Single-fraction Radiotherapy Research Articles

Targeting Non-Canonical NFκB2 to Determine the Effects on Radiation Sensitization

<h3>Purpose/Objective(s)</h3> Homologous recombination (HR) provides repair of DNA double stranded breaks and lesion that block DNA replication. While non-homologous end joining (NHEJ) proficiency is commonly attributed to tumor cell resistance to radiation, HR also plays a role. This is supported by the observation that simultaneous disruption of both pathways makes cells more sensitive to radiation than either pathway alone. Thus, HR inhibition may improve radiation sensitization. Since NF-κB is known to influence HR gene expression, we hypothesize that targeting NF-κB signaling pathways, specifically non-canonical signaling, may cause radiation sensitization. <h3>Materials/Methods</h3> The Cancer Cell Line Encyclopedia (CCLE) was used to evaluated <b>NFKB2</b> gene expression levels in various cell lines. Immunofluorescence, using an NFKB2 antibody (Santa Cruz sc-7386), was performed in several cell lines (including NHI-H650, A-172, MCF-7, and SK-N-BE2) to compare total NFKB2 protein expression level and nuclear protein expression level to CCLE data. Cells were irradiated using an irradiator at radiation doses between 0.0 Gy and 8.0 Gy. Cells were fixed 24 hours after irradiation and immunofluorescence was performed using NFKB2 antibody. We performed CRISPR-Cas mutagenesis to generate U2OS clones, which carry null mutations in either <b>NFKB2</b> (encodes p100/p52) or <b>Relb</b>. We used U2OS cells with a safe harbor control locus for a control cell line. Surviving cell fraction was determined after a single fraction of radiation at 2.0 Gy by using a fixable viability staining kit. <h3>Results</h3> <b>NFKB2</b> gene expression corresponds with total non-canonical NF-κB factor p52 protein expression and nuclear p52 protein expression at baseline when results from the Cancer Cell Line Encyclopedia (CCLE) are compared to p52 immunofluorescent protein expression levels. We find nuclear protein expression of p52 increases with increasing doses of radiation from 0.0 Gy-8.0 Gy. We compared a CRISPR knockout of <b>NFKB2</b> and <b>Relb</b> in a U2OS cell line to a U2OS cell line with a safe harbor control. We found that the surviving fraction of cells is decreased in the <b>NFKB2</b> CRISPR knockout compared to the safe harbor control when given 2.0 Gy of radiation and examined 24 hours later (<i>P</i> = 0.034), but is not decreased in the <b>Relb</b> CRISPR knockout (<i>P</i> = 0.558). <h3>Conclusion</h3> NFKB2 total and nuclear protein expression increases as radiation dose increases. Knocking out <b>NFKB2</b> causes radiation sensitization, suggesting that NFKB2 may be a useful target for future cancer therapies.

Pharmacologic Ascorbate Enhances the Therapeutic Index of ATM-Inhibitor Based Chemoradiation for Colorectal Cancer

Ataxia telangiectasia mutated protein (ATM) is one of the key sensors of DNA damage and specific inhibitors of ATM are potent radiosensitizers. However, their clinical utility with radiation (RT) is limited because they lack tissue specificity and increase normal tissue injury. Pharmacologic (high dose) ascorbate (P-AscH-) selectively increases oxidative stress in tumors while functioning as a donor antioxidant and reducing RT damage in normal tissues. We hypothesized that P-AscH- could enhance the therapeutic index of ATM-inhibitor based chemoradiation (CRT) for colorectal cancer (CRC) by simultaneously enhancing efficacy and reducing RT bowel injury.Human HCT116, SW480, and HT29 and murine CT26 and MC38 CRC models were used. Clonogenic survival was assessed following single-fraction RT (2-8 Gy) +/- P-AscH- (5 pM/cell) +/- veliparib (PARP), VE821 (ATR), or KU60019 (ATM). Catalase expression was induced using HCT116 cells expressing a doxycycline inducible catalase transgene. DNA double strand breaks (DSBs) were quantified using neutral comet assays 0-24 hours post RT. Cell cycle phases were assessed using flow cytometry. ATM and pATM localization were assessed using IF. Jejunal toxicity was assessed using IHC in fixed tissues following single fraction (10 Gy) whole abdominal RT in c57bl/6 mice. Tumor growth delay was assessed following RT (5 Gy x 3) +/- drug treatment in unilateral flank tumors.Veliparib, VE821, and KU60019 were potent radiosensitizers in HCT116, SW480, HT29, MC38, and CT26 CRC tumor models and P-AscH- further reduced clonogenic survival with DRIs in all lines except for HT29. In contrast, P-AscH- enhanced survival of cultured HUVEC and FHs-74 cells exposed to RT. Enhanced cell kill with P-AscH- is H202 mediated as it is completely attenuated by inducible catalase expression. P-AscH- significantly increased the number of DNA DSBs in tumors after RT in vitro. Despite the increase in DNA DSBs, P-AscH-significantly decreased nuclear localization of activated pATM after RT and significantly decreased the fraction of cells in G2/M phases of the cell cycle. In vivo, RT + P-AscH- + KU60019 induced more tumor growth delay/clearance than all other combinations in unilateral MC38 or HCT116 flank tumors. Finally, P-AscH- significantly reduced loss of jejunal crypt cell density, epithelial architecture, and markers of lipid and protein oxidation following whole abdominal RT.P-AscH- selectively enhances the efficacy of ATM-based CRT in CRC tumor models while simultaneously decreasing RT-mediated small bowel toxicity. In tumors, P-AscH- enhances DNA DSBs by stimulating an H202 flux and prevents activation of DNA repair pathways and cell cycle checkpoints by inhibiting RT-induced activation of ATM. Selective radioprotectors like P-AscH- could facilitate the clinical translation ATM inhibitors as radiosensitizers.

Utilization Patterns of Single Fraction and Short Course Radiotherapeutic Schedules in the Management of Bone Metastases

Bone metastases are a common oncologic development occurring in approximately 60-70% of patients with advanced malignancies. Historically, bone directed radiotherapy at doses of 30 Gy delivered over 10 daily fractions have been commonly employed. However, prospective randomized data suggests equivalent pain relief with shorter course regimens. As such, the ASTRO Choosing Wisely Campaign was created in an effort to encourage clinicians to consider shorter course palliative regimens in patients with uncomplicated bone metastases who have a limited prognosis. We performed a retrospective analysis of our large, integrated health system in an effort to assess utilization patterns of short course and single fraction radiotherapy regimens over the last 5 years.We queried our internal radiation oncology electronic medical record (MOSAIQ®) from 2016-2020 for patients with bone metastasis who received palliative bone-directed radiotherapy in our network. Patients receiving Medicare approved palliative courses of radiation (30 Gy/10 fractions, 24 Gy/6 fractions, 20 Gy/5 fractions, 8 Gy/1 fraction) were included, as well as, patients receiving > 10 fractions. Treatment site was defined as academic (n = 2) versus community (n = 12). Short course treatment was defined as radiation treatment courses of ≤ 6 fractions, whereas long course included patients receiving ≥ 10 fractions. Patients were subdivided into quartiles based upon age and site of disease (spine, hip/pelvis, extremity, and other). Physicians were grouped according to their year of radiation oncology residency completion (before versus after 2010). Multivariable logistic regression analysis was completed to identify predictors of short course and single fraction treatment.We identified 1,004 patients with 1,768 bony metastatic lesions meeting the above criteria. The median patient age was 68 years (Interquartile range: 61-76 years). The spine was the most commonly treated site (46%) followed by pelvis/hip (26%), extremity (15%), and other (13%). Use of short course treatment increased over time from 40% in 2016 to 50% in 2020. Single fraction treatment also increased over time from 7% in 2016 to 11% in 2020. Predictors of short course treatment included: treatment at an academic center, more recent treatment year, patient age > 76 years old, non-spine anatomic site. Predictors of single fraction treatment included: treatment at an academic center, treating physician residency completion after 2010, patient age > 76 years old, and treatment to extremity or other site.Rates of short course and single fraction bone-directed radiotherapy utilization increased within our integrated health system over time. Treatment receipt at an academic center was associated with both short course and single fraction regimens. Physicians completing residency after 2010 were more likely to deliver single fraction therapy.

DNA Damage Response Inhibitors as Potentiators of Radiation and Immunogenicity in Merkel Cell Carcinoma

<h3>Purpose/Objective(s)</h3> Both Merkel cell polyomavirus positive (VP) and negative (VN) Merkel cell carcinoma (MCC) are highly immunogenic with the highest response rates to immune checkpoint inhibitors (ICI) among solid tumors. Approximately 50% of patients with advanced VP or VN MCC attain durable disease control with ICI; but, patients with MCC (or other cancers) refractory to ICI have limited options necessitating new immune stimulating therapies. Cell cycle checkpoints and the DNA damage response (DDR) are promising targets, and selective inhibitors of key DDR components, including ATR, ATM & DNA-PK, are in early clinical trials. Deregulation of early cell cycle components (e.g., p53 & Rb inactivation paired with Myc protein upregulation) promotes rapid MCC cell division, suggesting high replication stress and susceptibility to DDR inhibitors (DDRi) or DNA damaging agents. Indeed, MCC is very radiosensitive. Animal studies show DDRi + radiation synergize to induce antitumor immunity. The mechanisms for how DDRi promote antitumor immunity are not well understood; however, they may drive immunogenic tumor cell death. Here, we assess potential synergy of DDRi + radiation to upregulate MCC immune markers. <h3>Materials/Methods</h3> MCC-VP (WaGa & MKL2) and VN (MCC13-HL) MCC cell lines were treated with various doses of single fraction radiation (0, 2, 4, 8, 16, 24 Gray; 160 kV x-rays) +/- inhibitors of ATR, ATM or DNA-PK. Cells were assessed for viability, expression of IFNβ (ELISA), and MHC-I expression (flow cytometry at 3 days post-radiation). <h3>Results</h3> In VN-MCC cells, ATRi and ATMi potentiated low-dose radiation (2-4 Gy) to induce IFNβ release and MHC-I upregulation compared to drug or radiation treatment alone at equivalent doses. DNA-PKi was the most potent radiosensitizer inducing rapid cell death when combined with low-dose radiation (2-4 Gy), but early cell death limited IFNβ production relative to VN-MCC treated with radiation alone. DNA-PKi + low-dose radiation to upregulated MHC-I in VN-MCC. All DDRi tested abrogated peak IFNβ production in VN-MCC at radiation doses ≥8 Gy. The Merkel cell polyomavirus inhibits cGAS/STING mediated IFNβ production, and radiation + DDRi did not induce detectable IFNβ release in two VP cell lines. All MCC cell lines were viable when treated with DDRi alone. <h3>Conclusion</h3> Given inherent immunogenicity, cell cycle checkpoint deficiencies and radiosensitivity, MCC is an ideal tumor to test the potential of DDRi to overcome ICI-resistance. Our preliminary data suggest that ATRi and ATMi may effectively potentiate immunogenic cell death in a VN-MCC cell line when paired with 2-4 Gy radiation, yet abrogate IFNβ production with higher radiation doses <b>in vitro</b> suggesting higher doses coupled with DDRi induce non-immunogenic cell death. DNA-PKi was the most potent radiosensitizer in 3 MCC cell lines by cell viability assays but less effective at inducing IFNβ. <b>In vitro</b> studies are ongoing to support future animal studies as we explore a potential trial for DDRi in ICI-resistant MCC.

The Effect of Breast Cancer Subtype on Symptom Improvement Following Palliative Radiotherapy for Bone Metastases

AimTo assess the relationship between breast cancer subtypes and patient-reported outcomes (PRO) following palliative radiotherapy for bone metastases. Materials and methodsProspectively collected PRO for all breast cancer patients treated with palliative, bone metastasis-directed radiotherapy from 2013 to 2016 in the province of British Columbia were analysed. The PRO questionnaire scored pain severity, level of function and symptom frustration at baseline and at 3–4 weeks following palliative radiotherapy using a 12-point scale. The primary outcome was the rate of overall response (any improvement in score); the secondary outcome was the rate of complete improvement in PRO (final PRO score of 0). Multivariate logistic analysis was used to compare response rates between molecular subgroup approximations of luminal A (LumA), luminal B (LumB), HER2-enriched (HER2) and triple negative (TN), as defined by grade and immunohistochemical staining. ResultsThere were 376 patients who underwent 464 courses of palliative radiation for bone metastases. Subtypes included: 243 LumA, 146 LumB, 46 HER2 and 29 TN. There were 216 multifraction radiotherapy courses (median dose 20 Gy) and 248 single-fraction radiotherapy courses (median dose 8 Gy). The overall response rate was 85% and the complete response rate was 25%. In comparison with LumA breast cancers, TN breast cancers were associated with a lower rate of overall response (69% versus 86%, P = 0.021) and a lower rate of complete response (10% versus 28.8%, P = 0.045) on multivariate analyses. ConclusionPatients with TN breast cancer have lower rates of pain, function and symptom frustration improvement following palliative radiation for bone metastases.

Prognostic Factors Influencing Survival and a Treatment Pattern Analysis of Conventional Palliative Radiotherapy for Patients with Bone Metastases.

Background: Treatment indication for bone metastases is influenced by patient prognosis. Single-fraction radiotherapy (SFRT) was proven equally effective as multiple fractionation regimens (MFRT) but continues to be underused. Objective: Primary objectives: (a) to identify prognostic factors for overall survival and (b) to analyze treatment patterns of palliative radiotherapy (proportion of SFRT indication and predictive factors of radiotherapy regimen) for bone metastases. Methods: 582 patients with bone metastases who underwent conventional radiotherapy between January 1st 2014–31 December 2017 were analyzed. The Cox proportional hazard model was used to identify predictors of overall survival. For the treatment pattern analysis, 677 radiotherapy courses were evaluated. The logistic regression model was used to identify potential predictors of radiotherapy regimen. Results: The 3-year overall survival was 15%. Prognostic factors associated with poor overall survival were multiple bone metastases [hazard ratio (HR = 5.4)], poor performance status (HR = 1.5) and brain metastases (HR = 1.37). SFRT prescription increased from 41% in 2017 to 51% in 2017. Predictors of SFRT prescription were a poor performance status [odds ratio (OR = 0.55)], lung (OR = 0.49) and urologic primaries (OR = 0.33) and the half-body lower site of irradiation (OR = 0.59). Spinal metastases were more likely to receive MFRT (OR = 2.09). Conclusions: Based on the prognostic factors we identified, a selection protocol for patients candidates for palliative radiotherapy to bone metastases could be established, in order to further increase SFRT prescription in our institution.

123: Do Sustainable Palliative Single Fraction Radiotherapy Practices Proliferate or Perish Two Years After a Knowledge Translation Campaign?

123: Do Sustainable Palliative Single Fraction Radiotherapy Practices Proliferate or Perish Two Years After a Knowledge Translation Campaign?

Stereotactic radiotherapy is a useful treatment option for patients with medullary thyroid cancer

The role of radiotherapy in advanced medullary thyroid carcinoma (MTC) is confined to patients in whom surgical treatment or the administration of tyrosine kinase inhibitors are not possible or contraindicated. High fractionated radiation doses during radiosurgery or fractionated stereotactic radiotherapy are applied to reduce cancer-related symptoms and stabilize irradiated lesions. This study aimed to retrospectively evaluate the therapeutic effect of stereotactic radiotherapy in MTC patients.Material and methodsThe study group involved 11 MTC patients, treated due to 16 cancer lesions, mainly bone metastases (10 lesions), lymph node (2 lesions) metastases, or liver metastases (2 lesions), one primary thyroid tumor, and one MTC recurrence in the thyroid bed. The fractionated and total radiation doses ranged between 5 and 12 Gy and 8–44 Gy, respectively. Six lesions were treated with a single radiation fraction, three lesions with 2 fractions, another 6 lesions with 3 fractions, whereas the remaining one metastatic lesion with 9 fractions of stereotactic radiosurgery.ResultsThe beneficial effect of stereotactic radiosurgery was obtained in all treated lesions. None of treated lesions progressed in the further disease course. Fourteen lesions were stable (87.5 %), including eight lesions showing progression before radiosurgery (good response). Disease control was obtained in all soft-tissue metastases. Regarding bone metastases, partial regression was achieved in 20 % lesions, whereas in 30 % lesions progressive before radiotherapy, the treatment led to disease stabilization.ConclusionsOur data pointed to the effectiveness of high-dose fractionated radiotherapy in MTC. However, an observation of a larger group of patients is required to confirm it.

HEDOS—a computational tool to assess radiation dose to circulating blood cells during external beam radiotherapy based on whole-body blood flow simulations

We have developed a time-dependent computational framework, hematological dose (HEDOS), to estimate dose to circulating blood cells from radiation therapy treatment fields for any treatment site. Two independent dynamic models were implemented in HEDOS: one describing the spatiotemporal distribution of blood particles (BPs) in organs and the second describing the time-dependent radiation field delivery. A whole-body blood flow network based on blood volumes and flow rates from ICRP Publication 89 was simulated to produce the spatiotemporal distribution of BPs in organs across the entire body using a discrete-time Markov process. Constant or time-varying transition probabilities were applied and their impact on transition time was investigated. The impact of treatment time and anatomical site were investigated using imaging data and dose distributions from a liver cancer and a brain cancer patient. The simulations revealed different dose levels to the circulating blood for brain irradiation compared to liver irradiation even for similar field sizes due to the different blood flow properties of the two organs. The volume of blood receiving any dose (V >0 Gy) after a single radiation fraction increases from 1.2% for a 1 s delivery time to 20.9% for 120 s delivery time for the brain cancer treatment, and from 10% (1 s) to 48.7% (120 s) for a liver cancer treatment. Other measures of the low-dose bath to the circulating blood such as the dose to small volumes of blood (D 2%) decreases with longer delivery time. Furthermore, we demonstrate that the blood dose-volume histogram is highly sensitive to changes in the treatment time, indicating that dynamic modeling of blood flow and radiation fields is necessary to evaluate dose to circulating blood cells for the assessment of radiation-induced lymphopenia. HEDOS is publicly available and allows for the estimation of patient-specific dose to circulating blood cells based on organ DVHs, thus enabling the study of the impact of different treatment plans, dose rates, and fractionation schemes.

PD-0884 Educational intervention to improve the rate of single fraction radiotherapy prescriptions

PD-0884 Educational intervention to improve the rate of single fraction radiotherapy prescriptions

The Risk Factors for Radiation Pneumonitis After Single-Fraction Carbon-Ion Radiotherapy for Lung Cancer or Metastasis.

Simple SummaryThere was no reports about the risk factors of high dose single-fraction carbon-ion radiotherapy. Although there were only small number of patients with symptomatic radiation pneumonitis after this treatment, we showed that the risk factors of radiation pneumonitis include the dose–volume parameter.There are no studies on the risk factors of radiation pneumonitis (RP) after carbon-ion radiotherapy at a dose of 50 Gy (relative biological effectiveness (RBE)) in a single fraction. The objective of this study was to identify factors associated with RP after radiotherapy, including dose–volume parameters. Ninety-eight patients without a history of thoracic radiotherapy who underwent treatment for solitary lung tumors between July 2013 and April 2016 were retrospectively analyzed. Treatment was planned using Xio-N. The median follow-up duration was 53 months, and the median clinical target volume was 32.3 mL. Three patients developed grade 2 RP, and one patient developed grade 3 interstitial pneumonitis. None of the patients developed grade 4 or 5 RP. The dose-volume parameters of the normal lung irradiated at least with 5–30 Gy (RBE), and the mean lung dose was significantly lower in patients with grade 0–1 RP than in those with grade 2–3 RP. Pretreatment with higher SP-D and interstitial pneumonitis were significant factors for the occurrence of symptomatic RP. The present study showed a certain standard for single-fraction carbon-ion radiotherapy that does not increase the risk of RP; however, further validation studies are needed.

Single Fraction Radiation for Myeloid Sarcoma Is as Effective as Multi-Fraction Regimens for Tumor Regression and Control

Introduction/BackgroundMyeloid sarcoma is a rare extramedullary manifestation of immature myeloid/monocyte cells. Radiotherapy (RT) yields good local control, but data on different fractionation schemes are limited. The goal of this retrospective study was to share our institutional experience and assess volumetric regression with differential fractionation. Materials and MethodsWe evaluated patients treated for myeloid sarcoma between 2000 and 2019 and categorized them into Group A (treated with RT) and Group B (no RT). We assessed local control using cumulative incidence function analysis. Post-treatment imaging sequences were analyzed for volumetric calculations. ResultsForty-four patients with 80 lesions were assessed. Twenty-three patients with 52 lesions received RT (Group A), and 6 lesions received a single fraction of RT. There were 2 instances of local progression in Group A and 8 in Group B, with a cumulative incidence function estimate of local progression in Group A of 2.4% at 1 year and 6.9% at 2 years, significantly reduced compared to 29.7% and 35.5% in Group B, respectively (hazard ratio 0.13 [95% confidence interval 0.030.63], P = .011). No lesion treated with a single fraction of RT developed local progression. Volumetric analysis for 19 chronologically followed lesions (including 3 treated with a single fraction) revealed no difference in regression between single or multi-fraction treatment. ConclusionRT for myeloid sarcoma yields excellent local control and may be as effective in a single fraction as more protracted courses, though this requires validation. For a diagnosis associated with poor survival, a single palliative fraction may be optimal with potential for higher utilization.

A time-resolved experimental-mathematical model for predicting the response of glioma cells to single-dose radiation therapy.

To develop and validate a mechanism-based, mathematical model that characterizes 9L and C6 glioma cells' temporal response to single-dose radiation therapy in vitro by explicitly incorporating time-dependent biological interactions with radiation. We employed time-resolved microscopy to track the confluence of 9L and C6 glioma cells receiving radiation doses of 0, 2, 4, 6, 8, 10, 12, 14 or 16 Gy. DNA repair kinetics are measured by γH2AX expression via flow cytometry. The microscopy data (814 replicates for 9L, 540 replicates for C6 at various seeding densities receiving doses above) were divided into training (75%) and validation (25%) sets. A mechanistic model was developed, and model parameters were calibrated to the training data. The model was then used to predict the temporal dynamics of the validation set given the known initial confluences and doses. The predictions were compared to the corresponding dynamic microscopy data. For 9L, we obtained an average (± standard deviation, SD) Pearson correlation coefficient between the predicted and measured confluence of 0.87 ± 0.16, and an average (±SD) concordance correlation coefficient of 0.72 ± 0.28. For C6, we obtained an average (±SD) Pearson correlation coefficient of 0.90 ± 0.17, and an average (±SD) concordance correlation coefficient of 0.71 ± 0.24. The proposed model can effectively predict the temporal development of 9L and C6 glioma cells in response to a range of single-fraction radiation doses. By developing a mechanism-based, mathematical model that can be populated with time-resolved data, we provide an experimental-mathematical framework that allows for quantitative investigation of cells' temporal response to radiation. Our approach provides two key advances: (i) a time-resolved, dynamic death rate with a clear biological interpretation, and (ii) accurate predictions over a wide range of cell seeding densities and radiation doses.

Pharmacologic ascorbate enhances the therapeutic index of ATM-inhibitor based chemoradiation for colorectal cancer.

3609 Background: Ataxia telangectasia mutated protein (ATM) is one of the key sensors of DNA damage and specific inhibitors of ATM are potent radiosensitizers. However, their clinical utility with radiation (RT) is limited because they lack tissue specificity and increase normal tissue injury. Pharmacologic (high dose) ascorbate (P-AscH-) selectively increases oxidative stress in tumors while functioning as a donor antioxidant and reducing RT damage in normal tissues. We hypothesized that P-AscH- could enhance the therapeutic index of ATM-inhibitor based chemoradiation (CRT) for colorectal cancer (CRC) by simultaneously enhancing efficacy and reducing RT bowel injury. Methods: Human HCT116, SW480, and HT29 and murine CT26 and MC38 CRC models were used. Clonogenic survival was assessed following single-fraction RT (2-8 Gy) +/- P-AscH- (5 pM/cell) +/- veliparib (PARP), VE821 (ATR), or KU60019 (ATM). Catalase expression was induced using HCT116 cells expressing a doxycycline inducible catalase transgene. DNA double strand breaks (DSBs) were quantified using neutral comet assays 0-24 hours post RT. Cell cycle phases were assessed using flow cytometry. ATM and pATM localization were assessed using IF. Jejunal toxicity was assessed using IHC in fixed tissues following single fraction (10 Gy) whole abdominal RT in c57blj/6 mice. Tumor growth delay was assessed following RT (5 Gy x 3) +/- drug treatment in unilateral flank tumors. Results: Veliparib, VE821, and KU60019 were potent radiosensitizers in HCT116, SW480, HT29, MC38, and CT26 CRC tumor models and P-AscH- further reduced clonogenic survival with DRIs in all lines except for HT29. In contrast, P-AscH- enhanced survival of cultured HUVEC and FHs-74 cells exposed to RT. Enhanced cell kill with P-AscH- is H202 mediated as it is completely attenuated by inducible catalase expression. P-AscH- significantly increased the number of DNA DSBs in tumors after RT in vitro. Despite the increase in DNA DSBs, P-AscH-significantly decreased nuclear localization of activated P-ATM after RT and significantly decreased the fraction of cells in G2/M phases of the cell cycle. In vivo, RT + P-AscH- + KU60019 induced more tumor growth delay/clearance than all other combinations in unilateral MC38 or HCT116 flank tumors. Finally, P-AscH- significantly reduced loss of jejunal crypt cell density, epithelial architecture, and markers of lipid and protein oxidation following whole abdominal RT. Conclusions: P-AscH- selectively enhances the efficacy of ATM-based CRT in CRC tumor models while simultaneously decreasing RT-mediated small bowel toxicity. In tumors, P-AscH- enhances DNA DSBs by stimulating an H202 flux and prevents activation of DNA repair pathways and cell cycle checkpoints by inhibiting RT-induced activation of ATM. Selective radioprotectors like P-AscH- could facilitate the clinical translation ATM inhibitors as radiosensitizers.

Radiation-induced nausea and vomiting: a clinical audit of prophylactic antiemetic use

AbstractIntroduction:Radiation-induced nausea and vomiting (RINV) is a common side effect of single fraction palliative radiotherapy. Patients experiencing RINV have significantly reduced quality of life and a prescription of prophylactic antiemetics, principally 5-HT3 antagonists, is recommended. There is a growing body of evidence relating to indications for this, but as yet there are no national guidelines.Methods:A retrospective audit aimed to determine the extent to which patients at high and moderate emetogenic risk receiving single fraction radiotherapy were prescribed prophylactic emetic medication in line with the current evidence base.Results:A total of 60 patients were included in the audit; of these patients, 50 were consented for the risk of nausea and/or vomiting. Prophylactic antiemetics were only prescribed to 28 (46·7%) of all audited patients. Out of the 50 patients who provided informed consent, only 24 (48%) were prescribed an antiemetic prior to their treatment.Conclusion:Antiemetic prescribing for single fraction patients at moderate to high emetogenic risk at a large regional centre is underutilised in relation to published evidence. Amended guidance and further audits are recommended to ensure that this patient group is best supported.

Outcomes of Palliative Radiotherapy in Metastatic Epidural Spinal Cord Compression in Lung Cancer-A Prospective Observational Study from Tata Memorial Hospital.

Background Metastatic epidural spinal cord compression (MESCC) secondary to lung cancer (LC) is a debilitating complication associated with poor prognosis and is commonly treated with radiotherapy (RT). There is no consensus for RT dose fractionation in spinal cord compression. Methods Forty consecutive patients of LC with radiological evidence of MESCC treated with palliative RT were evaluated for functional outcomes (pain, ambulation, and sphincter function) at 2-, 4-, and 24-week post RT completion. Pain assessment was done using visual analogue scale (VAS) and response was categorized according to international consensus criteria, ambulation status (AS) using Tomita’s scale, and sphincter function by the presence or absence of a catheter. Overall survival (OS) was assessed using Kaplan-Meier method and compared using log-rank test. Impact of potential prognostic factors on survival was also analyzed and p -value ≤0.05 was considered significant. Results Sixteen, 22, and two patients received 8 Gy single fraction (SF), 20 Gy in five fractions (20/5), and 30 Gy in 10 fractions (30/10), respectively. At 2 weeks, overall response (OR) rates of pain, ambulation, and sphincter control were 73, 81, and 81%, respectively. At 4 and 24 weeks, 93.7, 84.3, 87.5% and 88, 94, 76.5% had OR, respectively. Median OS was 4 months. Six- and 12-months OS was 50 and 37.5%. Nonsignificant difference in OS was seen between SF and 20/5 fractions (median 2.2 vs. 7.1 months, p = 0.39). Age ≤50 years was the only significant factor ( p <0.05) in univariate analysis for OS. Conclusion Radiotherapy provided equivalent pain control, ambulation, and sphincter function compared with reported literature in MESCC. Nonsignificant difference in OS exists between SF and multifraction RT regimens.

Palliative radiation therapy for symptomatic advance breast cancer

In this study, we evaluated the effectiveness of palliative breast radiation therapy (RT), with single fraction RT compared with fractionated RT. Our study showed that both RT fractionation schemas provide palliation. Single fraction RT allowed for treatment with minimal interference with systemic therapy, whereas fractionated RT provided a more durable palliative response. Due to equivalent palliative response, at our institution we have increasingly been providing single fraction RT palliation during the COVID-19 pandemic.

&lt;p&gt;&lt;strong&gt;Effect of edaravone on lungs and small intestine in rats with induced radiotherapy&lt;/strong&gt;&lt;/p&gt;

Radiotherapy is a frequently used method for treatment of cancer which is regarded as one of the top two diseases causing premature death worldwide. However, radiotherapy is known to have many side effects. In this study, we evaluated biologically and histologically the possible protective effects of edaravone, the free radical scavenger and neuroprotective agent used to treat amyotrophic lateral sclerosis, on lung and small intestine against radiation-induced early side effects of 15 Gy total body irradiation in single fraction. Thirty-two rats were divided randomly into four equal groups. Groups were administered 15 Gy of external ionizing radiation to the whole body after 30 minutes of EDA administration (a dose of 500 and 50 mg/kg). Rats were sacrified at 72 h of the experiment. Tissues were separated to investigate levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSHPX) and malondialdehyde (MDA); and evealuate histopathological changings. The protective effect of EDA showed statistically significant in MDA, SOD and GSHPX values of lungs except CAT and statistically significant effect was observed in MDA in small intestine. Also, we showed statistically significant values with histopathological changings. Pediatric cancer patients who have a longer life expectancy are as important as their recovery from their normal life. We are expecting that EDA as a modulator of free radical scavenging pathways in many organs can reduce the side effects of radiation damage on lungs and small intestine.

Characteristics and Predictors of Radiographic Local Failure in Patients With Spinal Metastases Treated With Palliative Conventional Radiation Therapy

PurposeAlthough local control is an important issue for longer-term survivors of spinal metastases treated with conventional external beam radiation therapy (EBRT), the literature on radiographic local failure (LF) in these patients is sparse. To inform clinical decision-making, we evaluated rates, consequences, and predictors of radiographic LF in patients with spinal metastases managed with palliative conventional EBRT alone. Methods and MaterialsWe retrospectively reviewed 296 patients with spinal metastases who received palliative EBRT at a single institution (2006-2013). Radiographic LF was defined as radiologic progression within the treatment field, with death considered a competing risk. Kaplan-Meier, cumulative incidence, and Cox regression analyses determined overall survival estimates, LF rates, and predictors of LF, respectively. ResultsThere were 182 patients with follow-up computed tomography or magnetic resonance imaging; median overall survival for these patients was 7.7 months. Patients received a median of 30 Gy in 10 fractions to a median of 4 vertebral bodies. Overall, 74 of 182 patients (40.7%) experienced LF. The 6-, 12-, and 18-month LF rates were 26.5%, 33.1%, and 36.5%, respectively, while corresponding rates of death were 24.3%, 38.1%, and 45.9%. Median time to LF was 3.8 months. Of those with LF, 51.4% had new compression fractures, 39.2% were admitted for pain control, and 35.1% received reirradiation; median time from radiation therapy (RT) to each of these events was 3.0, 5.7, and 9.2 months, respectively. Independent predictors of LF included single-fraction RT (8 Gy) (hazard ratio [HR], 2.592; 95% confidence interval [CI], 1.437-4.675; P = .002), lung histology (HR, 3.568; 95% CI, 1.532-8.309; P = .003), and kidney histology (HR, 4.937; 95% CI, 1.529-15.935; P = .008). ConclusionsPatients experienced a >30% rate of radiographic LF by 1 year after EBRT. Single-fraction RT and lung or kidney histology predicted LF. Given the high rates of LF for patients with favorable prognosis, assessing the risk of death versus LF is important for clinical decision-making.

Hypofractionated FLASH-RT as an Effective Treatment against Glioblastoma that Reduces Neurocognitive Side Effects in Mice.

Recent data have shown that single-fraction irradiation delivered to the whole brain in less than tenths of a second using FLASH radiotherapy (FLASH-RT), does not elicit neurocognitive deficits in mice. This observation has important clinical implications for the management of invasive and treatment-resistant brain tumors that involves relatively large irradiation volumes with high cytotoxic doses. Therefore, we aimed at simultaneously investigating the antitumor efficacy and neuroprotective benefits of FLASH-RT 1-month after exposure, using a well-characterized murine orthotopic glioblastoma model. As fractionated regimens of radiotherapy are the standard of care for glioblastoma treatment, we incorporated dose fractionation to simultaneously validate the neuroprotective effects and optimized tumor treatments with FLASH-RT. The capability of FLASH-RT to minimize the induction of radiation-induced brain toxicities has been attributed to the reduction of reactive oxygen species, casting some concern that this might translate to a possible loss of antitumor efficacy. Our study shows that FLASH and CONV-RT are isoefficient in delaying glioblastoma growth for all tested regimens. Furthermore, only FLASH-RT was found to significantly spare radiation-induced cognitive deficits in learning and memory in tumor-bearing animals after the delivery of large neurotoxic single dose or hypofractionated regimens. The present results show that FLASH-RT delivered with hypofractionated regimens is able to spare the normal brain from radiation-induced toxicities without compromising tumor cure. This exciting capability provides an initial framework for future clinical applications of FLASH-RT.See related commentary by Huang and Mendonca, p. 662.