RT Toxicity Research Articles

Kompleksna i retka prezentacija trovanja pirinčanom tabletom - prikaz slučaja

Aluminum phosphide, known as "rice tablet" (RT), is a common cause of suicide in adult women in Iran, with a high rate of lethal outcome. We report a patient with RT toxicity, with a complex syndrome of hepatic failure, renal failure, Brugada electrocardiography (ECG) patterns, and pleuropericardial effusion. The patient received conventional management with fluid therapy, gastric washing, activated charcoal followed by intra-aortic balloon pump insertion, inotropic drugs support, and mechanical ventilation. The unique features of our case are related to a combination of multiorgan failure with Brugada atypical ECG patterns and pleuropericardial effusion. Among the aforementioned complications, pleuropericardial effusion, ascites, and Brugada syndrome are exceedingly rare events. The patient was treated with high-dose inotropic drugs and intra-aortic balloon pump insertion. Despite tremendous management of metabolic acidosis, all efforts failed, and the patient died with sudden cardiac arrest.

PD-0664: Outcome and toxicity of RT in elderly HNSCC patients –experience from a large monocentric cohort

PD-0664: Outcome and toxicity of RT in elderly HNSCC patients –experience from a large monocentric cohort

Toxicity of Simultaneous Integrated Boost Intensity Modulated Radiation Therapy in Post-Operative Oral Cavity Cancer

To assess the acute toxicity of Simultaneous integrated boost intensity modulated radiation therapy (SIB-IMRT) in postoperative oral cavity cancers with intermediate risk features was the primary objective of this study. The secondary objectives were to assess late toxicity and efficacy. This was a prospective, interventional study conducted at a single center. Patient accrual was done from November 2017 to August 2018 and data was analyzed in November 2019. Patients of oral cavity carcinoma who underwent surgery and had at least one risk factor on histopathological evaluation i.e., T3/T4 stage, node positive without extra capsular extension, lymphovascular invasion (LVI), perineural invasion (PNI), close margin (<5 mm), depth of invasion ≥3 mm for tongue and ≥7 mm for buccal mucosa were included. All patients had indication for adjuvant RT alone without concurrent chemotherapy. Post-operative RT was delivered with SIB-IMRT technique using 6 MV X-rays on a Linear accelerator. A dose of 63.6 Gray (Gy) in 30 fractions was delivered to high risk clinical target volume (CTV), 54 Gy in 30 fractions to intermediate risk CTV and 51 Gy in 30 fractions to low risk CTV. Dose constraints for the spinal cord was Dmax ≤ 42Gy, PRV cord Dmax ≤ 48Gy, brainstem Dmax ≤50.4 Gy, each parotid Dmean ≤ 26 Gy. Weekly assessment was done during RT and acute radiation toxicities were recorded as per Radiation Therapy Oncology Group (RTOG) acute toxicity criteria in terms of oral mucositis (OM), skin toxicity and dysphagia. Subsequent visits were monthly for the first 3 months, 2 monthly for the next 6 months and 3 monthly thereafter. Clinical examination with an assessment of the late toxicity was done as per RTOG late morbidity scoring schema. Radiological imaging (CECT or MRI) was done at 3 months post RT. Statistical analysis was performed using statistical package for sciences (SPSS version 20.0). Survival analysis was done by Kaplan-Meier method with log rank test. A total of 30 patients were included in the study with a median age of 48.5 years (range 33-75 year). The frequency N (%) of primary site involved was tongue 13(43.33), buccal mucosa 12(40), alveolus 4 (13.33) and retromolar trigone 1 (3.33). All patients completed RT and the median duration of RT was 42 days [mean days 42.3±0.93]. Maximum acute grade ≤2 vs grade 3 oral mucositis was 46.67% vs 53.33%, skin toxicity was 86.67% vs 13.33 %, dysphagia was 66.67% vs 33.33% respectively. No patients had grade 4 or 5 acute toxicity. At a median follow up of 11 months [range 6-18 month], grade 1 late toxicities were 53.33% (subcutaneous toxicity) and 33.33% (xerostomia). Loco regional control was 96.67%. IMRT-SIB is safe in terms of acute toxicity however the short follow up duration limits assessment of late toxicity and locoregional control rates in post-operative oral cavity cancers with intermediate risk.Abstract 3966; TableRisk factor for adjuvant RTN (%)>pT316(53.33)p N+9(30)PNI+11(36.67)LVI+5(16.67)Close margin1(3.33)DOI20(66.67) Open table in a new tab

A comparison of quality of life and acute toxicity in patients applied with Tomo-helical IMRT and conformal radiotherapy for breast cancer

To compare quality of life and radiation toxicity in patients applied with Tomo-helical intensity-modulated radiation therapy (IMRT) and three-dimensional conformal radiation therapy (3D-CRT) as adjuvant radiotherapy because of breast cancer. The study included a total of 403 patients. Fifty-eight percent of patients were treated with 3D-CRT, and 42% of patients were treated with Tomo-helical IMRT. Radiation toxicity was evaluated according to the Radiation Therapy Oncology Group (RTOG) toxicity criteria. Quality of life was evaluated using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 Quality of life scale version 3-Turkish and the EORTC QLQ-BR23 questionnaires. These questionnaires were completed by all patients at 4 different time points: the start of RT (T1); the end of RT (T2); 1 month after completion of RT (T3); and 6 months after completion of RT (T4). Statistical data were analysed using the Chi-square and MANOVA tests. Radiotherapy-related skin, upper gastro-intestinal system, white blood count and neutrophil toxicity were observed to be higher in the patients treated with 3D-CRT (p 0.050). In the patients treated with Tomo-helical IMRT, the scores of breast symptoms (p = 0.014), sexual function (p = 0.003) and sexual pleasure (p = 0.020) in the sub-dimension scales of the EORTC-BR23 were found to be better compared with those of patients treated with 3D-CRT. The findings of RT toxicity and quality of life appear to be superior in patients applied with Tomo-helical IMRT compared with patients treated with 3D-CRT.

The implementation of an empty bladder filling protocol for localised prostate volumetric modulated arctherapy (VMAT): early results of a single institution service evaluation.

To examine the impact of an empty bladder filling protocol on patients receiving radical RT for localised prostate cancer on post RT toxicity and biochemical progression free survival (bPFS). Records of patients receiving radical external beam RT (EBRT) for localised prostate cancer with a full or empty bladder were reviewed. These included the bladder size on planning CT, daily online image guided RT (IGRT) setup data, treatment time and post treatment follow up data.These included bPFS, gastrointestinal(GI) and genitourinary(GU) toxicity scoring post RT using the CTCAE v4.0 scoring system. All patients included in the study were planned and treated under the same departmental clinical protocol with VMAT and daily online IGRT corrections. 90 patients were treated with 60 Gy in 20 fractions with a median follow up of 48 months. At 4 years bPFS in the empty bladder group was 100 and 98% in the full bladder group (p = 0.27). There were no statistically significant differences in cumulative ≥Grade 2GU (p = 0.10) and GI (p = 0.27) toxicity rates between the two bladder filling protocols. No statistically significant differences in the IGRT setup between the two groups of patients. Although the median treatment times per fraction were not statistically different between the two groups (p = 0.47), patients in the full bladder filling group were required to spend a longer time in the RT department per treatment session for bladder filling. An empty bladder filling protocol has non-inferior bPFS, GI and GU toxicities at 4 years in patients with localised prostate cancer using advanced RT techniques in comparison to a full bladder filling protocol. A longer follow up with a larger sample size is required to validate this approach. This study suggests that an empty bladder filling protocol can be used in external beam EBRT for localised prostate cancer with non-inferior treatment outcomes.

Impact of HIV infection on consolidative radiotherapy for non-Hodgkin diffuse large B-cell lymphoma

ObjectivesEven though frequent, it is not known how HIV infection and treatment impact in the consolidation by radiotherapy of non-Hodgkin diffuse large B-cell lymphomas (DBCL). This article aim to assess that difference that HIV makes on radiation treatment.Patients and methodsA retrospective cohort of all DBCL patients treated with chemotherapy and consolidative radiotherapy at a single institution between 2010 and 2018 was assessed. All patients had biopsy-proven lymphoma and were included if radiation was part of the treatment and had at least 6 months of follow-up or were followed until death.ResultsThree-hundred fifty-nine (359) patients were selected, with a median age at diagnosis of 57.7 years (13–90 years). Twenty-eight patients (7.8%) were HIV positive. Median follow-up was 48.0 months. Female patients were 51.3% and most had a good performance in the ECOG scale (78.8% are ECOG 0–1). Median overall survival was not reached, but mean OS was 50.1 months with 86 deaths. Median progression-free survival was 48.7 months. HIV infection had no impact on OS (p = 0.580) or PFS (p = 0.347) among patients treated with RT. HIV positive patients were more frequently staged only with CT (p > 0.05) with no impact on PFS (p = 0.191). No HIV positive patient received rituximab due to local policy restrictions and HIV positive patients were more prone to receive CHOP-like chemotherapy (p < 0.05), specially ones with etoposide (CHOEP). CHOP was associated with better survival (p = 0.015) in the overall population and in the HIV negative population (p = 0.002), but not in the HIV positive population (p = 0.982). RT toxicities were not overall more frequent in the HIV positive population (p = 0.567), except for fatigue (p < 0.05) and hematological toxicities (p = 0.022).ConclusionHIV status did not influence on survival when patients were treated with consolidative radiotherapy. HIV infection was a bias on our sample for staging methods and chemotherapy regimens choices. For HIV positive patients there was an increase in fatigue and hematological toxicities of any grade with radiation.

Effect of the oral CXCR4 inhibitor X4-136 on tumor control and side effects in cervical cancer treated with radiotherapy and concurrent chemotherapy.

e18010 Background: Cervical cancer is a global health problem. Despite scale up of prevention programs, there will be an ongoing need to improve the effectiveness of radiotherapy/cisplatin (RTCT) for women with established, locally advanced disease. We have shown that RTCT with the CXCR4 inhibitor plerixafor improves tumor control, reduces metastases and reduces RT-related side effects compared to RTCT alone. X4-136 is an oral CXCR4 inhibitor that is better suited to long-term, once daily use. In this study we examined: 1. The efficacy of RTCT and X4-136 in cervical cancer; 2. Biomarkers of response to RTCT and X4-136; and 3. Effects of RTCT and X4-136 on intestinal toxicity, an important dose-limiting RT side effect in these patients. Methods: Orthotopic cervical cancer xenografts derived from our patients were treated with RT (30 Gy; 2 Gy/day) and cisplatin (4 mg/kg/week ip) with or without concurrent X4-136 (100 mg/kg/day orally) for 3 weeks. Mice were sacrificed immediately after treatment for biomarker assessment. In separate experiments, mice had CT imaging weekly after treatment to evaluate tumor response. Acute and late intestinal toxicity was assessed histologically 3.5 and 90 days after treatment respectively. Results: RTCT alone increased CXCL12/CXCR4 signaling, intratumoral accumulation of myeloid cells and PD-L1 expression. The addition of X4-136 during RTCT abrogated these effects and improved tumor response in 2 cervical cancer models. Furthermore, the addition of X4-136 increased the proportion of surviving intestinal crypt cells in keeping with a reduction in acute RT toxicity, and reduced late histologic changes of late RT toxicity. Conclusions: The addition of X4-136 blunts RTCT-induced upregulation of the CXCL12/CXCR4 pathway, reduces intratumoral myeloid cells, improves tumor control and reduces side effects in cervical cancer. Few if any pharmacologic strategies have been identified previously that expand the therapeutic window with RT in this way. The combination of RTCT and CXCR4 inhibition warrants testing in clinical trials to validate these findings. These benefits may apply to other tumors where RTCT plays a curative role.

Dose-Escalated Intensity Modulated Radiation Therapy in Patients with Locally Advanced Vulvar Cancer- Does It Increase Response Rate?

The management for locally-advanced vulvar cancer includes preoperative and definitive chemoradiotherapy. By increasing dose from 47.6Gy to 57.6Gy, GOG 205 safely increased clinical (cCR) and pathologic complete response (pCR) to 64% and 50% from 48% and 31% in GOG 101. Intensity modulated radiotherapy (IMRT) has improved the tolerability of radiotherapy in vulvar cancer, such that the ongoing GOG 0279 is examining further dose-intensification to 64Gy with concurrent gemcitabine and cisplatin. The aim of the current study is to assess the response of dose-escalated IMRT in locally-advanced vulvar cancer. We performed a retrospective review of patients treated with dose-escalated (≥54Gy) IMRT from 2012-2018 for locally-advanced vulvar cancer. Patients treated with preoperative (n=30, 67%) or definitive intent (n=15, 33%) were included, while patients treated with adjuvant radiotherapy were excluded. Concurrent chemotherapy with weekly cisplatin (40mg/m2) was administered in 93%. Median dose to the vulva was 66.8 Gy (IQR: 66.0 Gy to 68.0 Gy) for definitive and 59.4 Gy (IQR: 58.0 Gy-61.2 Gy) for preoperative IMRT. Toxicity was graded using CTCAE v4.03. Predictors of disease free survival (DFS) were analyzed using the Kaplan Meier method with log rank test between groups and a parsimonious multivariate Cox multivariate model. p16 status was not analyzed as a variable, due to missing data for p16 in 69%. Of the included 45 patients: median age was 67 years, 60% were ≥ cT2, 53% were node-positive on PET imaging, and 57% were ≥ FIGO Stage IIIA. The overall rate of cCR was 78%, with a pCR rate for preoperative patients of 63%. At a median follow-up of 18 months (IQR: 7.7 – 33.7), the 2-year DFS was 65% (95%CI 49%-81%) for all patients, 84% (95%CI 62%-100%) for definitive IMRT, and 58% (95%CI 39%-78%) for preoperative IMRT. pCR was a significant predictor of DFS on both univariate [2-year DFS 83% (95%CI 65%-100%) versus 21% (95%CI 0%-46%), p <0.01] and on multivariate analysis (HR 0.28, 95% CI 0.08-0.96). There was no significant difference in DFS by RT dose, age, clinical nodal status, SUV, or presence of lichen sclerosis on multivariate analysis. Median treatment duration was 46 days (IQR: 45-50 days), with a treatment break required in 4 patients, 3 for reasons unrelated to RT and 1 for febrile neutropenia. Grade 3 acute RT toxicity was seen in 14 (31%) patients and consisted mainly of radiation dermatitis, pain, and GI. Grade 3 late RT toxicity was seen in 3 (7%) of patients: vaginal stricture (n=2) and perineal pain (n=1). Dose-escalated IMRT for locally advanced vulvar cancer was well tolerated with acceptable acute and chronic effects, with minimal treatment interruptions. cCR and pCR rates compared favorably with published data. pCR is a strong predictor of DFS and may serve as a viable endpoint for future clinical trial design in locally-advanced vulvar cancer.

A Matched Case-Control Analysis of Clinical Outcomes for Patients With Inflammatory Bowel Disease and Rectal Cancer Treated With Pelvic Radiation Therapy

Inflammatory bowel disease (IBD) is a known risk factor for rectal cancer, and RT is often an important part of therapy for these patients. Previously published studies have raised concerns for increased rates of RT toxicity in patients with IBD. We performed a matched case-control analysis to assess RT-related toxicity in a large sample of U.S. veterans afflicted with IBD and rectal cancer. We identified 186 veterans with rectal cancer (71 Patients with IBD treated with RT, 71 matched controls without IBD treated with RT, and 44 nonmatched controls with IBD treated without RT) diagnosed between 2000 and 2015. We analyzed short- and long-term toxicity and mortality in multivariable logistic regression, Fine-Gray, and frailty models, adjusting for potential confounders. When comparing patients with and without IBD treated with RT there were no differences in RT breaks (adjusted odds ratio [aOR], 1.70; 95% confidence interval [CI], 0.38-4.76; P = .49) or the need for antidiarrheal medication during RT (aOR, 1.53; 95% CI, 0.70-3.35; P = .29). There was a trend toward higher risk of hospital admission during RT for RT + patients with IBD (aOR, 2.69; 95% CI, 0.88-8.22; P = .08). There were higher rates of small bowel obstruction (OR, 15; 95% CI, 1.9-115; P = .009) and a trend toward higher rates of abdominopelvic adhesions (OR, 3.6; 95% CI, 0.98-13; P = .05) in the RT + IBD cohort. However, compared with a nonmatched cohort of patients with IBD treated without RT there were no differences in long-term complications. No differences were found in other acute or long-term toxicities. Rectal cancer-specific mortality appeared similar across all cohorts. RT does not appear to increase the rates of acute or long-term toxicity in patients with IBD and should be considered a standard part of therapy when otherwise indicated.

EP-1161 Clinical response and toxicity of VMAT lowdose RT with intravenous steroids for Graves’ Orbitopathy

EP-1161 Clinical response and toxicity of VMAT lowdose RT with intravenous steroids for Graves’ Orbitopathy

EP-1323 HeartSpare Plus: A comparison of the feasibility and acute toxicity of internal mammary chain RT

EP-1323 HeartSpare Plus: A comparison of the feasibility and acute toxicity of internal mammary chain RT

Abstract OT2-04-03: Examining personalized radiation therapy (EXPERT): A randomised phase III trial of adjuvant radiotherapy vs observation in patients with molecularly characterized luminal A breast cancer

Abstract Background Radiation therapy (RT) after breast conserving surgery (BCS) is the current standard of care for patients with early stage breast cancer. However, individual absolute recurrence risks and hence benefits of RT vary substantially. A study showed significant association between local recurrence (LR) risk and PAM50-defined intrinsic subtypes and Risk of Recurrence scores (ROR).1 The objective of EXPERT, a co-lead study of Breast Cancer Trials-Australia &amp; New Zealand (BCT-ANZ), and Breast International Group (BIG), is to optimize local therapy for early breast cancer through precise individualized quantification of LR risk to identify patients for whom RT after BCS may be safely omitted. Trial design This is a randomized, non-inferiority, phase III study of women who plan to receive adjuvant endocrine therapy for Prosigna (PAM50)-defined luminal A breast cancer with ROR ≤60 resected by BCS. Women are randomized to receive adjuvant whole breast RT and endocrine therapy or endocrine therapy alone and followed-up for 10 years after randomization. Major eligibility criteria Females aged ≥50 years; histologically confirmed invasive breast carcinoma ≤2 cm, grade 1 or 2, ER and PgR ≥10%, HER2-negative and node-negative; treated by BCS with negative margins for invasive carcinoma and associated DCIS; Prosigna (PAM50)-defined Luminal A subtype and ROR ≤60; and plan to receive adjuvant endocrine therapy. Specific aims Primary: To determine if omission of RT is not inferior to RT in terms of LR-free interval after BCS. Secondary: To evaluate the impact of omission of RT on regional, local-regional and distant recurrence-free interval; disease-free survival (DFS); invasive DFS; overall survival; salvage RT or mastectomy rate; toxicity; endocrine therapy adherence; patient reported outcomes; and health economic outcomes. Statistical methods An estimated 5-year LR rate in the target population is expected to be 1% with RT. A rate of 4% is considered non-inferior as a worthwhile trade-off against RT toxicity. Using O'Brien-Fleming boundary for rejecting non-inferiority, 29 LR events are required for final analysis expected 8 years after the first patient is randomized. Two interim analyses will be conducted after 10 and 21 events. If the stratified log-rank test statistic exceeds the upper boundary at interim or final analysis, the hypothesis of non-inferiority will be rejected and it will be concluded that no RT is inferior to RT. Accrual: Target (1170), actual: 82 (June 2018) The study was activated in Australia in August 2017, with global activation planned for Q4 2018. Recruitment is expected to be completed in 4.5 years. Contact information Professor Boon Chua, UNSW Sydney and Prince of Wales Hospital, NSW, Australia; email boon.chua@health.nsw.gov.au; T +61 2 49255239. Registration: NCT02889874 References Fitzal F, Filipits M, Fesl C, et al. Predicting local recurrence using PAM50 in postmenopausal endocrine responsive breast cancer patients. JCO 2014;32(15 suppl):1008. Citation Format: Chua BH, Gray K, Krishnasamy M, Regan M, Zdenkowski N, Loi S, Mann B, Forbes JF, Wilcken N, Spillane A, Martin A, Badger H, Jafari S, Fong A, Mavin C, Corachan S, Arahmani A, Martinez J-L, Francis P. Examining personalized radiation therapy (EXPERT): A randomised phase III trial of adjuvant radiotherapy vs observation in patients with molecularly characterized luminal A breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-04-03.

Histological evaluation of vital organs of the livebearer Jenynsia multidentata (Jenyns, 1842) exposed to glyphosate: A comparative analysis of Roundup® formulations

Roundup formulations are herbicides whose active principle is glyphosate. However, these formulations are potentially more toxic to non-target organisms than pure glyphosate. This study aimed to evaluate and compare the toxic potential of the Roundup formulations through histological alterations in fish. Thus, males and females of the neotropical fish species Jenynsia multidentata (Jenyns, 1842) were exposed for 24 or 96 h to the Roundup Original® (RO), Roundup Transorb® (RT) or Roundup WG® (RWG) formulations, at a fixed concentration of 0.5 mg/L of glyphosate. This concentration is close to the maximum glyphosate limits found in the environment and is non-lethal to J. multidentata. The three formulations caused histological damage to the liver, gills and brain of J. multidentata, which increased over the exposure time. Differences in the histological alterations between females and males were observed in the liver and brain. Females were more tolerant to RO and RT than RWG. Males did not exhibit these differences in sensitiveness with formulations. The RWG caused more damage in the liver and gills and RT in the brain. Overall, there were differences in the toxicity of RO, RT and RWG and the toxic effect was presented through histological damage, reinforcing the usefulness of histological biomarkers for Roundup® toxicity. The comparison of the toxic potential of glyphosate-based herbicides is important because it could give support to the governmental organizations to set protective rules for the water ecosystems and human health, as well as to reduce the use of highly toxic formulations in agriculture.

Effect of Radiation Field Size and Dose on Local Control or Re-fracture Events after Post-Operative Radiation Following Intramedullary Nailing Procedures for Palliation of Bone Metastases

Pathologic fracture of long bones carries a heavy symptomatic burden in patients with metastatic malignancy. Standard therapy typically includes intramedullary nail placement to stabilize the bone, followed by palliative post-operative radiation therapy (PORT) to reduce the risk of re-fracture or local recurrence. The radiation dose and fields for this treatment approach have wide variation without uniform standards. We sought to estimate the distribution of PORT dose/fractionation, and field size, and estimate any potential association with the risk of re-fracture and/or local recurrence. We retrospectively analyzed patients treated at our institution with pathologic fractures of long bones, treated with intramedullary nailing of the femur, tibia, or humerus, followed by post-operative palliative radiation to that site. We stratified patients by radiation fractionation (single vs multi-fraction regimen) and by radiation field size (coverage of whole hardware [full-field] vs partial coverage of hardware [limited field]), to determine if these factors may be associated with the primary endpoint, which was defined as local re-fracture and/or local recurrence of disease within the long bone. Fisher’s exact test was used for statistical comparison due to the relative paucity of events. Eighty-six evaluable patients, treated between 2010 and 2017, were identified. Median patient age was 60 years. Median Karnofsky performance status was 70. Median follow up was 2.6 months (range, 2 weeks to 74 months). Radiation doses ranged from 8 – 30Gy, apart from one patient who received 45Gy in 3 Gy fractions. Thirty-six patients (42%) received 8 Gy in a single fraction, and fifty (58%) received multi-fraction treatment. Ten patients (12%) underwent limited field radiation, while 47 (55%) underwent full field radiation, and 29 (34%) were unevaluable for field size. Nine patients (10%) reached the primary endpoint of local recurrence and/or local refracture, consistent with historical comparison. On Fisher’s two-sided exact test, field size was not found to correlate with local recurrence/re-fracture (p=0.366). Local recurrence/re-fracture was also not significantly associated with multi-fraction radiation, compared to those who received 8 Gy in a single fraction, although was numerically worse in the multifraction group (p=0.073). Increased total dose beyond 8 Gy was not associated with improvement in local control. Similarly, irradiation of the entire hardware was not associated with improved rates of local control as compared to limited field radiation. Our findings suggest that single-fraction, limited-field palliative PORT may be sufficient to achieve adequate rates of local control, thereby allowing for expedient initiation of systemic therapy and minimal RT toxicity. Further evaluation is needed.

Abstract 4159: Circadian clock protects against radiation-induced dermatitis and cardiomyopathy in mice

Abstract Radiation therapy (RT) is commonly used in cancer treatment. Despite technological advances to improve precision external-beam RT in treating breast, lung, and esophageal tumors, a substantial number of patients receive radiation to their hearts and the external skin region. This radiation insult results in acute and chronic toxicities including dermatitis and cardiomyopathy, affecting the patient's quality of life and survival. Hence, reducing toxicities associated with RT are desirable outcomes. With the knowledge that the natural circadian clock, present in almost every cells of the body including the skin and heart, regulates DNA repair, cell death and proliferation, and cardiac function processes, we hypothesize that molecular defensive mechanisms of the circadian system play regulatory roles to minimizing RT-induced skin and heart toxicity in cancer patients. To investigate acute toxicity of RT, studies were performed using SKH-1 hairless mice with healthy clock (wild-type day shift (DS)) and environmentally disrupted clock (wild-type rotating shift (RS) and genetically disrupted clock (Per1/2 knockout (Per1/2-/-)) conditions. We treated all groups (n=9 mice per group) with a single dose RT (6 grays of ionizing radiation) to the whole body. We used body weight as an indicator of overall toxicity, red spots as a measure of dermatitis, and left ventricular ejection fraction (LVEF) by ultrasound echocardiography as a readout for cardiomyopathy, relative to the measurements pre-RT as controls. After sacrifice, genotoxicity was detected using alkaline comet assay in PBMCs. Worse toxicities were observed until 2 weeks post-RT in mice with circadian clock disruption compared to mice with healthy clocks. Body weights of the disrupted clock groups were significantly reduced by up to 10% on day 2, unlike the DS group which reduced by only 2%. However, there was body weight loss recovery from day 6 in clock disrupted mice but this recovery was not sustained in Per1/2-/- mice. Dermatitis was counted where visible and there was 2.4- and 1.7- fold increases in RS and Per1/2-/- mice compared to DS mice. In the heart, LVEF was significantly decreased in RS and Per1/2-/- mice by days 1 and 4, and began to recover by day 8 in RS. Comparatively, the LVEF in DS mice was not significantly reduced. On a cellular level, genotoxicity in blood cells were significantly increased in RS and Per1/2-/- mice relative to DS mice. Taken together, these findings strongly suggest that the healthy circadian clock protects the whole body, skin, and heart from RT-induced toxicity. Future work includes mechanistic understanding of how the natural circadian clock system can be harnessed to minimize toxicity against RT. The successful completion of this project will provide a novel mechanistic understanding into the protective role of the circadian clock against acute and chronic skin and heart toxicities for cancer patients undergoing RT. Citation Format: Panshak P. Dakup, Kenneth I. Porter, Zhaokang Cheng, Shobhan Gaddameedhi. Circadian clock protects against radiation-induced dermatitis and cardiomyopathy in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4159.

EP-1323: Dosimetry results and toxicity of a 3-week schedule RT with SIB in breast cancer, with TomoDirect

EP-1323: Dosimetry results and toxicity of a 3-week schedule RT with SIB in breast cancer, with TomoDirect

Discontinuation of Curative Head and Neck Irradiation: Etiologies and Outcomes

There is scarcity of valid clinical data on survival after premature discontinuation of curative radiation therapy (PDCRT) for head and neck (H&N) cancers. This makes it challenging to advise patients seeking to withdraw from treatment early. In this study, we aimed to characterize causes of PDCRT and assess overall survival in this subset of patients A total of 1176 patients received H&N radiation therapy at our institution in the period 2010-2017. Of these patients, 59 (5%) were unable to complete a full course of prescribed curative RT and were included in the analysis. Mean follow-up time was 18 months (0-81.9 months). Primary endpoints were causes of PDCRT and overall survival (OS). PDCRT causes were classified into five categories: discontinuation against medical advice (DAMA), medical comorbidity, RT toxicity, disease progression, and social factors. Survival was examined using the life-table method and log-rank test. DAMA (32%), medical comorbidity (24%), and RT toxicity (18%) accounted for the majority of PDCRT causes. Of 59 analyzed patients, most were men (80%), ≥60 years old (59%), white (68%), lived ≥ 10 miles from hospital (61%), were undergoing a longer (definitive) course of RT (59%), and receiving bilateral neck irradiation (70%). At the same time, the majority of patients had ECOG ≤1 (78%) and ≤1 comorbidities (56%) at the start of the treatment. Most common primary sites were oropharynx (37%), larynx (20%), and oral cavity (12%). During RT, 66% of patients had treatment interruptions and 34% required inpatient admission. Supportive Oncology service was involved in care of only 20% patients on treatment. Radiation Therapy Oncology Group grade ≥2 dysphagia was observed in 47% patients, mucositis in 46%. Median prescribed dose was 69.96 Gy (range, 50-72 Gy). Median completed radiation dose was 50.9 Gy (range, 2-68 Gy). At the time of analysis, 25 (42%) deaths were recorded. Two-year and 4-year OS rates was 56% and 43%. There was a trend toward improved survival with total completed dose ≥ 50 Gy vs < 50 Gy, 67% vs 40% (P=.06). To the best of our knowledge, this is the largest modern study examining clinical outcomes after PDCRT. The principal reason for treatment withdrawal remains DAMA, and hence more effort need to be focused on educating and providing support to meet the unique needs of this challenging patient population. Addressing psycho-social and quality of life aspects may help increase completion rates of this often life-saving treatment. Overall survival appears to be poor after PDCRT. Advising a patient that reaching at least 50 Gy could offer a better chance for survival could prove vital.

Premature discontinuation of curative radiation therapy: Insights from head and neck irradiation

PurposeFactors related to premature discontinuation of curative radiation therapy (PDCRT) are understudied. This study aimed to examine causes and clinical outcomes of PDCRT at our institution by investigating the most common anatomical site associated with PDCRT. Methods and materialsAmong the 161 patients with PDCRT of various anatomic sites at our institution between 2010 and 2017, 36% received radiation to the head and neck region. Pertinent demographic, clinical, and treatment-related data on these 58 patients were collected. Survival was examined using the life-table method and log-rank test. ResultsThe majority of patients were male (81%), white (67%), ≥60 years old (59%), living ≥10 miles away from the hospital (60%), single (57%), with Eastern Cooperative Oncology Group score ≥1 (86%), experiencing significant pain issues (67%), and had treatment interruptions in radiation therapy (RT; 66%). The most common reasons for PDCRT were discontinuation against medical advice (33%), medical comorbidity (24%), and RT toxicity (17%). Of the comorbidities leading to PDCRT, 50% was acute cardiopulmonary issues and 43% was infection. The mean follow-up time was 15.9 months, and the 2-year overall survival and disease-specific survival rates were 61% and 78%, respectively. Patients with illicit substance abuse, cardiovascular disease, and Eastern Cooperative Oncology Group score ≥2 had worse survival. A trend toward improved survival with total completed dose ≥50 Gy versus <50 Gy existed (74% versus 44%, respectively; P = .07). ConclusionsIn this largest-to-date, modern analysis of PDCRT, the most common cause of discontinuation was discontinuation against medical advice, which underscores the importance of patient education, optimization of RT symptoms, involvement of social work, and integration of other supportive services early in treatment. Survival remains suboptimal after PDCRT for H&N tumors, with a 2-year overall survival rate of 61%. Completing >50 Gy appears to confer a relative therapeutic benefit.

Risk Tolerance in Radiation Oncology: A Multi-Institutional Survey

Radiotherapy requires deliberation to maximize the therapeutic ratio within the patient’s goals of care. Yet, there is a lack of data on the employment of dose constraints and physician risk tolerance in radiation oncology. The purpose of this study is to assess radiation oncologists’ attitudes towards radiation treatment planning, risk tolerance, and applied clinical ethics. An internet-based, IRB-approved 35 question survey was piloted and electronically distributed to all radiation oncologists (n=94) at three academic medical systems in 2017. Participation was voluntary and responses were anonymously aggregated. A total of 35 responses were received (29 complete, 6 partial), for a response rate of 37% and completion rate of 31%. Most respondents practice at academic centers (89%) and regional satellite clinics (27%). Half of respondents had at least 10 years of clinical experience. A majority of respondents (77%) incurred a significant or debilitating radiation toxicity in their practice experience. Physicians most frequently use dose constraints from QUANTEC for conventional RT (94%) and published trials for hypofractionated RT or re-irradiation cases (84%, 81% respectively). Respondents “rarely/never” (81%) exceed dose constraints in initial radiation cases, but do so “sometimes/often”in re-irradiation cases (75%). Physicians agree that following published dose constraints help protect patients from harm (73%) and the physician from liability (92%). Nearly all respondents (88%) agreed that they should “first, do no harm,” and defined “harm” as RT toxicity (59%) rather than local failure (6%), or both (34%). The majority of respondents prioritized toxicity reduction over tumor control when faced with dosimetric dilemmas, particularly for patients with an unfavorable prognosis. Most physicians’ patients prefer shared decision making (55%) versus deferring to physician recommendation (29%) when making treatment decisions. Yet, physicians believe that their risk tolerance should govern radiotherapy planning (59%), rather than the patient (22%), or physician and patient equally (19%). Similarly, physicians reported that they are better able to determine the patient’s best interests (58%), rather than the patient (8%), or the physician and patient equally (35%). This survey describes the current state of the practice in three large academic medical systems concerning the use of dose constraints and approach to resolving dosimetric delimmas. While recognizing patient preference for shared decision making, a majority of radiation oncologists report that they are better able to determine appropriate risk and benefit than patients. Though counter to contemporary emphasis on patient autonomy, this may be necessary in a field that is both technically complex and concerned about late effects of treatment. The appropriate model for shared decision making warrants further investigation in Radiation Oncology.

Contribution of Common SNPs to Variability in Late Radiation Therapy Toxicity in Prostate Cancer

Late toxicities following prostate cancer RT are dose-limiting and negatively affect quality of life. Inter-individual variability in the development of these toxicities is partly due to genetics. Several single nucleotide polymorphisms (SNPs) have been identified, but have modest effect sizes, so larger studies are needed to identify further associations. Also, it is not known whether the genetic contribution to late toxicities is mainly from common SNPs with modest effects or rarer, unknown variants that may have large effects. It is also not known whether SNPs contribute equally to different toxicities. We analyzed many genome-wide SNPs simultaneously in two prostate cancer cohorts from the RAPPER and RADIOGEN studies to estimate the variance in late RT toxicities explained by common SNPs. Participants received external beam RT and were followed prospectively for development of late toxicity toxicities between from 6 months to 5 years post-RT (measured as cumulative incidence) in RAPPER (LENT-SOM, RMH scales) and RADIOGEN (CTCAEv3.0). Selected binary endpoints were urinary frequency (increase ≥ 2x pre-RT or requiring treatment), hematuria (macroscopic or worse), and rectal bleeding (mild or worse). Logistic regression using restricted maximum likelihood estimated the variance in each endpoint explained by common (frequency > 1%) SNPs (methods in Yang et al, Nature Genetics 2010). A likelihood ratio test compared each model with genetic components to the reduced model without genetic components. Analyses were adjusted for age at RT, total biologically effective dose, hormone use (in RADIOGEN; all RAPPER participants received hormones), and pre-RT symptoms (in RAPPER; toxicity grade in RADIOGEN accounts for pre-RT symptoms). Analysis of rectal bleeding was also adjusted for diabetes and percent rectal volume receiving ≥65Gy. In RAPPER, 140/1707 patients (8%) reported increased urinary frequency, 45/1705 (3%) frank hematuria, and 199/1542 (13%) rectal bleeding. In RADIOGEN, 155/569 patients (27%) reported increased urinary frequency, 39/569 (7%) hematuria, and 131/569 (23%) rectal bleeding. The proportion of variance in toxicity explained by common SNPs was 0.35 (standard error, se 0.20, P=0.035) in RAPPER and 0.36 (se 0.58, P=0.28) in RADIOGEN for urinary frequency; 0.08 (se 0.21, P= 0.38) in RAPPER and 0.01 (se 0.54, P=0.5) in RADIOGEN for hematuria, and 0.11 (se 0.22, P=0.31) in RAPPER and 0.27 (se 0.55, P=0.30) in RADIOGEN for rectal bleeding. Common, known SNPs explain approximately 35% of the variance in late urinary frequency among men treated with RT for prostate cancer. Common SNPs explain less variance for late rectal bleeding and hematuria, suggesting that dose and other clinical factors are more important. Rare variants, not captured on SNP arrays, likely explain an additional proportion of variance in all toxicities.