Single-fraction Radiotherapy Research Articles

Abstract 2781: Diffusion weighted MRI evaluation of response to immunotherapy and radiotherapy in CT26 and 4T1 syngeneic mouse models of cancer

Abstract Immunotherapy has potential to improve outcome for cancer patients. The MRI biomarker apparent diffusion co-efficient (ADC) can map response to radiotherapy (RT) through its sensitivity to changes in tumor fluid and cellularity. The role of ADC in evaluating immunotherapy agents is unknown, despite investigators using ADC change as an exploratory endpoint in early phase clinical trials. Our study sought to evaluate and validate ADC changes induced by both RT and immunotherapy agents in syngeneic mouse tumor models. Three experiments were performed in BALB/c mice bearing CT26 colorectal cancers: (1) single 10Gy fraction RT versus control (sham); (2) TLR 7/8 agonist R848 versus control (saline); (3) anti-PD-L1 antibody versus control (saline). We acquired MRI data at 7T Bruker system at days 0, 3, 7, +/- 10 after therapy start, with tumors measuring between 250-300 mm3 at day 0. Median ADC and the inter-quartile range (IQR; a measure of tumor heterogeneity) were derived. Three further equivalent experiments were performed in BALB/c mice bearing triple negative 4T1 breast tumors. All CT26 and 4T1 tumors were bisected at cull for immunohistochemistry and FACS analysis. For CT26 model, RT-induced tumor growth inhibition (p<0.001) and increased median ADC and IQR at days 7-10 (p<0.05) were accompanied by increased numbers of CD8 cells at days 7-10 on both immunohistochemistry and FACS (p<0.01) and increased necrosis (P<0.05), relative to control. Neither R848 nor anti-PD-L1 modified tumor growth, CD8 cells or macrophages on FACS. R848 induced marked increase in median ADC and IQR at day 3 (p<0.01) accompanied by decrease in CD4 cells at day 3. In distinction, the increased ADC in 4T1 tumors treated with RT (p<0.05 at d7 and d10) and R848 (p<0.05 at d3) were not associated with any change of immune cell populations in tumors as determined by FACS. Anti-PD-L1 therapy did not alter median ADC in either CT26 or 4T1 models, although diffusion heterogeneity, measured by the IQR of ADC was increased markedly in 3/7 CT26 tumors. In conclusion, our data are the first to evaluate ADC changes induced by RT and immunotherapy agents in syngeneic mouse models of cancer. RT, R848 and anti-PD-L1 induced different ADC responses, each with varied relationships to immune cells. This highlights the need for extensive validation before diffusion weighted MRI biomarkers can be used in clinical trials to monitor response to immunotherapies alone or in combination with RT. Citation Format: Grazyna Lipowska-Bhalla, Damien J. McHugh, Muhammad Babur, Isabel Peset Martin, Michael Berks, Ross A. Little, Susan Cheung, Yvonne Watson, Denis G. Alferez, Kaye J. Williams, Jamie Honeychurch, James P. O'Connor. Diffusion weighted MRI evaluation of response to immunotherapy and radiotherapy in CT26 and 4T1 syngeneic mouse models of cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2781.

Intraoperative Radiation Therapy Versus Whole Breast Radiation for Early-Stage Breast Cancer Treatment in Rural Appalachia.

Intraoperative radiation therapy (IORT) is an alternate accelerated form of radiation following breast-conserving surgery (BCS). Lack of data regarding long-term outcomes has limited adoption. We report our experience with IORT in patients undergoing BCS versus whole breast radiation therapy (WBRT). Retrospective review of patients undergoing BCS with IORT versus WBRT (2012-2017). Inclusion: low grade, T1-2N0M0, estrogen receptor/progesterone receptor positive, and Her2-negative infiltrating ductal carcinomas. IORT was delivered as a single fraction of radiation (20 Gy) intraoperatively. Outcomes were compared using Fisher's test for discrete variables or Wilcoxon signed-rank test for continuous variables. Kaplan-Meier method was used to estimate disease-free survival (DFS). Fifty-one patients (44%) received IORT, and 66 (56%) received WBRT. There was no difference in age, tumor size, receptor status, or in-breast recurrence (1.9% vs 0%, all P > .05). Length of follow-up was longer in the WBRT group due to time to inception of IORT (mean ± SD: 44 ± 8.1 vs 73 ± 13 months, P < .001). There was no difference in DFS between the 2 groups (HR 2.5; P = .44). IORT patients experienced delay to BCS (mean ± SD: 38 ± 12.7 vs 27 ± 12.2 days, P < .001) likely due to coordination of care. Analysis demonstrated IORT patients would have traveled a mean distance of 20 miles to the closest WBRT center (range 1-70, miles) for a mean travel time of 31 minutes (range 4-90, minutes) per WBRT treatment. IORT produces noninferior oncologic outcomes and decreased skin toxicity compared with WBRT. It can be convenient for patients in rural regions with limited health care access.

Does dissemination of guidelines alone increase the use of palliative single-fraction radiotherapy? Initial report of a longitudinal change management campaign at a provincial cancer program.

Despite level 1 evidence demonstrating the equivalence of single-fraction radiotherapy (sfrt) and multiple-fraction radiotherapy (mfrt) for the palliation of painful bone metastases, sfrt remains underused. In 2015, to encourage the sustainable use of palliative radiation oncology resources, CancerCare Manitoba disseminated, to each radiation oncologist in Manitoba, guidelines from Choosing Wisely Canada (cwc) that recommend sfrt. We assessed whether dissemination of the guidelines influenced sfrt use in Manitoba in 2016, and we identified factors associated with mfrt. All patients treated with palliative radiotherapy for bone metastasis in Manitoba from 1 January 2016 to 31 December 2016 were identified from the provincial radiotherapy database. Patient, treatment, and disease characteristics were extracted from the electronic medical record and tabulated by fractionation schedule. Univariable and multivariable logistic regression analyses were performed to identify risk factors associated with mfrt. In 2016, 807 patients (mean age: 70 years; range: 35-96 years) received palliative radiotherapy for bone metastasis, with 69% of the patients having uncomplicated bone metastasis. The most common primary malignancies were prostate (27.1%), lung (20.6%), and breast cancer (15.9%). In 62% of cases, mfrt was used-a proportion that was unchanged from 2015. On multivariable analysis, a gastrointestinal [odds ratio (or): 5.3] or lung primary (or: 3.3), complicated bone metastasis (or: 4.3), and treatment at a subsidiary site (or: 4.4) increased the odds of mfrt use. Dissemination of cwc recommendations alone did not increase sfrt use by radiation oncologists in 2016. A more comprehensive knowledge translation effort is therefore warranted and is now underway to encourage increased uptake of sfrt in Manitoba.

Postoperative, Single-Fraction Radiation Therapy in Merkel Cell Carcinoma of the Head and Neck

PurposeConventionally fractionated, postoperative radiation therapy (cPORT; 50 Gy in 25 fractions) is considered for patients with Merkel cell carcinoma (MCC) to improve locoregional control. However, cPORT is associated with acute toxicity, especially in the head and neck (H&N) region, and requires daily treatments over several weeks. We previously reported high rates of durable local control with minimal toxicity using 8-Gy single-fraction radiation therapy (SFRT) in the metastatic setting. We report early results on a cohort of patients with localized H&N MCC who received postoperative SFRT if a cPORT regimen was not feasible. Methods and MaterialsTwelve patients with localized MCC of the H&N (clinical/pathologic stages I-II) and no prior radiation therapy to the region were identified from an institutional review board-approved prospective registry who underwent surgical resection followed by postoperative SFRT. Time to event was calculated starting from the date of resection before SFRT. The cumulative incidence of in-field locoregional recurrences and out-of-field recurrences was estimated with death as a competing risk. ResultsTwelve patients with H&N MCC were identified with clinical/pathologic stages I-II H&N MCC. Median age at diagnosis was 81 years (range, 58-96 years); 25% had immunosuppression. At a median follow-up of 19 months (range, 8-34), there were no in-field locoregional recurrences. A single out-of-field regional recurrence was observed, which was successfully salvaged. There were no MCC-specific deaths. No radiation-associated toxicities greater than grade 1 (Common Terminology Criteria for Adverse Events v5) were observed. ConclusionsPreliminary data suggest that SFRT could offer a potential alternative to cPORT to treat the primary site for localized H&N MCC, particularly in elderly or frail patients, with promising in-field local control and minimal toxicity. Further data with validation in larger cohorts are needed to confirm the sustained safety and efficacy of postoperative SFRT.

Cost Effectiveness of External Beam Radiation Therapy versus Percutaneous Image-Guided Cryoablation for Palliation of Uncomplicated Bone Metastases

PurposeTo evaluate the cost effectiveness of incorporating cryoablation in the treatment regimens for uncomplicated bone metastases using radiation therapy (RT) in single-fraction RT (SFRT) or multiple-fraction RT (MFRT) regimens. Materials and MethodsA Markov model was constructed using 1-month cycles over a lifetime horizon to compare the cost effectiveness of multiple strategies, including RT followed by RT (RT-RT) for recurrent pain, RT followed by cryoablation (RT-ablation), and cryoablation followed by RT (ablation-RT). RT-RT consisted of 8 Gy in 1 fraction/8 Gy in 1 fraction (SFRT-SFRT) and 30 Gy in 10 fractions/20 Gy in 5 fractions (MFRT-MFRT). Probabilities and utilities were extracted from a search of the medical literature. Costs were calculated from a payer perspective using 2017 Medicare reimbursement in an outpatient setting. Incremental cost effectiveness ratios (ICERs) were calculated using strategies evaluated for willingness-to-pay threshold of $100,000 per quality-adjusted life-year (QALY). To account for model uncertainty, one-way and probabilistic sensitivity analyses were performed. ResultsIn the base case analysis, SFRT-ablation was cost effective relative to SFRT-SFRT at $96,387/QALY. MFRT-ablation was cost effective relative to MFRT-MFRT at $85,576/QALY. Ablation-SFRT and ablation-MFRT were not cost effective with ICERs >$100,000/QALY. In one-way sensitivity analyses, results were highly sensitive to variation in multiple model parameters, including median survival (base: 9 months), with SFRT-SFRT favored at median survival ≤8.7 months. Probabilistic sensitivity analysis examining SFRT-based regimens showed that SFRT-ablation was preferred in 36.9% of simulations at WTP of $100,000/QALY. ConclusionsCryoablation is a potentially cost-effective alternative to reirradiation with RT for recurrent of pain following RT; however, no strategy incorporating initial cryoablation was cost effective.

Tumour response 3 months after neoadjuvant single-fraction radiotherapy for low-risk breast cancer.

Standard treatment for early-stage invasive breast cancer (bca) consists of breast-conserving surgery and several weeks of adjuvant radiotherapy (rt). Neoadjuvant single-fraction rt is a novel approach for early-stage bca. We sought to investigate the effect of delaying surgery after neoadjuvant rt with respect to the rate of pathologic response (pr). Women 65 years of age or older with a new diagnosis of stage i luminal A bca were eligible for inclusion. A single 20 Gy dose to the primary breast tumour was given, followed by breast-conserving surgery 3 months later. The primary endpoint was the pr rate assessed by microscopic evaluation using the Miller-Payne system. To date, 10 patients have been successfully treated. Median age of the patients was 72 years (range: 65-84 years). In 8 patients, neoadjuvant rt resulted in a tumour pr with median residual cellularity of 3%. No immediate rt complications other than mild dermatitis were noted. This study demonstrates a method for delivering single-fraction rt that can lead to a high level of pr in most patients. Continued accrual to this study and subsequent trials are needed to determine the feasibility, safety, and role of this novel technique in the management of early-stage bca.

Increased effect of two-fractionradiotherapy in conjunction with IDO1 inhibition in experimental glioblastoma.

ObjectivesThe aim of the study was to investigate therapeutic efficacy of single- or two-fraction radiotherapy in conjunction with IDO1-inhibition in a syngeneic rat glioblastoma model. IDO is known to cause immunosuppression through breakdown of tryptophan in the tumor microenvironment.MethodsGene expression analyses of IDO in glioblastoma were performed with data from publicly available datasets. Fractionation studies were done on animals to evaluate tumor size, immune cell infiltration of tumors and serum profile on day 18 after tumor inoculation. Survival analyses were done with animals carrying intracranial glioblastomas comparing two-fraction radiotherapy+IDO1-inhibition to controls. IDO inhibition was achieved by administration of 1-methyl tryptophan (1-MT), and radiotherapy (RT) was delivered in doses of 8Gy.ResultsThe expression of IDO1 was increased on gene level in glioblastoma stem cells. Tumor size was significantly reduced in animals treated with 1-MT+RTx 2 (both long and short intervals, i.e. 7 and 4 days between the treatments) as compared to control animals, animals treated with only 1-MT or animals treated with 1-MT+RTx1. Serum levels of IL-1A were significantly altered in all treated animals as compared to control animals. Survival was significantly increased in the animals treated with 1-MT+RTx2 (7-day interval) compared to control animals.ConclusionsAddition of two-fraction RT to IDO1 inhibition with 1-MT significantly reduced tumor size in animals with glioblastoma. Survival was significantly increased in animals treated with two-fractioned RT+1-MT as compared to untreated controls increased significantly.Advances in knowledgeThe currently used combination of only two fractions of radiotherapy and immune therapy is a promising area of research, increasing efficacy compared to single fraction irradiation, while potentially lowering radiation side effects compared to radiation in current clinical practice.

Simultaneous Metabolic and Perfusion Imaging Using Hyperpolarized 13C MRI Can Evaluate Early and Dose-Dependent Response to Radiation Therapy in a Prostate Cancer Mouse Model

To investigate use of a novel imaging approach, hyperpolarized (HP) 13C magnetic resonance imaging (MRI) for simultaneous metabolism and perfusion assessment, to evaluate early and dose-dependent response to radiation therapy (RT) in a prostate cancer mouse model. Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice (n = 18) underwent single-fraction RT (4-14 Gy steep dose across the tumor) and were imaged serially at pre-RT baseline and 1, 4, and 7 days after RT using HP 13C MRI with combined [1-13C]pyruvate (metabolic active agent) and [13C]urea (perfusion agent), coupled with conventional multiparametric 1H MRI including T2-weighted, dynamic contrast-enhanced, and diffusion-weighted imaging. Tumor tissues were collected 4 and 7 days after RT for biological correlative studies. We found a significant decrease in HP pyruvate-to-lactate conversion in tumors responding to RT, with concomitant significant increases in HP pyruvate-to-alanine conversion and HP urea signal; the opposite changes were observed in tumors resistant to RT. Moreover, HP lactate change was dependent on radiation dose; tumor regions treated with higher radiation doses (10-14 Gy) exhibited a greater decrease in HP lactate signal than low-dose regions (4-7 Gy) as early as 1 day post-RT, consistent with lactate dehydrogenase enzyme activity and expression data. We also found that HP [13C]urea MRI provided assessments of tumor perfusion similar to those provided by 1H dynamic contrast-enhanced MRI in this animal model. However, apparent diffusion coefficien , a conventional 1H MRI functional biomarker, did not exhibit statistically significant changes within 7 days after RT. These results demonstrate the ability of HP 13C MRI to monitor radiation-induced physiologic changes in a timely and dose-dependent manner, providing the basic science premise for further clinical investigation and translation.

Single Radiotherapy Fraction with Local Anti-CD40 Therapy Generates Effective Abscopal Responses in Mouse Models of Cervical Cancer.

Current treatment options for advanced cervical cancer are limited, especially for patients in poor-resource settings, with a 17% 5-year overall survival rate. Here, we report results in animal models of advanced cervical cancer, showing that anti-CD40 therapy can effectively boost the abscopal effect, whereby radiotherapy of a tumor at one site can engender therapeutically significant responses in tumors at distant untreated sites. In this study, two subcutaneous cervical cancer tumors representing one primary and one metastatic tumor were generated in each animal. Only the primary tumor was treated and the responses of both tumors were monitored. The study was repeated as a function of different treatment parameters, including radiotherapy dose and dosing schedule of immunoadjuvant anti-CD40. The results consistently suggest that one fraction dose of radiotherapy with a single dose of agonistic anti-CD40 can generate highly effective abscopal responses, with a significant increase in animal survival (p = 0.0004). Overall, 60% of the mice treated with this combination showed long term survival with complete tumor regression, where tumors of mice in other cohorts continued to grow. Moreover, re-challenged responders to the treatment developed vitiligo, suggesting developed immune memory for this cancer. The findings offer a potential new therapy approach, which could be further investigated and developed for the treatment of advanced cervical cancer, with major potential impact, especially in resource-poor settings.

Trends in Radiation Fractionation for Bone Metastases: A Contemporary Nationwide Analysis

PurposeRadiation therapy remains an important palliative tool for patients with bone metastases. The guidelines from the American Society for Therapeutic Radiation Oncology recommend the use of fewer fractions based on randomized data. We used the National Cancer Database to examine trends in radiation fractionation for patients with bone metastases. Methods and MaterialsWe queried breast, prostate, and non-small cell lung cancer in the National Cancer Database from 2010 to 2015 for patients with bone metastases at the time of diagnosis who received bone-directed radiation therapy of 8 Gy in 1 fraction, 20 Gy to 24 Gy in 5 to 6 fractions, 30 Gy in 10 fractions, or >30 Gy in 10 fractions. We tabulated the baseline characteristics, and a multivariable logistic regression analysis was used to identify predictors of single-fraction treatment. ResultsWe identified 17,859 patients who met the study criteria. The median patient age was 67 years, and the majority of patients (67%) had primary prostate cancer. Most patients (62%) received spine treatment. Single-fraction treatment increased over time from 3% in 2010 to 7% by 2015. Use of more protracted courses (>30 Gy in 10 fractions) decreased from 34% to 15% over the same interval. The most commonly used regimen (50%-60% of cases) remained 30 Gy in 10 fractions. Predictors of single-fraction treatment included increased age, no systemic therapy, increasing distance from facility, treatment at an academic center, nonspine/nonskull metastasis, and more recent treatment year. ConclusionsUse of single-fraction radiation for bone metastases has increased steadily but still accounts for <10% of palliative courses. The use of more protracted regimens has decreased significantly, although 30 Gy in 10 fractions remains the most widely used regiment.

Comparison between Single Fraction versus Multiple Fraction Radiotherapy in Terms of Pain Control and Prevention of Skeletal Related Events in Patients with Bone Metastasis Candidates for Radiotherapy

Abstract Background Metastasis are the most common type of malignant tumor which involve bone, according to OSCER (Oncology Services Comprehensive Electronic Record) among 382,733 study patients, breast cancer (36 %), lunge cancer (60%), and colorectal cancer (12%) were the most common, incidence of bone metastasis was 2.9% at 30 days, 4.9% at 1 year, 5.6% at 2 years, 6.9% at 5 years, 8.4 % at 10 years. Incidence varied by tumor type with prostate cancer patients were at highest risk (18%-29%) followed by lunge, renal and breast cancer. Aim of the Work This study aim to prove the equivalency and the efficacy of single fraction radiotherapy (800cGY) and multiple fraction radiotherapy (10 fractions, 300 cGY / fraction, 1 fraction / day, 5 days per week over 2 weeks to a total of 3000cGy) in terms of pain relief and prevention of skeletal related events. Results In this study we collected data of 60 patients, 5 patients died and 55 patients received active treatment who were divided into 2 arms, Arm I represented 28 patients received single fraction radiotherapy on sites of bone metastasis (800cGY) and Arm II represented 27 patients received multiple fraction radiotherapy on sites of bone metastasis (total of 3000cGY in 10 fractions). Regarding to pain response, it was evaluated at zero, 2,4 weeks and 2,4 months using Visual Analogue Scale and Numeric Rating Scale or telephone interviews. Complete response was defined as no pain for 4 months, partial response was defined as at least 2 points lower than initial response, stable response was defined as 1 point change in pain score and progressive response was defined as pain score that’s at least 2 points higher than initial response. In our study, in Arm I patient achieving complete response represented 50% and in Arm II 40.7% which is non significant of P value 0.490, while partial response in Arm I represented 39.3% and 18.5 % in Arm II which is non significant of P value 0.090, stable response in Arm I represented 3.6% and 33.3% in Arm II which is highly significant of P value 0.004 and progressive response in Arm I represented 7.1% and in Arm II 7.4% which is non significant of P value 0.974. Conclusion Single fraction radiotherapy is equivalent to multiple fraction radiotherapy in terms of palliating pain of bone metastasis and prevention of skeletal related events.

Tumor cell intrinsic androgen biosynthesis by 3β-hydroxy steroid dehydrogenase (HSD3B1) to modulate radiosensitivity in prostate cancer cells.

349 Background: Resistance to ADT is associated with a gain of function mutation in the 3β-HSD enzyme, which catalyzes extragonadal/intratumoral DHT synthesis. As androgen signaling is known to upregulate the DNA damage response (DDR), we investigated whether HSD3B1 genotype modulates DDR and radiosensitivity in PCa. Methods: We stably knocked down HSD3B1 in LNCaP, C42 and VCaP cell lines (which carry the protein stabilizing variant allele) and overexpressed the variant HSD3B1 allele in LAPC4 (harbors a WT allele which readily undergoes degradation). We examined the proliferative and clonogenic capacity of these cells in presence and absence of substrate, DHEA, followed by treatment with IR (400-800 cGy, single fraction). We studied DNA DSB formation and resolution kinetics using γH2AX foci formation in response to radiation. We also measured changes in mRNA expression of DDR response genes pre- and post-radiation. Results: Control shRNA transduced cell lines had increased cell proliferation (p&lt;0.001) and clonogenic survival (2 logs at 800cGy single fraction radiation, p&lt;0.001) in the presence of DHEA compared to HSD3B1 knockdown cells. Variant HSD3B1 cell lines were more radioresistant and exhibited more efficient γH2AX foci resolution at 24 hrs (p &lt;0.05) in a DHEA dependent manner. We observe increased mRNA expression of DDR genes from specific repair networks including non-homologous end joining (PRKDC, XRCC4, XRCC5) and homologous recombination (RAD51, RAD54) in variant HSD3B1 cells. Transcriptional induction of DDR genes following radiation in presence of DHEA was significantly more pronounced in HSD3B1 variant cells, suggesting a more permissive chromatin context. Conclusions: Increased intracellular 3β-HSD drives transcription of NHEJ and HR genes, more rapid resolution of γH2AX foci, and radioresistance in prostate cancer. This work has therapeutic implications related to strategies for combined radiation and androgen directed therapy in localized and metastatic prostate cancer. Prospective validation of treatment strategies combining blockade of adrenal steroid precursor synthesis, ADT, and XRT in high risk disease is warranted.

Abstract P3-09-07: A multicenter phase Ib/II study for evaluating safety and efficacy of Nivolumab in combination with radiation therapy in patients with HER2-negative metastatic breast cancer (KBCRN-B-002 trial)

Abstract BACKGROUND: In metastatic breast cancer, Overall Response Rate (ORR) for checkpoint inhibitor monotherapy has been limited. Since Radiation Therapy (RT) stimulates anti-cancer immune responses, we evaluated safety and efficacy of a combinatorial therapy of RT with Nivolumab (a Programmed cell death protein 1 (PD-1) inhibitor) on HER2-negative metastatic breast cancer patients in a multicenter and non-randomized phase Ib/II study. PATIENTS AND METHODS: Patients with HER2-negative breast cancer, measurable metastasis (RECIST1.1) and at least one bone metastasis requiring radiation therapy were enrolled. The patients were divided into two cohorts, A and B. Cohort A constitutes estrogen and/or progesterone receptor-positive breast cancer patients that had 1 or 2 lines of endocrine therapy for the metastatic disease. Cohort B constitutes triple negative breast cancer patients that had two or more lines of chemotherapy for metastatic disease and anthracycline and taxane treatment for any disease setting. Single fraction RT of 8 Gy was delivered on day 0. Patients received 3 mg/kg Nivolumab intravenously every 2 weeks from day 1 until the disease progressed. Combined use of endocrine therapy of the physician’s choice was allowed in Cohort A. Primary endpoints were safety and ORR (RECIST1.1) in phase Ib and phase II, respectively. Secondary endpoints were Duration of Response (DOR), Disease Control Rate (DCR) and Progression-Free Survival (PFS). For translational research, we integrated time series multi-omics data that are correlated with Tumor Immune Microenvironment (TIME) to identify novel drug sensitivity-associated signatures using machine learning method. The multi-omics data included data from RNAseq, DNAseq, mass cytometry (CyTOF), multiple cytokines, human leukocyte antigen, radiomics, drug concentrations, tuberculin reaction using Peripheral Blood Mononuclear Cells (PBMCs), serum, plasma, imaging and Formalin-Fixed Paraffin-Embedded (FFPE) samples. RESULTS: 31 patients were enrolled from Jan 2017 to Nov 2018 and 29 patients (18 in Cohort A and 11 in Cohort B) were included in the full analysis set. While seven patients in Cohort A had received 1 or 2 lines of chemotherapy earlier for the metastatic disease, eight patients in Cohort B received three or more lines of chemotherapy. Dose limiting toxicities were not observed in phase Ib. In Cohort A, the ORR was 11.1% (90% with a Confidence Interval (CI) of 3.7-28.6). The best overall responses were: Partial Response (PR) in 2 patients (11.1%), Stable Disease (SD) in 11 patients (61.1%) and Progressive Disease (PD) in 5 patients (27.8%). In Cohort B, ORR was 0% as none of the patients responded to the treatment. The best overall responses were: SD in 4 patients (36.4%), PD in 6 patients (54.5%) and one patient (9.1%) was not evaluated (NE). While the DCR for Cohorts A and B were 72.2% (90% CI: 52.9-85.8) and 36.4% (90% CI: 17.5-60.6), respectively, the median PFS were 4 months (95% CI: 2.1-5.5 months) and 2 months (95% CI: 1.2-4.0 months), respectively. Common toxicities were mild; including 3 patients in Cohort A (16.7%) and 2 patients in Cohort B (18.2%) that experienced grade 3 or 4 toxicity. There were no deaths due to adverse effects. Furthermore, our integrated analysis identified novel candidates for drug sensitivity-associated signatures. CONCLUSIONS: The combination of RT and Nivolumab had a manageable safety profile and demonstrated clinically significant disease control outside the RT fields. Periodic abscopal response data and multi-omics data are also presented. (UMIN: UMIN000026046; ClinicalTrials.gov: NCT03430479). Citation Format: Masahiro Takada, Michio Yoshimura, Kosuke Kawaguchi, Takeshi Kotake, Ryuji Uozumi, Masako Kataoka, Takahiko Koyama, Hironori Kato, Hiroshi Yoshibayashi, Hirofumi Suwa, Wakako Tsuji, Hiroyasu Yamashiro, Tatsuki Kataoka, Hiroshi Ishiguro, Reitaro Tokumasu, Maya Honda, Rikiya Yamashita, Atsushi Yonezawa, Yuki Himoto, Natsuko Onishi, Laxmi Parida, Satoshi Morita, Masakazu Toi. A multicenter phase Ib/II study for evaluating safety and efficacy of Nivolumab in combination with radiation therapy in patients with HER2-negative metastatic breast cancer (KBCRN-B-002 trial) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-09-07.

Optimal dose-fractionation schedule of palliative radiotherapy for patients with bone metastases: a protocol for systematic review and network meta-analysis

IntroductionThe optimal dose-fractionation schedule of palliative radiotherapy has been debated in patients with bone metastases. Our objective is to comprehensively compare multiple fraction schedules with single fraction radiotherapy in terms...

Independent External Validation of a Score Predicting Survival After Radiotherapy for Bone Metastases and Expansion to Patients Treated With Single Fraction Radiotherapy.

BackgroundRecently a prognostic score that predicts 12-month survival in patients treated with fractionated radiotherapy for painful bone metastases has been developed. Fractionated radiotherapy might cause unnecessary burden for patients with limited survival, thus estimation of survival is clinically relevant. The purpose of the present study was independent external validation of the new score and, in addition, its application in patients who received single fraction irradiation, a convenient option currently endorsed in several guidelines.MethodsWe conducted a retrospective analysis of 270 patients, including 24% who had received single fraction irradiation. The three-tiered score was assigned as described in the development study, and included age, performance status and primary tumor type. Additional prognostic factors not studied in the development cohort, such as the Glasgow prognostic score (GPS) and presence of liver metastases, were included in this validation study.ResultsThe three-tiered score was valid in this independent cohort (12-month survival rates were 7%, 30% and 71%, respectively, P = 0.0001). Its performance and validity were also confirmed in the single fraction radiotherapy group. Three additional prognostic factors were significant in the multivariate analysis and may therefore contribute to decision making.ConclusionsIrrespective of fractionation, the score based on age, performance status and primary tumor type provides a readily available estimate of 12-month survival.

The impact of COVID-19 pandemic on the practice of radiotherapy: A retrospective single-institution study

Background: The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 led to the imposition of a nationwide lockdown as a control measure, which in turn disrupted the diagnosis and treatment of other diseases including cancer.Objectives: The primary objective of this study was to assess the impact of the COVID-19 pandemic on patients receiving radiotherapy and whether it correlated with the patients' age, gender, site of disease, and intent of radiotherapy. The secondary objective was to assess the compliance to radiotherapy and the treatment modifications, if any.Materials and Methods: This is a retrospective analysis of all patients planned for radiotherapy at the Mahavir Cancer Sansthan, a tertiary cancer center, in Patna, India from January 1, 2020, to May 31, 2020. The study cohort was divided into two groups: Group A comprised patients who received radiotherapy in the period before the lockdown and Group B comprised patients who received radiotherapy during the lockdown. Data regarding the age, gender, site of disease, intent of treatment, completion of planned treatment, use of concurrent chemotherapy, and modifications of the radiation protocol, if any, were analyzed. The categorical variables were compared using the Chi-square test.Results: A total of 1412 patients were planned for radiotherapy during the study period. Of these, 1020 patients, 759 in Group A and 261 in Group B, actually received radiotherapy during the entire study period. The proportion of female patients decreased by 10.5% and that of patients receiving palliative intent radiotherapy increased by 12% during the lockdown. Head and neck, gynecological, and breast cancers were the most common cancer types in both the periods. There was no significant difference in the compliance to radiotherapy between the two groups (88.2% in Group A and 90.8% in Group B). Similar protocols were used during both the periods in patients being treated with a curative intent, but there was a significant increase in the use of single fraction radiation treatment in patients being treated with palliative intent with conventional fields.Conclusions: There was a sharp decline in the number of patients, especially women, during the lockdown. The number of patients being treated with palliative intent increased significantly, with an increased use of single-fraction radiation treatment.

Therapy-Induced Changes in CXCR4 Expression in Tumor Xenografts Can Be Monitored Noninvasively with N-[11C]Methyl-AMD3465 PET

PurposeChemokine CXCL12 and its receptor CXCR4 are constitutively overexpressed in human cancers. The CXCL12-CXCR4 signaling axis plays an important role in tumor progression and metastasis, but also in treatment-induced recruitment of CXCR4-expressing cytotoxic immune cells. Here, we aimed to demonstrate the feasibility of N-[11C]methyl-AMD3465 positron emission tomography (PET) to monitor changes in CXCR4 density in tumors after single-fraction local radiotherapy or in combination with immunization.ProcedureTC-1 cells expressing human papillomavirus antigens E6 and E7 were inoculated into the C57BL/6 mice subcutaneously. Two weeks after tumor cell inoculation, mice were irradiated with a single-fraction 14-Gy dose of X-ray. One group of irradiated mice was immunized with an alpha-viral vector vaccine, SFVeE6,7, and another group received daily injections of the CXCR4 antagonist AMD3100 (3 mg/kg -intraperitoneal (i.p.)). Seven days after irradiation, all animals underwent N-[11C]methyl-AMD3465 PET.ResultsPET imaging showed N-[11C]methyl-AMD3465 uptake in the tumor of single-fraction irradiated mice was nearly 2.5-fold higher than in sham-irradiated tumors (1.07 ± 0.31 %ID/g vs. 0.42 ± 0.05 % ID/g, p < 0.01). The tumor uptake was further increased by 4-fold (1.73 ± 0.17 % ID/g vs 0.42 ± 0.05 % ID/g, p < 0.01) in mice treated with single-fraction radiotherapy in combination with SFVeE6,7 immunization. Administration of AMD3100 caused a 4.5-fold reduction in the tracer uptake in the tumor of irradiated animals (0.24 ± 0.1 % ID/g, p < 0.001), suggesting that tracer uptake is indeed due to CXCR4-mediated chemotaxis.ConclusionThis study demonstrates the feasibility of N-[11C]methyl-AMD3465 PET imaging to monitor treatment-induced changes in the density of CXCR4 receptors in tumors and justifies further evaluation of CXCR4 as a potential imaging biomarker for evaluation of anti-tumor therapies.

Effect of Single-Fraction vs Multifraction Radiotherapy on Ambulatory Status Among Patients With Spinal Canal Compression From Metastatic Cancer

Malignant spinal canal compression, a major complication of metastatic cancer, is managed with radiotherapy to maintain mobility and relieve pain, although there is no standard radiotherapy regimen. To evaluate whether single-fraction radiotherapy is noninferior to 5 fractions of radiotherapy. Multicenter noninferiority randomized clinical trial conducted in 42 UK and 5 Australian radiotherapy centers. Eligible patients (n = 686) had metastatic cancer with spinal cord or cauda equina compression, life expectancy greater than 8 weeks, and no previous radiotherapy to the same area. Patients were recruited between February 2008 and April 2016, with final follow-up in September 2017. Patients were randomized to receive external beam single-fraction 8-Gy radiotherapy (n = 345) or 20 Gy of radiotherapy in 5 fractions over 5 consecutive days (n = 341). The primary end point was ambulatory status at week 8, based on a 4-point scale and classified as grade 1 (ambulatory without the use of aids and grade 5 of 5 muscle power) or grade 2 (ambulatory using aids or grade 4 of 5 muscle power). The noninferiority margin for the difference in ambulatory status was -11%. Secondary end points included ambulatory status at weeks 1, 4, and 12 and overall survival. Among 686 randomized patients (median [interquartile range] age, 70 [64-77] years; 503 (73%) men; 44% had prostate cancer, 19% had lung cancer, and 12% had breast cancer), 342 (49.8%) were analyzed for the primary end point (255 patients died before the 8-week assessment). Ambulatory status grade 1 or 2 at week 8 was achieved by 115 of 166 (69.3%) patients in the single-fraction group vs 128 of 176 (72.7%) in the multifraction group (difference, -3.5% [1-sided 95% CI, -11.5% to ∞]; P value for noninferiority = .06). The difference in ambulatory status grade 1 or 2 in the single-fraction vs multifraction group was -0.4% (63.9% vs 64.3%; [1-sided 95% CI, -6.9 to ∞]; P value for noninferiority = .004) at week 1, -0.7% (66.8% vs 67.6%; [1-sided 95% CI, -8.1 to ∞]; P value for noninferiority = .01) at week 4, and 4.1% (71.8% vs 67.7%; [1-sided 95% CI, -4.6 to ∞]; P value for noninferiority = .002) at week 12. Overall survival rates at 12 weeks were 50% in the single-fraction group vs 55% in the multifraction group (stratified hazard ratio, 1.02 [95% CI, 0.74-1.41]). Of the 11 other secondary end points that were analyzed, the between-group differences were not statistically significant or did not meet noninferiority criterion. Among patients with malignant metastatic solid tumors and spinal canal compression, a single radiotherapy dose, compared with a multifraction dose delivered over 5 days, did not meet the criterion for noninferiority for the primary outcome (ambulatory at 8 weeks). However, the extent to which the lower bound of the CI overlapped with the noninferiority margin should be considered when interpreting the clinical importance of this finding. ISRCTN Identifiers: ISRCTN97555949 and ISRCTN97108008.

Exploring the Utilization of Single Fraction Radiation Therapy (SFRT) for Bone Metastases at the Durham Regional Cancer Centre (DRCC) from 2014-2018: A Retrospective Analysis and Comparison to Canadian Literature

Exploring the Utilization of Single Fraction Radiation Therapy (SFRT) for Bone Metastases at the Durham Regional Cancer Centre (DRCC) from 2014-2018: A Retrospective Analysis and Comparison to Canadian Literature

Quality improvements in palliative radiotherapy at end of life: The FutRE Study.

306 Background: Palliative radiation therapy (RT) is offered to patients with cancer for symptom management. RT planning and delivery is resource intensive. Benefits may take weeks to develop. Palliative RT at the end of life may not be completed due to patient and disease factors. RT courses that are not completed may indicate a need for improved patient selection for RT and choice of RT prescription, minimizing the likelihood of delivering futile treatment. Methods: The FUTile Radiotherapy at End of life survey was implemented in the electronic RT workspace across Alberta in 2018. Radiation oncologists (ROs) were tasked with survey completion, at the time of palliative RT prescription approval, as part of their workflow on domains pertaining to patient and treatment decision-making. This survey data was linked to the cancer registry and date of death. Data association were examined among patients completing RT within 90 days of death for the accuracy of oncologist’s provided survival prognostication estimates, number of RT fractions prescribed, number of RT fractions completed, prescribing physician, including disease factors and treatment intent. Results were explored using descriptive statistics and tests of associations (STATA 11.1) Results: 1963 RT surveys were included in our analysis. Prescribing ROs overestimated patient survival 67% of the time, by a mean of 145 days, and underestimated survival 12% of the time by a mean of 109 days. Multi-fraction RT (1403 courses) was more frequently prescribed over single fraction (SF) RT (560 courses)(one-sample t-test, p≤0.001). SF treatments were more likely to be completed than MF treatments (RR = 10.3, 95% CI = [4.85, 21.7], p &lt; 0.0001). Treatments were less likely to be completed when survival was overestimated by 6 or more months and were over twice as likely to be completed than when patient survival was underestimated (RR = 2.6, 95% CI = [1.04, 6.50], p = 0.04). Conclusions: Survival among end of life patients is overestimated by ROs prescribing palliative MF RT treatments.