fiducial or retained ethiodized oil guidance warrants greater than 5 mm planning target volumes.

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.

Thermal Ablation Versus Stereotactic Body Radiotherapy After Transarterial Chemoembolization for Inoperable Hepatocellular Carcinoma: A Propensity Score-Weighted Analysis.

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.

Targeting MerTK Enhances Adaptive Immune Responses After Radiation Therapy.

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 non-small 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.

Stop hedging your bets: reasons for non-adherence to a tri-modality regimen in the treatment of esophageal cancer in a multidisciplinary setting.

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.