Common Terminology Criteria For Adverse Events Grade Research Articles

Daratumumab and antineoplastic therapy versus antineoplastic therapy only for adults with newly diagnosed multiple myeloma ineligible for transplant.

Daratumumab and antineoplastic therapy versus antineoplastic therapy only for adults with newly diagnosed multiple myeloma ineligible for transplant.

Minimising Adverse Drug Reactions and Verifying Economic Legitimacy-Pharmacogenomics Implementation in Children (MARVEL- PIC): protocol for a national randomised controlled trial of pharmacogenomics implementation

IntroductionDNA-informed prescribing (termed pharmacogenomics, PGx) is the epitome of personalised medicine. Despite international guidelines existing, its implementation in paediatric oncology remains sparse.Methods and analysisMinimising Adverse Drug Reactions and Verifying Economic...

Evaluation of colitis induced by immune-checkpoint inhibitors therapy in melanoma patients by an overall grading scale.

Colitis was the third most common immune-related adverse effect in melanoma patients treated with immune-checkpoint inhibitor (ICI). With the limitation of real-world data in the UK population, this study was conducted in a UK hospital where a fresh colitis guidance was introduced to evaluate the overall grading (OG) to assess colitis severity and guide the treatment. This study aimed to investigate colitis severity by Common Terminology Criteria for Adverse Events (CTCAE) grade and overall grade at time of presentation. Colitis treatment and outcome were evaluated to compare the impact of these two categories. A single-center, retrospective observational study was performed in melanoma patient developing colitis symptoms. A total of 44 advanced melanoma patient with colitis symptoms were included. Median time to colitis onset was 67 days (range 4-890). Majority of patients developed G1/ G2 of CTCAE scale (70.4%) but moderate or severe overall grade (84.1%). There were 65.9% of patients treated with steroids, and 38.2% with infliximab and 4.5% with vedolizumab. The median time of colitis resolution was 28 days (range 0-282). Both treatment modality and time to resolution were associated with severity of colitis assessed by complete OG(p<0.0001) rather than CTCAE grading (p>0.05). This study provided a comprehensive description about ICI-induced colitis management in a single center of the UK. The more completed OG was proposed to stratify colitis patient and guide the investigation and treatment decision at presenting time, replacing the old CTCAE grading.

Abstract 2235: Epigenetic inflammation scores for C-Reactive protein and interleukin-6 associate with adverse cardiometabolic and cardiac outcomes among survivors of childhood cancer

Abstract Background: Inflammaging, a chronic low-grade inflammation as individuals age, is measured by elevated levels of circulating markers of inflammation (e.g., C-reactive protein [CRP] and interleukin-6 [IL-6]) and is associated with age-related chronic health conditions (CHCs). We aim to evaluate epigenetic inflammation scores (EIS) for CRP and IL-6 and their associations with cardiometabolic and cardiac-based CHCs and epigenetic age acceleration (EAA) in childhood cancer survivors (CCS). Methods: Among 2,052 CCS (47.2% female; mean [SD] = 33.7 [9.3] years of age at blood draw) from the St Jude Lifetime Cohort, EIS of CRP and IL-6 were calculated as the weighted sum of the DNA methylation (DNAm) levels of CpGs that are associated with circulating levels of CRP or IL-6, where blood DNAm data were generated with Infinium EPIC BeadChip, and weights are regression coefficients from previously published EWAS studies. CHCs with a CTCAE (Common Terminology Criteria for Adverse Events) grade ≥2 were considered except for myocardial infarction (MI) where a minimum CTCAE grade of 3 was applied. Residuals of EIS were calculated by regressing EIS on age at blood draw and sex. A multivariable Cox proportional hazard regression model evaluated the associations between the EIS residuals and each CHC adjusting for sex and cancer treatments. The timeframe was years since age at blood draw. All participants alive at the last follow-up were censored. EAA was calculated as residuals from regressing epigenetic age (both GrimAge and PhenoAge) on age at blood draw. A linear regression model evaluated the association between the EIS residual and EAA adjusting for sex and treatments. Results: The incidence of cardiometabolic conditions (i.e., after the blood draw) included: abnormal glucose metabolism (AGM, 5.1%), hypertension (HTN, 16.6%), hypercholesterolemia (HCL, 3.9%), hypertriglyceridemia (HTG, 6.0%), and cardiomyopathy (CMP, 9.0%), MI (4.4%), and obesity (24.2%). CRP-EIS and IL6-EIS were correlated (r=0.62). The CRP-EIS residual was significantly associated with increased risk of AGM (Hazard Ratio [95% CI] = 1.33 [1.01-1.75], P=0.04) and CMP (1.44 [1.19-1.74], P=1.58 × 10−4) and suggestively associated with HTN (1.16 [0.99-1.36], P=0.07) and MI (1.55 [0.94-2.57], P=0.09). IL6-EIS residual was associated with CMP (1.25 [1.04-1.49], P=0.02). In addition, both CRP- and IL6-EIS were positively associated with PhenoAge-EAA (β = 0.53 and 0.50 years per SD increase of EIS) and GrimAge-EAA (β = 0.30 and 0.36 per SD increase of EIS). Conclusion: The CRP- and IL6-EIS are associated with increased risk of cardiometabolic and cardiac-based CHCs and EAA among CCS, suggesting that EIS may be used as clinical tools to identify survivors at higher risk of such CHCs and inflammation may be targeted for intervention to reduce the burden of CHCs. Citation Format: Qian Dong, Yan Chen, Xijun Zhang, John Easton, Heather Mulder, Emily Walker, Geoffrey Neale, Kyla Shelton, Stephanie B. Dixon, Jinghui Zhang, Gregory T. Armstrong, Melissa M. Hudson, Kirsten K. Ness, Zhaoming Wang. Epigenetic inflammation scores for C-Reactive protein and interleukin-6 associate with adverse cardiometabolic and cardiac outcomes among survivors of childhood cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2235.

Peg-asparaginase associated toxicities in children with acute lymphoblastic leukemia: A single-center cross-sectional study

BackgroundLeukemia is the most prevalent type of cancer affecting children, representing approximately 35% of cancer diagnoses in Saudi Arabia. Notably, significant improvement in the overall survival and cure rates for pediatrics with acute lymphoblastic leukemia (ALL) has been attributed to adding asparaginase to the chemotherapy regimen. However, the administration of these agents may lead to a multifactorial range of toxicities that often alter treatment outcomes. ObjectiveThe study aimed to characterize the prevalence of common toxicities related to polyethylene glycol (PEG) asparaginase in children aged 0–14 years diagnosed with ALL. Additionally, it assessed the types of toxicities associated with intravenous (IV) and intramuscular (IM) administration of Peg-asparaginase. MethodIt was an observational retrospective cross-sectional study. Data was extracted from the hospital's electronic health record (EPIC). Using EPIC, we reviewed medical charts of all pediatric patients below 14 years old diagnosed with ALL who received at least one dose of PEG-asparaginase between January 2020 and March 2023. The toxicity grading was based on the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). ResultsOne hundred and ninety-one patients with ALL were included in the study. Overall, 79 toxicity episodes were experienced by the study patients. Anaphylaxis/hypersensitivity (36.7%) and hepatotoxicity (31.6%) were the most prevalent toxicities reported, followed by pancreatitis and hyperglycemia (12.7% each). According to the CTCAE grading, approximately 70% of toxicities were categorized as Grade 3 and 4. Notably, 60% of the events occurred during the induction and consolidation phase of therapy. Interestingly, there was no significant difference in rates of toxicities between patients receiving IV or IM PEG-asparaginase. ConclusionThe distribution of toxicities highlighted in our study aligns with findings from previously published studies. Furthermore, multivariate analysis indicated that patients with high-risk ALL and T-ALL were more likely to develop toxicities compared to other forms of ALL.

Incidence of amoxycillin-clavulanic acid associated hepatotoxicity in an Australian children's hospital.

Amoxycillin/clavulanic acid is the most common antimicrobial cause of drug-induced liver injury in adults. It is a less common cause of severe drug-related hepatotoxicity in children despite its frequent use. We studied the incidence, characteristics and predictive factors for amoxycillin/clavulanic acid hepatoxicity in children. Retrospective cohort study of children who received oral or intravenous amoxycillin/clavulanic acid at a quaternary children's hospital over a 5-year period. Children were included if they had liver function tests (LFTs) determined at baseline, during and within 3 months after the treatment course. Causality was assessed using the Naranjo criteria for adverse drug reactions and Roussel Uclaf Causality Assessment Method. Of 3271 children prescribed amoxycillin/clavulanic acid, 374 were included. Forty-nine (13%) had LFT abnormalities related to amoxycillin/clavulanic acid. Fourteen (3.6%) fulfilled Common Terminology Criteria for Adverse Events (CTCAE) grade 2 criteria with clinically significant hepatotoxicity. Age <2 years, sepsis, post-gastrointestinal surgical indications, prolonged treatment course of >7 days and higher cumulative amoxycillin (>10 g) and clavulanic acid dose (>1 g) were predictive of hepatotoxicity. The median time to resolution of LFT abnormalities was 4 weeks (range 3-7). The incidence of amoxycillin/clavulanic acid related LFT abnormalities (CTCAE Grade 2 or above) in children was 3.6%. A prolonged treatment course >7 days, high cumulative amoxycillin (10 g) and clavulanic acid (>1 g) doses, those aged <2 years, and patients with sepsis or post-gastrointestinal surgery were predictive of a higher likelihood of abnormal LFTs. LFT monitoring should be considered in children receiving ≥7 days of treatment, particularly in those with other predisposing factors.

Applying the EHA/EBMT grading for ICAHT after CAR-T: comparative incidence and association with infections and mortality

AbstractCytopenias represent the most common side effect of CAR T-cell therapy (CAR-T) and can predispose for severe infectious complications. Current grading systems, such as the Common Terminology Criteria for Adverse Events (CTCAE), neither reflect the unique quality of post–CAR-T neutrophil recovery, nor do they reflect the inherent risk of infections due to protracted neutropenia. For this reason, a novel EHA/EBMT consensus grading was recently developed for Immune Effector Cell-Associated HematoToxicity (ICAHT). In this multicenter, observational study, we applied the grading system to a large real-world cohort of 549 patients treated with BCMA- or CD19-directed CAR-T for refractory B-cell malignancies (112 multiple myeloma [MM], 334 large B-cell lymphoma [LBCL], 103 mantle cell lymphoma [MCL]) and examined the clinical sequelae of severe (≥3°) ICAHT. The ICAHT grading was strongly associated with the cumulative duration of severe neutropenia (r = 0.92, P < .0001), the presence of multilineage cytopenias, and the use of platelet and red blood cell transfusions. We noted an increased rate of severe ICAHT in patients with MCL vs those with LBCL and MM (28% vs 23% vs 15%). Severe ICAHT was associated with a higher rate of severe infections (49% vs 13%, P < .0001), increased nonrelapse mortality (14% vs 4%, P < .0001), and inferior survival outcomes (1-year progression-free survival: 35% vs 51%, 1-year overall survival: 52% vs 73%, both P < .0001). Importantly, the ICAHT grading demonstrated superior capacity to predict severe infections compared with the CTCAE grading (c-index 0.73 vs 0.55, P < .0001 vs nonsignificant). Taken together, these data highlight the clinical relevance of the novel grading system and support the reporting of ICAHT severity in clinical trials evaluating CAR-T therapies.

Development of a Novel Methotrexate-Related Neurotoxicity Risk Score in Pediatric Acute Leukemia: A Report from the Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium

Introduction: Methotrexate (MTX) chemotherapy is a critical component of contemporary pediatric acute lymphoblastic leukemia (ALL) treatment regimens. However, intrathecal (IT) and intravenous (IV) MTX can result in dose-limiting acute neurotoxicity, which has been associated with an increased risk of ALL relapse. Emerging data suggest the likelihood of MTX neurotoxicity is elevated in Latino patients and those diagnosed at older age or treated with high-dose MTX (&amp;gt; 1g/m2); however, there are no established methods for identifying those at greatest risk. Therefore, we used machine learning algorithms to develop a neurotoxicity risk prediction model in a diverse, multi-ethnic cohort of pediatric patients with ALL. Methods: The Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium enrolls patients diagnosed with ALL from six participating treatment centers in the Southwestern U.S. This interim analysis included pediatric patients (age &amp;lt;20 years) diagnosed and treated for ALL at Texas Children's Hospital (2005-2019). Individuals diagnosed with infant leukemia (&amp;lt;1 year of age) and/or with preexisting neurologic disease were excluded. We retrospectively reviewed medical records to identify clinical, sociodemographic, and Common Terminology Criteria for Adverse Events (CTCAE) grading of toxicities such as transaminitis and hyperbilirubinemia. Address information at the time of diagnosis was geocoded and aligned to the American Community Survey at the census-tract level to define residential social determinants of health (SDOH). Cases of MTX neurotoxicity were identified by manual review of records for any patient who underwent brain MRI imaging during ALL therapy. Cases of acute MTX neurotoxicity were defined following Ponte di Legno Delphi Consensus definitions as neurologic episodes (e.g., seizure, stroke-like symptoms, altered mental status) occurring within 21 days of IV or IT MTX with no other identifiable underlying cause. Demographic and clinical factors were compared between cases of acute MTX-related neurotoxicity and controls using logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (CI). The dataset was randomly split with 80% of observations used in the training stage and 20% reserved for testing. Random forest algorithms with boosting and down sampling were grown using 5-repeat, 10-fold cross validation to optimize tuning parameters. Model performance was evaluated using test and train error rate, area under the curve of the receiver operating characteristic (AUC-ROC), sensitivity, and specificity. Results: A total of 770 patients were eligible and met inclusion criteria. Patients were a mean age of 7.0 years at diagnosis, 54% male, 55% Latino and 45% treated with high-risk protocols. Acute MTX neurotoxicity developed in 134 (17.4%) of patients. In logistic regression models, neurotoxicity odds increased with older age at diagnosis (OR = 1.20, 95% CI: 1.15-1.26), Latino ethnicity (OR = 2.14, 95% CI: 1.38-3.38), treatment on high-risk protocols (OR=4.32, 95% CI: 2.75-6.99), obesity at diagnosis (vs normal weight, OR = 2.54, 95% CI: 1.51-4.22), and CTCAE grade 3 or higher transaminitis (OR = 2.02, 95% CI: 1.03-4.47) or hyperbilirubinemia (OR = 4.71, 95% CI: 1.21-18.41) during induction therapy. Overall, the random forest machine learning algorithm resulted in an AUC-ROC of 0.79 with an error rate of 0.26 in both the training and test sets. The overall sensitivity was 0.71, with a specificity of 0.67. Recognizing ethnic disparities in MTX neurotoxicity may exist, random forest models were generated stratifying on ethnicity (Figure 1), which yielded slightly better performance in non-Latino patients (AUC-ROC = 0.77) than Latino patients (AUC-ROC = 0.73). Conclusions: This interim analysis of data from the REDIAL Consortium demonstrates the potential utility of machine learning algorithms to develop a novel risk prediction model for acute MTX-related neurotoxicity. Efforts to expand this work within the larger REDIAL cohort (n&amp;gt;2,000) and incorporate inherited genetic data are ongoing. Ultimately, this work may inform efforts to preemptively risk-stratify patients and deliver targeted interventions to vulnerable individuals.

Safe and Effective Escalation of Evidence-Based Chemotherapy for Mature B Cell Non-Hodgkin's Lymphoma in a Low Resource Setting

BACKGROUND Although high intensity chemotherapy regimens result in &amp;gt;90% long term survival of children with Mature B-cell Non-Hodgkin Lymphoma (MB-NHL), low intensity chemotherapy regimens are used in most Sub-Sahara African (SSA) setting resulting in decades of less than 20% long term survival. This is in part because dose-intense chemotherapy strategies that are standard of care in high income countries (HIC) have not been widely or effectively implemented in low- and middle income countries (LMIC). We investigated the toxicity and outcomes of children with MB-NHL who were treated with a treatment regimen that includes 1g/M2 of methotrexate per dose (mini COPADM) at Mulago National Referral Hospital in Uganda. The objective of this study was to evaluate the safety and effectiveness of an incremental chemotherapy escalation strategy to control treatment-related toxicities and increase response and survival of children treated for MB-NHL at a pediatric oncology center in the SSA setting. METHODS We prospectively collected clinical outcomes on children under 18 years with MB-NHL at Mulago National Referral Hospital (MNRH) in Uganda between January 2020 and July 2023. Overall (OS) and event-free survival (EFS) were calculated using the Kaplan-Meier method. Events in the EFS analysis were: 1) Death; 2) Relapse; or 3) Persistent or progressive disease at the end of Cycle 3. Patients were censored at the earlier of two years from presentation or their last day of follow-up. Descriptive statistics were presented. Toxicities were graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5. RESULTS We identified 77 patients, among whom 16 (21%) died prior to commencement of the first cycle of chemotherapy and 6 (8%) treated with alternative therapies. The 55 patients who were treated with mini COPADM with 1g/M 2 of methotrexate and are included in this analysis had similar demographics and clinical phenotypes to the 22 that were excluded. The median age was 9.6 years (interquartile range ((IQR) 6.6 - 11.7 years) with 38 (69%) males. Patients were Stage III (53%, 29/55), stage IV (38%, 21/55); and 55%, (30/55) were high-risk. The most common presentations were abdominal mass 43 (78%) and jaw mass 14 (25%). With a median follow-up time of 9 months (IQR 6 - 24 months), the 1-year overall survival (OS) and event free survival (EFS) were 56%; 95% CI (41 - 76) and 41%; 95%CI (27 - 61) respectively. For children with high-risk disease, 1-year OS was 44%; 95%CI (28 - 72) and EFS 25%; 95% CI (12 - 51). Toxicities included febrile neutropenia (83%) and CTCAE grade ≥3 mucositis (44%). For the 12 patients whose cause of mortality was recorded, 1 case (8.3%) was treatment-related and 11 (91.7%) were due to cancer. CONCLUSION: This study establishes baseline response rates, survival, and toxicity for patients with pediatric MB-NHL in Uganda treated with 1g/M2 of methotrexate. Toxicities were consistent with treatment received, perhaps exacerbated by synergy of anthracycline (50 mg/m2) along with intermediate dose MTX. These findings suggest that mini-COPADM with 1g/M 2 of methotrexate can be safely supported with the current clinical resources at MNRH and this low dose regimen accounts for the poor survival of children with MB-NHL in our center. We plan to escalate our therapy to mini-COAPDM with 3g/M2 and addition of Rituximab, with contingent intensification of supportive care to curb treatment-related toxicities.

Safety profile of methotrexate used off-label in ectopic pregnancy: an active monitoring study based on a Chinese hospital pharmacovigilance system

Objective Methotrexate (MTX) is characterized as first-line therapy although its indication of ectopic pregnancy is off-label use. We aimed to conduct a retrospective cohort study to investigate the incidence, characteristics of adverse drug reactions (ADRs) of MTX, provide valuable insights for medical workers. Methods Basing on China Hospital Pharmacovigilance System (CHPS), a retrospective analysis was performed to evaluate the safety of MTX (n = 672). An active monitoring model was set to detect ADR signals from the hospital information system. Frequency, Common Terminology Criteria for Adverse Events (CTCAE) grade proportion and association of dose exposure with ADRs were presented as outcomes. Results The total incidence of ADRs was 54.0%. Anaemia (37.6%) was the most frequent ADR, followed by hepatic function abnormal (11.3%), hyperuricemia (6.1%), neutropenia (4.6%), leukopenia (4.0%), and dyslipidaemia (2.5%). For the composition of all ADRs, CTCAE grade one, two and three dominated for 86.3%, 12.1% and 1.6%, respectively. The severity of hepatic function abnormal was more serious in the two-dose exposed group (p = .021), while other types of ADRs had no statistical or clinical differences. Logistic regression analysis showed the incidence of any ADRs (OR 1.87 [1.31–2.64]; p = .001), hepatic function abnormal (OR 2.75 [1.69–4.48]; p < .001), dyslipidaemia (OR 5.15 [1.87–14.13]; p = .001) were significantly higher in the two-dose exposed group. After adjusted, the positive associations were still maintained. Conclusions MTX is quite safe in ectopic pregnancy, despite its mild to moderate hematotoxicity, hepatotoxicity and nephrotoxicity. Taking CHPS can present the accurate denominator of the incidence of adverse drug reactions into account, our study advocates that it may have great potential to be used as an active monitoring tool for off-label drug use risk management.

Comprehensive analysis of risk factors for the severity of immune checkpoint inhibitor-associated myocarditis in cancer patients

Abstract Purpose To explore the predictive significance of patients’ clinical features and examination results, including blood laboratory tests, echocardiogram, cardiovascular magnetic resonance (CMR), and electrocardiogram (ECG), for the severity of immune checkpoint inhibitors (ICIs)-associated myocarditis. Methods Data from a real-world cohort of 81 cancer patients who developed ICI-associated myocarditis after immunotherapy were retrospectively analyzed. Myocarditis of Common Terminology Criteria for Adverse Events (CTCAE) grades 3-5 and the development of the major adverse cardiovascular event (MACE) were set as endpoints. Logistic regression was used to evaluate each parameter’s value in predicting myocarditis of grades 3-5 and MACE. Results Eventually, CTCAE grades 3-5 and MACE developed in 43/81 (53.1%) and 28/81 (34.6) cases, respectively. The occurrence of CTCAE grades 3-5 (HR, 95%CI: 4.48, 2.02-9.91, p&amp;lt;0.001) and MACE (HR, 95%CI: 16.21, 6.93-37.94, p&amp;lt;0.001) were strongly related to patients’ overall survival from ICI-associated myocarditis to death. The likelihood of CTCAE grades 3-5 and MACE increased with the accumulation of organs affected by the ICI-associated adverse events and initial clinical symptoms. Concurrent systematic therapies during ICI treatment did not raise the risk of myocarditis severity, while prior chemotherapy did. Apart from the classical cardiac markers, such as myoglobin, brain natriuretic peptide, and troponin T, a higher neutrophil ratio was also related to poorer cardiac outcomes, whereas a higher lymphocyte and monocyte ratios were predictors of favorable cardiac outcomes. Besides, the CD4+ T cell ratio and CD4/CD8 ratio were negatively related to CTCAE grades 3-5. Several cardiovascular magnetic resonance parameters were associated with myocarditis severity. In contrast, the predictive value of echocardiography and electrocardiogram was weak. Conclusions This study comprehensively evaluated the prognostic value of different patients’ clinical factors and examination results and discovered several predictors of severe ICI-associated myocarditis, which will facilitate early detection of severe ICI-associated myocarditis in patients receiving immunotherapy.

Combined Photon and Carbon Ion Radiation Therapy for Sinonasal Malignancies: Results of the HIT–SNT Prospective Phase 2 Trial

Radiation treatment of sinonasal malignancies is a challenging task due to proximity to critical structures of the head and neck and skull base. Local tumor control is highly dose-dependent, but dose application is limited due to accompanying toxicity and dose constraints. To evaluate the toxicity and efficacy of combined radiation treatment with intensity-modulated radiation therapy (IMRT) and carbon ion boost, we conducted a prospective phase 2 IMRT-Heidelberg Ion-Beam Therapy Sinonasal Tumors (HIT-SNT) trial. Between 2011 and 2019, we treated 35 patients with histologically proven, incompletely resected or inoperable adeno- (51%) or squamous cell carcinoma (49%) of the paranasal sinuses with combined IMRT (50 Gy) and carbon ion boost (24 Gy relative biologic effectiveness) to a total dose of 74 Gy. Acute mucositis Common Terminology Criteria for Adverse Events (CTCAE) grade 3 occurred in 12% of patients (n = 4) and was accompanied by odynophagia CTCAE grade 3. Except for 1 case of grade 3 weight loss, no other acute high-grade toxicity (grade 3-4) was observed. In a small patient cohort of 15 patients eligible for long-term follow-up we have seen no high-grade (grade ≥3) long-term side effects 2 years after radiation therapy. None of these patients suffered from therapy-associated vision or hearing loss. Secondary endpoints were 2-year overall survival, 2-year local progression-free survival, 2-year progression-free survival, and 2-year metastases-free survival with 79.4%, 61.8%, 61.8%, and 64.8%, respectively. To our knowledge, this is the first prospective data on toxicity and outcome of bimodal radiation therapy for the rare entity of sinonasal malignancies. Our study shows a low rate of CTCAE-reported acute toxicity with reasonable tumor control and survival rates after bimodal radiation therapy, which therefore remains a therapy approach to be further evaluated.

THU513 Are Endocrinologists Using CTCAE Grading System For Endocrine Side Effects Of Cancer Treatment With Immune Checkpoint Inhibitors?

Abstract Disclosure: N. Arnouk: None. S. AbuOmar: None. A. Halik: None. A. Saif: None. P.R. Schroeder: None. Introduction: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of diverse types of cancer but can have serious endocrine system side effects. Common Terminology Criteria for Adverse Events (CTCAE) is a grading system for ICI side effects used by oncologists to aid in treatment decisions. We hypothesize that endocrinologists are not involved in managing immune-related adverse events (irAEs) and are not aware of the CTCAE grading system. Further, we hypothesize that endocrinologists in an academic setting are more likely to use CTCAE compared to endocrinologists in community setting. Methods: A retrospective review of 800 charts in our EMR from January 2018-July 2022 for patients seen in outpatient oncology and endocrinology clinics in our large Mid-Atlantic hospital system. Inclusion criteria were age ≥18 years; diagnosis of advanced melanoma, metastatic non-small cell cancer, head and neck squamous cell cancer, urothelial carcinoma, gastric adenocarcinoma, Hodgkin lymphoma, hepatocellular carcinoma, breast cancer, and renal cell carcinoma; and treatment with one or more ICIs. Patients with endocrinopathies due to chemotherapy or other classes of cancer treatment, no ICI treatment, or pre-existing endocrinopathies were excluded, thus 677 were analyzed.We also surveyed all endocrinologists practicing in our hospital network to determine whether they are involved in managing endocrinopathies associated with ICIs and whether they use the CTACE grading system. Results: Of the 677 reviewed 124 (18%) developed irAEs. In 74 (60%) of those cases, an endocrinologist was involved in management, 47 (70%) in community hospitals and 27 (47%) in academic centers. CTCAE was used in one case. Of 24 endocrinologists surveyed (14 practicing in academic centers and 10 practicing in community centers),12 (50%) responded, 3 (25%) at academic centers and 9 (75%) at community centers. Of the respondents, 9 (75%) said they sometimes are involved in managing irAEs due to ICIs, 11 (91%) had never used the CTCAE, 8 (67%) would participate in a multidisciplinary clinic to manage irAEs, and 6 (50%) preferred to see the patient in their regular clinic. Conclusion: In this study, 60% of the irAE cases resulting from ICI immunotherapy were managed by an oncologist and endocrinologist. CTCAE was used in only one case. More endocrinologists in the community were involved in management of these patients than those in academic centers. A majority of endocrinologists surveyed said they are sometimes consulted in these cases but only one had used CTCAE, thus CTCAE was not used more frequently in an academic versus community setting. More than half prefer to treat these patients in regular versus multidisciplinary clinics. More endocrinologists need to be aware of and use the CTCAE to foster a multidisciplinary team approach to treating endocrinopathies associated with ICIs. Presentation: Thursday, June 15, 2023

Cancer germline predisposing variants and late mortality from subsequent malignant neoplasms among long-term childhood cancer survivors: a report from the St Jude Lifetime Cohort and the Childhood Cancer Survivor Study

Carriers of cancer predisposing variants are at an increased risk of developing subsequent malignant neoplasms among those who have survived childhood cancer. We aimed to investigate whether cancer predisposing variants contribute to the risk of subsequent malignant neoplasm-related late mortality (5 years or more after diagnosis). In this analysis, data were included from two retrospective cohort studies, St Jude Lifetime Cohort (SJLIFE) and the Childhood Cancer Survivor Study (CCSS), with prospective follow-up of patients who were alive for at least 5 years after diagnosis with childhood cancer (ie, long-term childhood cancer survivors) with corresponding germline whole genome or whole exome sequencing data. Cancer predisposing variants affecting 60 genes associated with well-established autosomal-dominant cancer-predisposition syndromes were characterised. Subsequent malignant neoplasms were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 with modifications. Cause-specific late mortality was based on linkage with the US National Death Index and systematic cohort follow up. Fine-Gray subdistribution hazard models were used to estimate subsequent malignant neoplasm-related late mortality starting from the first biospecimen collection, treating non-subsequent malignant neoplasm-related deaths as a competing risk, adjusting for genetic ancestry, sex, age at diagnosis, and cancer treatment exposures. SJLIFE (NCT00760656) and CCSS (NCT01120353) are registered with ClinicalTrials.gov. 12 469 (6172 male and 6297 female) participants were included, 4402 from the SJLIFE cohort (median follow-up time since collection of the first biospecimen 7·4 years [IQR 3·1-9·4]) and 8067 from the CCSS cohort (median follow-up time since collection of the first biospecimen 12·6 years [2·2-16·6]). 641 (5·1%) of 12 469 participants carried cancer predisposing variants (294 [6·7%] in the SJLIFE cohort and 347 [4·3%] in the CCSS cohort), which were significantly associated with an increased severity of subsequent malignant neoplasms (CTCAE grade ≥4 vs grade <4: odds ratio 2·15, 95% CI 1·18-4·19, p=0·0085). 263 (2·1%) subsequent malignant neoplasm-related deaths (44 [1·0%] in the SJLIFE cohort; and 219 [2·7%] in the CCSS cohort) and 426 (3·4%) other-cause deaths (103 [2·3%] in SJLIFE; and 323 [4·0%] in CCSS) occurred. Cumulative subsequent malignant neoplasm-related mortality at 10 years after the first biospecimen collection in carriers of cancer predisposing variants was 3·7% (95% CI 1·2-8·5) in SJLIFE and 6·9% (4·1-10·7) in CCSS versus 1·5% (1·0-2·1) in SJLIFE and 2·1% (1·7-2·5) in CCSS in non-carriers. Carrying a cancer predisposing variant was associated with an increased risk of subsequent malignant neoplasm-related mortality (SJLIFE: subdistribution hazard ratio 3·40 [95% CI 1·37-8·43]; p=0·0082; CCSS: 3·58 [2·27-5·63]; p<0·0001). Identifying participants at increased risk of subsequent malignant neoplasms via genetic counselling and clinical genetic testing for cancer predisposing variants and implementing early personalised cancer surveillance and prevention strategies might reduce the substantial subsequent malignant neoplasm-related mortality burden. American Lebanese Syrian Associated Charities and US National Institutes of Health.

Frameless Fractionated Linear Accelerator-Based Stereotactic Radiotherapy for Brain Metastases: Results of a Single-Arm Phase II Multi-Institutional Clinical Trial

Stereotactic radiotherapy (SRT) yields high rates of local control for brain metastases while minimizing neurocognitive side effects. While advanced SRT platforms are widely available in urban centers, rural/suburban patients face geographic and socioeconomic barriers to access SRS. For this reason, we conducted a multi-institutional Phase 2 clinical trial to test the safety and efficacy of 3-5 fraction frameless fractionated stereotactic radiotherapy (FFSRT) for brain metastases in an integrated academic satellite network MATERIALS/METHODS: This IRB-approved Phase 2 trial was conducted for patients ≥18-years-old with 1-4 brain metastases. Brain metastases involving the optic pathway or brainstem were excluded. Gross tumor volume (GTV) was delineated with a volumetric brain MRI and planning target volume (PTV) was GTV + 2 mm margin. Radiation dose was based on GTV size: < 3.0 cm, 27 Gy in 3 fractions, and 3.0-3.9 cm, 30 Gy in 5 fractions. Toxicity was evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version 4. Of 76 evaluable patients, the median age was 67 years, 56.6% were female, 82.9% were white/Caucasian and 89.6% had an Eastern Cooperative Oncology Group performance status ≤ 2. Most brain metastases were from lung cancer (51.3%) and breast cancer (15.7%). With median follow-up of 10 months, local control was 93%, median survival was 1.8 years (95% confidence interval (CI): 1.5-2.4 years), 1-year OS was 73.8% (95% CI: 0.59-0.84), and 2-year OS was 31% (95% CI: 0.12-0.52). There were no CTCAE Grade ≥ 3 protocol-related adverse events. Outcomes of this trial compare favorably with contemporary SRT trials for brain metastases. FFSRT may provide opportunities to expand SRS access for underserved populations across the MDACC enterprise and in future clinical trials for brain metastases.

Real-World Complications of the SpaceOAR Hydrogel Spacer: A Review of the Manufacturer and User Facility Device Experience Database

To characterize adverse events related to use of the perirectal spacing agent SpaceOAR, we examined the Manufacturer and User Facility Device Experience (MAUDE) database. The MAUDE database was queried for "SpaceOAR" and "Augmenix" from June 2015 (when SpaceOAR was approved by the Food and Drug Administration) to October 2022. Reports were reviewed for adverse events (AEs), operative procedures performed because of the AE, and changes to the radiation plan. AEs were categorized using Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Six hundred fifty-four reports were reviewed. Eighty-four were excluded and 4 reports reviewed 2 separate cases of SpaceOAR administration. Five hundred seventy-four cases were ultimately included. Three deaths were reported (0.5% of all AEs). One point six percent of cases represented CTCAE grade 4 injuries (life-threatening consequences; urgent intervention indicated), 15.9% grade 3 (severe but not immediately life-threatening; hospitalization), 24.2% grade 2 (moderate; local/noninvasive intervention), and 57% of events were CTCAE grade 1 (mild; asymptomatic or mild symptoms). Bowel diversion occurred in 29 cases (9%). Both asymptomatic (n=311) and debilitating (n=12) complications of SpaceOAR hydrogel use were identified. Death, gel embolization, anaphylaxis, rectal ulcerations, and infections requiring bowel or urinary diversions were among the complications reviewed. Providers should consider these potential complications before perirectal spacer administration and during patient counseling.

Impact of reduced margin pelvic radiotherapy on gastrointestinal toxicity and outcome in gynecological cancer

PurposeTo investigate the effect of reduced margin pelvic radiotherapy on gastrointestinal toxicity and outcomes in gynecological cancer. Materials and methodsThis retrospective study analyzed data of 590 patients who underwent hysterectomy and adjuvant pelvic radiotherapy between 2010 and 2020 at two tertiary centers. The pelvic nodal region was delineated based on a reduced margin definition or the Radiation Therapy Oncology Group (RTOG) guidelines. All patients were treated with intensity-modulated radiotherapy with imaging guidance. Gastrointestinal toxicity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) and the Patient-Reported Outcome version (PRO-CTCAE). ResultsOverall, 352 (59.7%) and 238 (40.3%) patients underwent RTOG and reduced margin pelvic radiotherapy, respectively. Median follow-up was 6.4 years (IQR: 3.7–9.6). Reduced margin pelvic radiotherapy significantly lowered the radiation dose to the small bowel. For CTCAE grade ≥ 2 or 3, acute gastrointestinal toxicity was lower in the reduced margin group than in the RTOG group (16.4% vs. 33.5%, p < 0.001; 2.9% vs. 8.5%, p < 0.001). The reduced margin group reported less severe acute gastrointestinal toxicity (PRO-CTCAE score ≥ 3) than the RTOG group (12.5% vs. 28.7%, p < 0.001). Late grade 3 gastrointestinal toxicity was lower in the reduced margin group than in the RTOG group (0.8% vs. 4.8%, p = 0.006). The 5-year pelvic recurrence-free survival and disease-free survival in the RTOG and reduced margin pelvic radiotherapy groups were 97.4% and 97.9% (p = 0.55) and 80.7% and 83.5% (p = 0.18), respectively. ConclusionReduced margin pelvic radiotherapy decreased acute and late gastrointestinal toxicity and achieved favorable outcomes.

Incidence of blast phase in myelofibrosis according to anemia severity.

Myelofibrosis (MF) is a clonal malignancy frequently characterized by anemia and in 10%-20% of cases it can evolve into blast phase (BP). Anemia in MF is associated with reduced survival and -in primary MF- also with an increased probability of BP. Conventional treatments for anemia have limited effectiveness in MF. Within a dataset of 1752 MF subjects largely unexposed to ruxolitinib (RUX), BP incidence was 2.5% patients per year (p-y). This rate reached respectively 4.3% and 4.5% p-y in case of patients with common terminology criteria for adverse events (CTCAE) grade 3/4 and grade 2 anemia, respectively, that represented together 32% of the cohort. Among 273 MF cases treated with RUX, BP incidence was 2.89% p-y and it reached 4.86% p-y in subjects who started RUX with CTCAE grade 2 anemia (one third of total). Within patients with red blood cell transfusion-dependency at 6 months of RUX (21% of the exposed), BP rate was 4.2% p-y. Our study highlights a relevant incidence of BP in anemic MF patients, with a similar rate whether treated with or without RUX. These findings will help treating physicians to make decisions on the safety profile of innovative anemia treatments.

Intravascular Ultrasound Guidance for Transjugular Intrahepatic Portosystemic Shunt Creation Reduces Laboratory Markers of Acute Liver Injury

PurposeTo compare the laboratory markers of acute liver injury after transjugular intrahepatic portosystemic shunt (TIPS) creation performed using intravascular ultrasound (IVUS) guidance with those using other techniques. Materials and MethodsThis single-center, retrospective study examined 293 TIPS procedures performed between 2014 and 2022 (160 men; mean age, 57.4 years; 71.7% with ascites, 158 with IVUS). Laboratory changes on postprocedural day (PPD) 1 were classified based on Common Terminology Criteria for Adverse Events (CTCAE) grades and were compared between IVUS and non-IVUS cases. ResultsIVUS cases had a lower baseline Model for End-Stage Liver Disease (MELD) score (12.5 vs 13.7, P = .016), higher pre- (16.8 vs 15.2, P = .009), and post-TIPS (6.6 vs 5.4 mm Hg, P < .001) pressure gradient, smaller stent diameter (9.2 vs 9.9 mm, P < .001), and fewer needle passes (2.4 vs 4.2, P < .001). IVUS predicted a lower PPD 1 CTCAE grade for aspartate transaminase (8.0% vs 22.2% grade ≥ 2, P = .010), alanine transaminase (ALT) (2.2% vs 7.1%, P = .017), and bilirubin (9.4% vs 26.2%, P < .001), findings confirmed using multivariable regression and propensity score analysis. IVUS predicted fewer adverse events (1.3% vs 8.1%, P = .008) and an increased likelihood of PPD 1 discharge (81% vs 59%, P = .004). IVUS was not associated with differences in PPD 30 MELD scores or 30-day survival; however, higher PPD 1 ALT (β = 1.96, P = .008) and bilirubin levels (β = 1.38, P = .004) predicted larger PPD 30 MELD score increase. Higher increases in ALT level predicted worse 30-day survival (hazard ratio, 1.93; P = .021). ConclusionIVUS resulted in less laboratory evidence of acute liver injury immediately following TIPS creation.

A meta-analysis studying the utility of cryotherapy in the prevention of peripheral neuropathy in breast cancer patients receiving paclitaxel and nab-paclitaxel.

12025 Background: Debilitating Peripheral Neuropathy (PN) caused by paclitaxel adversely impacts the quality of life in Breast Cancer (BC) patients. Cryotherapy using cooling devices during taxane infusion is a non-invasive strategy to prevent PN, but its efficacy has not been established. We hope to answer this question through our meta-analysis. Methods: A systematic search with keywords and controlled vocabulary encompassing BC, antineoplastics, and paclitaxel was conducted in PubMed, CINHAL, Embase, Scopus, Web of Science Collections, and CENTRAL. All databases were searched on March 7, 2022. There were no search restrictions on date, language, status, or outcomes. 405 records were identified, and duplicates were removed using EndNote 20. The remaining 372 records were imported into Covidence, and the titles and abstracts were screened independently by 2 reviewers. 22 out of 63 full texts were relevant to our question of which 14 [12 Randomized control studies and 2 retrospective studies] were included for the meta-analysis using R package meta. Only studies that analyzed cryotherapy use in BC patients who received paclitaxel or nab-paclitaxel were included. Relative risk (RR) derived from random effects model with Mantel-Haenszel method was used to compare the occurrence of PN between cryotherapy vs placebo groups. Results: Pooled incidence of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 2 PN was 24.85% (81/326) in the cryotherapy arm and 42.35% (72/170) in the placebo arm. Overall RR for CTCAE grade ≥ 2 PN with cryotherapy compared to placebo was 0.45 [0.27,0.77, p = 0.0031]. RR for sensory PN was 0.19 [0.05,0.66, p = 0.009] and for motor PN was 0.18 [0.03,0.99, p = 0.0491]. RR for Patient Neurotoxicity Questionnaire (PNQ) score ≥ D which connotes severe neuropathy was 0.24 [0.09,0.62, p = 0.0035]. Cold intolerance was the predominant adverse effect at 15% (37/247). Fingernail paronychia and skin irritation were reported at 0.8% (2/247) each. 5.1% (15/294) stopped cryotherapy use prior to completion. However, this number was driven by a single study (10/16 patients stopped using cryotherapy due to cold intolerance) and 7/11 studies had no discontinuations. Visual inspection of our funnel plots revealed no publication bias. Conclusions: Use of cryotherapy decreased the occurrence of CTCAE grade ≥ 2 PN by 55% in BC patients getting paclitaxel or nab-paclitaxel. Occurrence of both sensory and motor PN were lower. Cold intolerance was the most frequently reported issue with its use but lead to relatively low discontinuation rates in most studies. Given the lack of any severe adverse effect, cryotherapy use must be encouraged for patients receiving paclitaxel and nab-paclitaxel. Further studies are needed establish a standardized way of applying cryotherapy in terms of the device to use, timing and other logistical factors.