This manuscript reports the results of a phase I clinical trial combining intratumoral vidutolimod, hypofractionated radiotherapy, nivolumab and ipilimumab in MSS mCRC. Of the 19 patients accrued, none responded, aside from 1 patient, attributed to high tumor mutational burden. The juxtaposition of liver irradiation and intratumoral vidutolimod injection was associated with hepatic toxicity.Introduction: Microsatellite stable metastatic colorectal cancer (MSS mCRC) is largely refractory to immune checkpoint inhibition. We hypothesized that a combination of intratumoral TLR9 agonist, radiosurgery and dual PD-1 and CTLA-4 blockade would induce a local focus of immune stimulation, evoking a systemic immune response.Patients and Methods: In this phase I single-institution study, patients with MSS mCRC were treated with a priming dose of s.c vidutolimod, 3 intratumoral injections of vidutolimod and radiosurgery, combined with nivolumab and ipilimumab. Cytokine levels were measured at baseline and at 7 (+/- 2) weeks. Patients were accrued to 4 consecutive cohorts: (1) Safety run-in without radiosurgery, (2) Radiosurgery prior to intratumoral therapy, (3) Radiosurgery prior to intratumoral therapy with a condensed timeline, and (4) Radiosurgery to extrahepatic lesion following completion of intratumoral therapy.Results: A total of 19 patients were accrued. Median age was 59 years (range 40-71), 68% were male, median number of previous systemic treatments was 3 (range 2-5). None of the patients responded, aside from 1 patient, attributed to high tumor mutational burden. Grade 3 liver toxicity was reported in 0%, 0%, 75%, and 17% in cohorts 1 to 4, respectively. Systemic levels of CXCL10 and IL-10 increased, with a median of 407 versus 78 pg/mL ( P = .01), and 66 versus 40 pg/mL ( P = .03), respectively. Conclusions: The combination of intratumoral vidutolimod, radiosurgery, nivolumab and ipilimumab was not found to be efficacious in MSS mCRC with liver metastases. The juxtaposition of liver irradiation and intratumoral vidutolimod injection was associated with high hepatic toxicity.

123 Background: Microsatellite stable (MSS) or mismatch repair proficient (MMR-P) metastatic colorectal cancer is refractory to immune checkpoint inhibition. We hypothesized that a combination of intratumoral TLR9 agonist, radiosurgery and dual PD-1 and CTLA-4 blockade would induce a local focus of immune stimulation, evoking a systemic immune response. Methods: In this single institution investigator-initiated phase I study, patients with MSS / MMR-P metastatic colorectal cancer were treated with a priming dose of subcutaneous (s.c.) vidutolimod, three intratumoral injections of vidutolimod, and radiosurgery to a metastasis, combined with nivolumab 3mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks. Following conclusion of intratumoral therapy, s.c. injections of vidutolimod commenced. Efficacy endpoints were based upon a non-irradiated and non-injected lesion. Cytokine levels were measured at baseline and at 7 (± 2) weeks. Patients were placed in 4 cohorts: (1) Safety run-in without radiosurgery (No RT); (2) Radiosurgery prior to intratumoral therapy (Early Liver RT Slow). An amendment was made due to early patient fall-out due to progressive disease; (3) Radiosurgery prior to intratumoral therapy with a condensed timeline (Early Liver RT Quick). An additional amendment was made due to unacceptable liver toxicity; (4) Radiosurgery to extrahepatic lesion following completion of intratumoral therapy (Late Extrahepatic RT). ClinicalTrials.gov Identifier NCT03507699. Results: A total of 19 patients were accrued (No RT, n=2; Early Liver RT Slow, n=7; Early Liver RT Quick, n=4; Late Extrahepatic RT, n=6). Median age was 59 years (range 40-71), 68% were male, median number of previous systemic treatments was 3 (range 2 – 5). None of the patients responded, aside from one patient in cohort #4 who achieved complete response, and was subsequently found to have a high tumor mutational burden (TMB) 79 mutations / Mb. Grade 3 liver toxicity, including elevated transaminases and hyperbilirubinemia, was reported in 0%, 0%, 75% and 17% in cohorts 1-4, respectively. Reactions following intratumoral injections, typically within 12 hours, included fever (68%), tachycardia (21%), chills (63%) and hypotension (47%). There was an increase in systemic CXCL10 levels at 7 (± 2) weeks compared to baseline, with a median of 407 versus 78 pg/ml, respectively, p<0.01. Conclusions: Intratumoral liver injection of vidutolimod was associated with acute systemic symptoms attributed to cytokine release. The juxtaposition of liver irradiation and intratumoral vidutolimod injection to the same lesion was associated with unacceptable hepatic toxicity. The combination of intratumoral vidutolimod, radiosurgery, nivolumab and ipilimumab was not found to be efficacious in MSS / MMR-P colon cancer. Clinical trial information: NCT03507699 .

OBJECTIVES:Anatomic changes may occur during chemoradiation treatment for lung cancers, requiring adaptive replanning. Here we characterize these cases. METHODS:We retrospectively studied lung cancer cases that underwent resimulation and adaptive replanning during 1/2016-3/2019. We compared first and second CT-simulation regarding tumor location, timing of change, tumor volume, anatomical alteration and change in simulation technique. We also compared dosimetric parameters between the plans, recorded local control, and overall survival outcomes. RESULTS:Out of 281 patients, 58 underwent replanning (20.6%). Histology included small cell (22.4%) and non-small cell (77.6%). Stage III was in 91.4%. Mean radiation dose of 59.4 Gray (Gy) (range 50-66Gy).Tumor location was peribronchial in 53.5%. Timing of replanning was in the first, second and final third of the treatment course in 26%, 43% and 31% respectively. Changes in gross tumor volume were observed in 74%; mean gross tumor volume was 276.7cc vs 192.7 cc (first vs second simulation, p = 0.001). Anatomical changes were identified in 35.4% including pleural fluid accumulation, atelectasis or pneumothorax alteration. Change in simulation technique was performed in 25.9%, including breath-hold or continuous positive airway pressure.Changes in dosimetric parameters when the same technique was used: lung V20Gy 26% (standard deviation, SD 7.6) vs 25.3% (SD 6.6) (p = 0.36), mean lung dose 15.1 Gy (SD 3.7) vs 14.7Gy (SD 3.3) (p = 0.23), heart V40Gy 10.2% (SD13) vs 7.2% (SD 9.8) (p = 0.037). When simulation technique changed: lung V20Gy 30.8% (SD 8.2) vs 27.3% (SD 8) (p = 0.012), mean lung dose 17.3 Gy (SD 4.4) vs 15.3 Gy (SD 3.8) (p = 0.007), heart V40Gy 11.1% (SD 14.7) vs 6.5% (SD 6.7) (p = 0.014).2 year local control was 60.7% (95% confidence interval, 34.5-79.2%), and median overall survival was 19.7 months. CONCLUSION:Adaptive replanning of radiation was performed in a fifth of locally advanced lung cancer patients. In most cases tumor volume decreased, or atelectasis resolved, causing mediastinal shifts, which, if unidentified and left uncorrected, may have led to local failure and increased toxicity. The heart V40Gy was reduced significantly in all cases, but significant reduction in lung doses was evident only if simulation technique was altered. ADVANCES IN KNOWLEDGE:In locally advanced lung cancer image-guidance with cone beam CT can detect significant mediastinal shifts and gross tumor volume changes that raise the need for adaptive replanning. Image guidance-triggered adaptive replanning should be added to the armament of advanced radiation treatment planning in locally advanced lung cancer.

Objective: Intensity-modulated radiotherapy (IMRT) has better normal-tissue sparing compared with 3-dimensional conformal radiation (3DCRT). We sought to assess the impact of radiation technique on pathological and clinical outcomes in locally advanced non-small cell lung cancer (LANSCLC) treated with a trimodality strategy. Methods: Retrospective review of LANSCLC patients treated from August 2012 to August 2018 at Sheba Medical Center, Israel. The trimodality strategy consisted of concomitant chemoradiation to 60 Gray (Gy) followed by completion surgery. The planning target volume (PTV) was defined by co-registered PET/CT. Here we compare the pathological regression, surgical margin status, local control rates (LC), disease free (DFS) and overall survival (OS) between 3DCRT and IMRT. Results: Our cohort consisted of 74 patients with mean age 62.9 years, male in 51/74 (69%), adenocarcinoma in 46/74 (62.1%), stage 3 in 59/74 (79.7%) and chemotherapy in 72/74 (97.3%). Radiation mean dose: 59.2 Gy (SD ± 3.8). Radiation technique : 3DCRT in 51/74 (68.9%), IMRT in 23/74 (31%). Other variables were similar between groups.Major pathological response (including pathological complete response or less than 10% residual tumor cells) was similar: 32/51 (62.7%) in 3DCRT and 15/23 (65.2%) in IMRT, p=0.83. Pathological complete response (pCR) rates were similar: 17/51 (33.3%) in 3DCRT and 8/23 (34.8%) in IMRT, p=0.9. Surgical margins were negative in 46/51 (90.1%) in 3DCRT vs. 17/19 (89.4%) in IMRT (p=1.0).The 2-year LC rates were 81.6% (95% CI 69-89.4%); DFS 58.3% (95% CI 45.5-69%) and 3-year OS 70% (95% CI57-80%). Comparing radiation techniques, there were no significant differences in LC (p=0.94), DFS (p=0.33) and OS (p=0.72). Conclusion: When used to treat LANSCLC in the neoadjuvant setting, both IMRT and 3DCRT produce comparable pathological and clinical outcomes. Advances in knowledge: This study validates the real-world effectiveness of IMRT compared to 3DCRT.

Background: Radiotherapy is one of the primary therapies for localized prostatic carcinoma. Therefore, there is an emerging need to sensitize prostatic cancer cells to chemotherapy/radiotherapy. Modified citrus pectin (MCP) is an effective inhibitor of galectin-3 (Gal-3), which is correlated with tumor progression, proliferation, angiogenesis, and apoptosis. Purpose: This study was directed to evaluate the efficacy of combining ionizing radiation (IR) with MCP on PCa cells. Study Design: Effects of treatments on PCa cells survival were evaluated using XTT assay, flow cytometry, and clonogenic survival assay. Expression of selected proteins was estimated using western blotting. Cell motility, migration, and invasion were determined. Contribution of reactive oxygen species production to treatment effects on cell viability was tested. Results: Radiotherapy combined with MCP reduced viability and enhanced radiosensitivity associated with a decrease in Gal-3, cleavage of the precursor of caspase-3, increased expression of the pro-apoptotic protein Bax, and downregulation of DNA repair pathways, poly-ADP-ribose polymerase, and proliferating cell nuclear antigen. MCP significantly reduced the invasive and migratory potential of PCa cells. Combining sodium pyruvate with MCP and IR mitigated the effect on cell viability. Conclusion: Our findings demonstrated that MCP sensitized PCa cells to IR by downregulating anti-apoptotic Gal-3, modulating DNA repair pathways, and increasing ROS production. For the first time the correlation between MCP, radiotherapy, and Gal-3 for prostatic cancer treatment was found. In addition, MCP reduced the metastatic properties of PCa cells. These findings provide MCP as a radiosensitizing agent to enhance IR cytotoxicity, overcome radioresistance, and reduce clinical IR dose.

Background: Family physicians and internal medicine specialists play an essential role in treating cancer patients. Modern technological advances in radiotherapy are not widely appreciated by primary care physicians. Bone metastases are a frequent complication of cancer. Palliative radiation therapy, as a component of modern advances in radiation treatments, should not subject normal bodily structures to excessive doses of irradiation. The sacrum is a common destination site for bone metastases, yet its concave shape along with its proximity to the rectum, intestines, and femoral heads creates treatment-planning challenges. Objectives: To investigated whether the volumetric modulated arc therapy (VMAT) technique is preferable to more conventional radiation strategies. Methods: The study comprised 22 patients with sacral metastases who were consecutively treated between 2013 and 2014. Two plans were generated for the comparison: three-dimensional (3D) and VMAT. Results: The planning target volume (PTV) coverage of the sacrum was identical in VMAT and 3D planning. The median values for the rectal dose for 3D and VMAT were 11.34 +/- 5.14 Gy and 7.7 +/- 2.76 Gy, respectively. Distal sacral involvement (54 and S5) was observed in only 2 of 22 cases, while the upper pole of the rectum ended at the level above S3 in just 3 cases. Conclusions: Radiation therapy continues to be an integral component of the palliative armamentarium against painful metastases. Radiation oncologist, in conjunction with referral physicians, can tailor treatment plans to reflect the needs of a given patient.

This study utilizes the Taguchi Method to evaluate the VMAT planning parameters of single isocenter treatment plans for multiple brain metastases. An optimization model based on Taguchi and Principal component analysis is employed to optimize the planning parameters including: arc arrangement, calculation grid size, calculation model, and beam energy on multiple performance characteristics, namely conformity index and dose to normal brain. Treatment plans, each with 4 metastatic brain lesions were planned using single isocenter technique. The collimator angles were optimized to avoid open areas. In this analysis, four planning parameters (a-d) were considered: (a)-Arc arrangements: set1: Gantry 181cw179, couch0; gantry179ccw0, couch315; and gantry0ccw181, couch45. set2: set1 plus additional arc: Gantry 0cw179, couch270; (b)-Energy: 6-MV; 6MV-FFF; (c)-Calculation grid size: 1mm; 1.5mm; (d)-Calculation models: AAA; Acuros. Treatment planning was performed in Varian Eclipse (ver.11.0.30). A suitable orthogonal array was selected (L8) to perform the experiments. After conducting the experiments with the combinations of planning parameters, the conformity index (CI) and the normal brain dose S/N ratio for each parameter was calculated. Optimum levels for the multiple response optimizations were determined. We determined that the factors most affecting the conformity index are arc arrangement and beam energy. These tests were also used to evaluate dose to normal brain. In these evaluations, the significant parameters were grid size and calculation model. Using the utility concept we determined the combination of each of the four factors tested in this study that most significantly influence quality of the resulting treatment plans: (a)-arc arrangement-set2, (b)-6MV, (c)-calc.grid 1mm, (d)-Acuros algorithm. Overall, the dominant significant influences on plan quality are (a)-arcarrangement, and (b)-beamenergy. Results were analyzed using ANOVA and were found to be within the confidence interval. Further investigation using this methodology. Such parameters might include: virtual OAR and optimization criterion such as normal tissue objective.

SRS has been widely employed for treating multiple brain lesions using various techniques with multiple isocenters. A disadvantage of this approach is the prolonged treatment time, which is proportional to the number of lesions. Prolonged treatment time may lead to patient discomfort and movement with attendant risk of undertreating the lesion and increasing dose to normal brain tissue. To shorten treatment time, we and others have moved to a single iso-center approach, which enables parallel irradiation of multiple lesions instead of the conventional serial approach. The aim of this study is to evaluate the clinical results of this treatment approach. Between November-2010 and May-2014 we treated 162 patients with 2 or more lesions (2-5) with a single isocenter SRS approach. Pathologies treated included non-small cell lung cancer, breast cancer, colo-rectal cancer and melanoma, 46%, 22%, 10.7% and 8.7%, respectively. Patients were RPA class I (41.3%), II (26.7%), III (32.0%). Treatment plans were created using ERGO ++ (Elekta, Sweden) planning software or Eclipse™ (Varian, USA) planning software to create inverse intensity-modulated arc therapy (VMAT). Treatments were performed using Synergy-S micro-leaf beam modulator with 4mm leaves, or TruebeamSTx- Novalis with 2.5mm microleaf collimator in the center and 5mm in the periphery. Plans were created using single isocenter with fixed beams, static arcs and/or combination of the both with manual modification of the leave configuration to accommodate the shape and position of the lesions or VMAT plans consistent of 3-4 dynamic arcs. Median survival for RPA I, II, and III was 13.3 months (10.9-17.5), 6.48 months (4.9-8.7) and 4.6 months (3.9-5.5), respectively on Kaplan Meier Survival Analysis. Our initial results suggest that single-isocenter plans can be utilized to deliver conformity equivalent to that of multiple isocenter techniques and efficiently delivered requiring less than half the beam time required for multiple isocenter set ups.

Abstract Radio-resistance is a major cause of decreasing the efficiency of radiotherapy for prostate cancer. Modified citrus pectin (MCP) has been previously shown to demonstrate anti-proliferative and anti-metastatic activity in prostate cancer cells. However, its combination with radiation has not been evaluated. The aim of the present study was to investigate whether MCP radiosensitized prostate cancer cell lines and to unravel its underlying mechanism(s). XTT cell proliferation and clonogenic assays were used to assess MCP effect alone and in combination with radiation on viability of prostate cancer cell lines (DU-145, PC-3 and Cl-1). Calcusyn software analysis was used to determine the mode of interaction between the treatments tested. Flow cytometry analysis with propidium iodide staining, annexin-V-FITC and 7-aminoactinomycin D (7-AAD) double staining were used to evaluate effect on cell cycle, apoptosis and necrosis. Standard Transwell Assay with and without Matrigel was used to assess effect of MCP on invasiveness of cells. The effect of MCP and radiation on reactive oxygen species (ROS) production, and expression of galectin-3, PARP, caspase-3, caspase-9, Bak, Bax, and Bcl-2 and NF-κB pathways in treated cells are currently being investigated, and will be included in the presentation. Treatment of DU-145, PC-3 and Cl-1 prostate cancer cells with MCP induced a dose dependent decrease in cell viability tested by XTT assay (IC50 values were 1.07, 1.48, 1.29 mg/ml respectively). These cells demonstrated similar radio-sensitivity. The effect of the combined treatment were either synergistic (Combined index∼0.7, DU-145 and Cl-1 cells) at high dose (2 mg/ml) of MCP or additive (Combined index 1.1-0.9, PC-3 cells). Flow cytometric analysis showed that neither MCP nor radiation either alone or combined resulted in significant changes in cell cycle distribution. Double staining of DU-145 cells with annexin-V-FITC and 7-AAD revealed effect of combined treatment on apoptosis and necrosis. Treatment of cells with 2 mg/ml MCP reduced 20% of migrating cells and 40% of invasive cells. The effects of MCP and radiation on ROS production, pro-apoptotic and NF-κB pathways in treated cells are currently being investigated. These results suggest that MCP is a radiosensitizer in prostate cancer cells. Its mechanism of action is being investigated, and will be included in this presentation. Citation Format: Isaac G. Eliaz, Sefora Conti, Akiva Vexler, Ben Koren, Nir Honig, Natan Shtraus, Yaron Meir, Shahar Lev-Ari, Ilan Ron. Combined effect of modified citrus pectin and ionizing radiation on survival and metastatic activity of prostate cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5555. doi:10.1158/1538-7445.AM2015-5555

Objectives: Lung metastasectomy is regarded as the standard procedure for improving the prognosis of patients with metastatic sarcoma. Few reports are available in the literature describing the value of stereotactic body radiation therapy (SBRT) of lung metastases from primary sarcoma as an alternative to surgical treatment. We therefore sought to expand the evidence base for this modality. Materials and Methods: Twenty-two patients with metastatic sarcoma to lung were treated by SBRT. The retrospective analysis of overall survival, toxicity, and local control of 53 treated lesions is presented in the study. Lung lesions were grouped into 2 categories for follow-up: <10 mm or ≥10 mm diameter. Results: Of 34 lesions <10 mm, 24 achieved complete response, 3 partial response, and 7 stable disease. The results of 18 lesions measuring >10 mm were as follows: 5 complete response, 5 progressive disease, and 8 stable disease. No progressive disease of all SBRT treated lesions was found at a median follow-up of 95 months (SD 32). Five-year overall survival of the entire group was 62% from the time of diagnosis and 50% from start of treatment. The treatment was well tolerated with minimal, mainly skin toxicity. Conclusion: SBRT is an effective tool that might be used as an alternative to operative treatment of lung metastases in sarcoma patients