Gastrointestinal Toxicity Research Articles

Impact of Rectal Spacer on Toxicity Reduction in Men Treated With Proton Versus Photon Therapy

PurposeRectal toxicity after prostate cancer (PCa) radiation therapy (RT) may be greater with protons compared with photon intensity-modulated RT, perhaps due to lateral penumbra and end-of-range uncertainty. Rectal spacers (RSs) have been shown to mitigate RT-associated acute/late rectal toxicity in men treated with photons. The relative benefit of RS in men treated with protons versus photons is unknown. We hypothesize that RS will confer greater bowel toxicity benefits in PCa treated with protons versus photons. Materials and MethodsWe conducted a single institution, retrospective review of men receiving photon intensity-modulated RT or pencil-beam scanning proton RT for localized PCa. Four cohorts were compared: photon with or without RS, and proton with or without RS. Acute (<3 months), late (≥3 months), and most recent toxicity were compared among the 4 cohorts. The cumulative incidence of physician-reported grade 1 to 2 gastrointestinal (GI) toxicity (common terminology criteria for adverse events V5.0) was compared using χ2 or Fisher exact test. Patient-reported toxicity was evaluated using the International Prostate Expanded Prostate Composite Index-Clinical Practice and compared using linear mixed modeling. ResultsIn total, 164 patients were eligible for analysis: 38 photons without RS, 50 photons with RS, 26 protons without RS, and 50 protons with RS. The median follow-up was 17.6 months. In proton patients, acute (6.12% vs 30.77%, P = .009) and most recent (4.26% vs 26.09%, P = .01) G1-2 GI toxicity was lower with versus without RS. In photon patients, there were no significant differences in toxicity with versus without RS. No significant differences in patient-reported outcomes were observed with versus without RS in photon or proton groups. ConclusionThe rectal spacer was associated with lower G1-2 acute and most recent GI toxicity in men treated with protons; this difference was not observed in men treated with photons. While this study is limited by sample size, a relatively greater benefit of RS with proton versus photon therapy was observed.

Concurrent Use of Abemaciclib and Radiotherapy in Metastatic Breast Cancer Patients: A Single-Center Experience.

There is little evidence regarding the safety and efficacy of the combination of abemaciclib plus radiotherapy (RT). The majority of studies investigated the combination of RT with palbociclib or ribociclib reporting that hematological toxicity is common. Given the unique toxicity profile of abemaciclib with greater gastrointestinal toxicity compared to hematological toxicity, we wanted to evaluate the toxicity of the combination with RT in metastatic breast cancer (BC) patients. Patients with histologically proven metastatic or locally advanced BC treated with RT and concurrent abemaciclib were selected. Toxicity was assessed according to the NCI-CTCAE V4.0. Thirty-two metastatic sites were treated in 19 patients and analyzed. All patients received abemaciclib during the RT course. A total of 68% of patients received a full dose of abemaciclib during RT. Also, 71.9% of patients received a palliative intent (median dose = 30 Gy, range = 8-30 Gy), and 26.3% were treated for 9 oligo-metastatic or oligo-progressive sites of disease with stereotactic body RT (median dose = 30 Gy, range 21-30 Gy, given in 3-5 fractions). Overall, the rate of G3 toxicity was 15.7%. The rate of G3 hematological toxicity was 10.6% (2/19 patients, one G3 neutropenia and one G3 anemia). No patient presented diarrhea, including those treated for RT sites close to the bowel. One patient developed G3 skin toxicity. Pain significantly improved after RT (mean value NRS pre-RT = 3.9, SD = 3.07; mean value NRS after RT = 0.9, SD = 0.46; p &lt; 0.0001). Abemaciclib and concomitant RT seem well tolerated showing acceptable toxicity.

Gut microbiota biotransformation of drug glucuronides leading to gastrointestinal toxicity: Therapeutic potential of bacterial β-glucuronidase inhibition in mycophenolate-induced enteropathy

AimsDrug-induced enteropathy is often associated with the therapeutic use of certain glucuronidated drugs. One such drug is mycophenolic acid (MPA), a well-established immunosuppressant of which gastrointestinal adverse effects are a major concern. The role of bacterial β-glucuronidase (β-G) from the gut microbiota in MPA-induced enteropathy has recently been discovered. Bacterial β-G hydrolyzes MPAG, the glucuronide metabolite of MPA excreted in the bile, leading to the digestive accumulation of MPA that would favor in turn these adverse events. We therefore hypothesized that taming bacterial β-G activity might reduce MPA digestive exposure and prevent its toxicity. Main methodsBy using a multiscale approach, we evaluated the effect of increasing concentrations of MPA on intestinal epithelial cells (Caco-2 cell line) viability, proliferation, and migration. Then, we investigated the inhibitory properties of amoxapine, a previously described bacterial β-G inhibitor, by using molecular dynamics simulations, and evaluated its efficiency in blocking MPAG hydrolysis in an Escherichia coli-based β-G activity assay. The pharmacological effect of amoxapine was evaluated in a mouse model. Key findingsWe observed that MPA impairs intestinal epithelial cell homeostasis. Amoxapine efficiently blocks the hydrolysis of MPAG to MPA and significantly reduces digestive exposure to MPA in mice. As a result, administration of amoxapine in MPA-treated mice significantly attenuated gastrointestinal lesions. SignificanceCollectively, these results suggest that the digestive accumulation of MPA is involved in the pathophysiology of MPA-gastrointestinal adverse effects. This study provides a proof-of-concept of the therapeutic potential of bacterial β-G inhibitors in glucuronidated drug-induced enteropathy.

Severe morel mushroom poisonings in France – a nationwide French poison centres study 2010–2020

Introduction In 2023, two fatalities attributed to the ingestion of uncooked morels (Morchella spp.) were reported in the United States; both patients developed severe gastrointestinal symptoms. Morel-induced gastrointestinal toxicity is well recognized, but no deaths had been reported until 2023, suggesting a potential shift in the severity of morel poisoning. Methods Using the Poisoning Severity Score, we analyzed the severity of symptomatic cases of morel ingestion recorded in the French National Database of Poisonings from 2010 to 2020. Results We found 446 cases of exposure in which morels were the sole mushroom species involved. Of these, 83.6 per cent and 53.3 per cent developed gastrointestinal and neurological symptoms, respectively. Eight patients developed shock attributed to severe gastrointestinal symptoms, resulting in two deaths. Discussion Morel ingestion can lead to severe complications. As in the United States, the deaths reported in this study were attributed to imported cultivated morels. The shift, since 2006, towards a predominance of cultivated over wild morel sales may have played a role in the reporting of severe cases of morel poisoning. Conclusions Reports of severe morel poisoning highlight the need for cautious consumption, particularly of raw or undercooked preparations. Emerging complications signal potential changes in toxicity. Surveillance and awareness are key to reducing the risks of consuming morels.

Analysis of the fecal metagenome in pelvic radiation survivors with or without chronic gastrointestinal toxicity.

e24041 Background: Whole pelvis radiation therapy (WPRT) is often used as a definitive or adjuvant treatment in patients with genitourinary, gynecologic, and gastrointestinal (GI) malignancies. Irradiation of nearby bowel can cause acute and chronic GI symptoms, which can affect patients’ quality of life. Radiation therapy has been shown to alter the microbial flora and may select for pathogenic species, which may enhance toxicity. Characteristics of the fecal metagenome in patients with or without chronic GI toxicity is unknown. Severity of GI symptoms can vary between patients who receive a similar radiation dose to normal bowel; therefore, there is a critical need to evaluate the interaction of RT and microbial species in the development of toxicity. Methods: An institutional database was used to identify survivors that completed WPRT for prostate, gynecologic, and anal cancer within the last 5 years. Patients were excluded if they had evidence of recurrent disease requiring additional therapy. Eligible patients were asked to participate via telephone. Consenting patients provided a stool sample and completed a customized PRO-CTCAE form (scale 1-5) assessing chronic GI symptoms. Comprehensive shotgun metagenomics were performed on stool. Stool was sequenced using an Illumina NextSeq500. The fecal metagenome in patients with or without chronic GI symptoms were compared. Patients were dichotomized by PRO-CTCAE diarrhea score (0-1 [mild] vs ≥2 [moderate-severe]). Raw reads were processed with Kneaddata for trimming, Kracken2 for taxonomic profiling, and Bracken for abundance estimation for bacterial, fungal and viral genomes using sequences from the National Center for Bioinformatics to determine quantitative genus and species differences. For microbial diversity assessments, estimated inverse Simpson and Shannon indices were performed. Results: Fecal metagenome and PRO-CTCAE results were available for 13 survivors. Thirty percent (n = 4) of patients reported moderate to severe diarrhea. The mean age was 66 years, 38% were male, 46% received concurrent or adjuvant chemotherapy, and the mean time from completion of WPRT to stool analysis was 34 months (range 14-62 months). Conventional radiation bowel constraints were met for each patient. Several species were enriched in patients with mild GI toxicity. Notably, Akkermansia muciniphilia had the largest differential enrichment in patients with without chronic GI toxicity. Conclusions: In this cohort of patients, A. muciniphilia, a mucin-degrading bacteria that modulates the gut barrier integrity and mucin layer thickness, was enriched in patients with no to mild diarrhea compared to patients with moderate to severe diarrhea. A. muciniphilia supplementation has been shown to decrease systemic inflammation in Western diet-fed mice. Evaluation of A. muciniphilia as a radioprotective gut bacterium warrants further evaluation.

Patterns and risk factors of immune-related adverse events in a real-world cohort with lung cancer receiving immunotherapy.

12130 Background: Immune checkpoint inhibitors (ICIs) have emerged as a core pillar of lung cancer (LC) therapy, but ICIs are commonly associated with a spectrum of immune-related adverse effects (irAEs). The real-world patterns and risk factors of irAEs in LC remain uncertain. Methods: Patients with LC newly started on ICIs between 10/01/2018 and 09/30/2021 were retrospectively collected from the Tufts Medical Center cancer registry and pharmacy records. irAEs occurring within 12 months after initiation of ICIs were identified. Univariable logistic regression was used to assess the risk factors of irAEs. Those with p-value&lt;0.20 were included in multivariable logistic regression analysis (MVA), along with clinically relevant factors. Results: Of 125 LC adult patients (median age: 70 years, 68 males), 104 had non-small cell lung cancer (NSCLC), 123 had advanced stages, and 16 had preexisting autoimmune diseases (ADs). Six patients were treated with dual-agent ICIs. Pembrolizumab was the most often used single agent (67.2%). In total 50 irAEs occurred in 39 patients. The most common irAEs were endocrinopathies (34%), pneumonitis (20%), dermatitis (14%), and gastrointestinal toxicity (14%) with the median onset time of 148, 136, 19, and 68 days, respectively. 70% of irAEs were grade 1 or 2. 44% of irAEs were treated with immunosuppression, 38% were referred to specialist care, and 30% required hospitalizations. 56% of irAEs resolved within 12 months and 67.9 % of those were rechallenged with ICIs. In exploratory univariable analyses among all the patients, age, small cell lung cancer (SCLC), PDL1 positivity (TPS≥1%), concurrent NSAIDs use, and radiation therapy had p&lt; 0.2. In MVA, SCLC remained significantly associated with irAEs (OR=4.14, 95% CI [1.50, 12.09], p=0.007). Among NSCLC subset (N=104), age, PDL1 positivity, concurrent NSAIDs, and acetaminophen use had p&lt;0.2. Age (OR=0.94, 95% CI [0.883, 0.990], p=0.026) and PDL1 positivity (OR=3.17, 95% CI [1.12, 9.87], p=0.036) remained significant in MVA (Table). Conclusions: Our study described the real-world patterns of irAEs in LC patients. SCLC was found to be an independent risk factor of irAEs in our cohort. In NSCLC, younger age and PDL1 positivity were associated with irAEs occurrence. Future studies are required to validate these findings in larger samples. [Table: see text]

FLAG-IDA + venetoclax in newly diagnosed (ND) or relapsed/refractory (RR) AML.

6519 Background: We report the outcomes of a phase 2 study of FLAG-IDA+VEN in AML. Methods: Pts ≥18 with ND or RR AML / MDS-EB2 fit for intensive chemotherapy were eligible. Induction comprised fludarabine 30mg/m2 D2–6, cytarabine 1.5g/m2 D2–6, idarubicin 8 (6 if RR) mg/m2 D4–6 &amp; filgrastim 5mcg/kg D1–7. VEN 400mg was administered D1–14 with CYP3A inhibitor dose adjustment until Jul 2023; following a protocol modification, VEN is now administered D1–7. The primary outcome was ORR (CR + CRh + CRi + MLFS + PR). Secondary outcomes were CRc (CR + CRh + CRi), overall survival (OS), event-free survival (EFS) &amp; duration of response (DOR). Measurable residual disease (MRD) was assessed by flow cytometry. Results: As of Jan 2024, 134 pts have enrolled, 127 (68 ND &amp; 59 RR) evaluable at data cut. Median age was 45 (18 – 73); 19 (15%) age ≥60. 13 (19%), 22 (32%) &amp; 33 (49%) ND pts were ELN22 favorable, intermediate &amp; adverse respectively. There were 7 (10%) secondary (s), including 4 hypomethylating agent failure, &amp; 7 (10%) therapy-related (t) AML. In RR pts, 40 (68%) were in salvage 1 (S1), of whom 32 (54%) were TP53WT. 20 (34%) had prior stem cell transplant (SCT). Median of 2 cycles were given. In ND pts, ORR was 99%, (96% CRc, of whom 89% MRD negative [Table]). Similar responses were seen across ELN groups &amp; s/tAML. At median follow-up (mFU) of 30 months (mo), the mOS, mEFS &amp; mDOR were not reached. The 2yr OS, EFS &amp; DOR were 75% (64 – 88), 68% (56 – 81) &amp; 71% (59 – 85) respectively, with no differences among ELN groups. 57% went to SCT in CR1. 4/4 pts with TP53mut became CRc MRD–, but mDOR was only 8.2 mo (95% CI, 2.2 – NE), resulting in poor mOS (13.5 mo, 95% CI, 8.6 – NE). In RR pts, ORR was 70% (66% CRc, of whom 79% MRD negative [Table]). At mFU 27 mo, the mOS, mEFS &amp; mDOR were 12 (7 – 33), 7 (4 – 23) &amp; 21 (8 – NE) mo respectively. The 2yr OS, EFS &amp; DOR were 40% (28 – 55), 34% (23 – 49) &amp; 49% (35 – 68) respectively. 58% went to SCT. S1+ TP53WT pts had mOS of 34 mo (12 – NE), with 72% going to SCT. 30d &amp; 60d mortality were 0% &amp; 3%. Of the 4 deaths within 60d, 1 was sepsis-related in CR in a ND pt while 3 were disease-related in NR RR pts. The most frequent adverse event was infection. Grade ≥3 infections, gastrointestinal toxicities &amp; bleeding occurred in 102 (80%), 20 (16%) &amp; 9 (7%) pts respectively. The median time to neutrophil &gt;1x109/L &amp; platelet &gt;50x109/L were 27d &amp; 28d for C1, 39d &amp; 67d for C2 &amp; 35d &amp; 50d for C3 respectively. Conclusions: FLAG-IDA+VEN results in high MRD negative response rates, leading to impressive survival outcomes across ELN risk groups in ND AML. It is an effective salvage regimen for RR AML, especially for S1+ TP53WT pts. Clinical trial information: NCT03214562 . [Table: see text]

Real world data of safety of immune-checkpoint inhibitors in patient with cancer at tertiary care hospital in Saudi Arabia.

e24104 Background: Immune checkpoint inhibitors (ICIs) become an integral part of many cancer therapies, such as melanoma, esophageal carcinoma, breast cancer and other malignancies. Immune checkpoint inhibitors work by activation the immune system that blocks negative regulators expressed on immune or tumor cells. Accordingly, the mechanism of action of ICI may cause autoimmunity-like symptoms called immune-related adverse events (irAEs) that affect many organs in body like skin, liver, lung, endocrine and gastrointestinal tract. These irAEs may reduce the organ function, quality of life and it may cause death. The present work addressed the knowledge gap in understanding real-world outcomes of irAEs associated with ICIs. Real-world patients are more diverse than clinical trial. Methods: This retrospective cohort study investigated the use of immune checkpoint inhibitor (ICI) therapy in an oncology and hematology patients treated at King Fahad Medical City (KFMC) comprehensive cancer center between February 2021 and February 2023. Adult patients (≥ 18 years old) diagnosed with any malignancy or hematological disorder who received at least one dose of ICI therapy during the study period have been included. Patients younger than 18 years old have been excluded. Demographic, clinical, and treatment data have been extracted from the electronic medical records (EMR). The study protocol has been reviewed and approved by the KFMC Institutional Review Board (IRB). The trial still undergoing not yet finished. Results: A total of 44 patients were included by the time preliminary data analysis was conducted on January 1st, 2024. All Patient included were receiving Pembrolizumab 44 patients. In regards to demographics, 27 (61.4%) of the patients were female. Breast cancer was the most common diagnosis (34.1%), followed by non-small cell lung cancer (22.7%). Among patients undergoing ICI, 34.1% had at least one Emergency Room (ER) visit. Notably, 25% of these patients had 1-2 ER visits. The most common reason for ER visits was patient complaints of GI toxicity related to ICI, including nausea, vomiting, and diarrhea (colitis). 12 (26.8%) patients required hospitalization, and 9 (20.5%) stayed for more than seven days.The time to first adverse event of ICI therapy was most commonly seen after nine weeks in 8 (18.2%) patients. Hypothyroidism was the most common adverse event (11.4%), followed by gastrointestinal toxicity (6.8%). Skin, grade 2 hepatotoxicity, and renal toxicity were also reported in 1 (2.3%) patient respectively. Conclusions: Overall, this initial analysis suggests that while ICI known to offers promising potential, it also carries the risk of various adverse events, including a significant rate of ER visits and hospitalizations. Further investigation with larger patient cohorts is warranted to confirm these findings and optimize IO therapy management.

Cannabidiol mitigates radiation-induced intestine ferroptosis via facilitating the heterodimerization of RUNX3 with CBFβ thereby promoting transactivation of GPX4

Radiation enteritis remains a major challenge for radiotherapy against abdominal and pelvic malignancies. Nevertheless, there is no approved effective therapy to alleviate irradiation (IR)-induced gastrointestinal (GI) toxicity. In the current study, Cannabidiol (CBD) was found to mitigate intestinal injury by GPX4-mediated ferroptosis resistance upon IR exposure. RNA-sequencing was employed to investigate the underlying mechanism involved in the radio-protective effect of CBD, wherein runt-related transcription factor 3 (RUNX3) and its target genes were changed significantly. Further experiment showed that the transactivation of GPX4 triggered by the direct binding of RUNX3 to its promoter region, or by stimulating the transcriptional activity of NF-κB via RUNX3-mediated LILRB3 upregulation was critical for the anti-ferroptotic effect of CBD upon IR injury. Specially, CBD was demonstrated to be a molecular glue skeleton facilitating the heterodimerization of RUNX3 with its transcriptional chaperone core-biding factor β (CBFβ) thereby promoting their nuclear localization and the subsequent transactivation of GPX4 and LILRB3. In short, our study provides an alternative strategy to counteract IR-induced enteritis during the radiotherapy on abdominal/pelvic neoplasms.

Beacon: A phase II study of bevacizumab, atezolizumab, and cobimetinib in patients with recurrent, platinum resistant, high grade serous ovarian cancer.

5565 Background: Platinum resistant high grade serous ovarian cancer (HGSC) is associated with a poor prognosis and limited treatment options. Immune checkpoint inhibitors have failed to show significant impact in treatment of HGSC to date. Bevacizumab (anti-VEGF) and atezolizumab (anti-PDL1) have shown synergy in multiple cancer types. Cobimetinib (MEK inhibitor) may also potentiate immune responses, particularly by altering the tumour microenvironment. We sought to evaluate the efficacy of cobimetinib, bevacizumab and atezolizumab in women with platinum resistant HGSC. Methods: BEACON is a Phase II single arm study of cobimetinib (60mg oral D1-21 q 28-days), bevacizumab (5mg/kg IV q2w) and atezolizumab (840mg IV q2w from Cycle 2) in patients with platinum-resistant recurrent HGSC. Patients continued therapy until progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) according to RECIST 1.1 at 24 weeks. Secondary endpoints included best overall response (BOR), safety, progression free survival, and response duration. Correlative studies on paired tumor biopsy and blood samples will explore molecular characteristics/subtypes and potential biomarkers of response as exploratory objectives. This study has now completed accrual and we present the 24-week response data, with a data cut off 21st December 2023. Results: Twenty-nine patients were enrolled between September 2018 and June 2023. Median age was 62 years (range 37 - 79) and 97% had received ≥ 2 prior lines of chemotherapy. The median number of cycles received was 3 cycles of atezolizumab and cobimetinib, and 4 cycles of bevacizumab. The ORR at 24 weeks was 21% [95% CI: 8-40], and a further 28% had stable disease as assessed per RECIST. Five patients (17%) have remained on study treatment for ≥ 52 weeks to date, suggesting that in some patients there was durable disease control. In terms of safety, 22 patients (76%) required a dose reduction in cobimetinib, mainly due to gastrointestinal and skin toxicity. Seventeen patients (59%) experienced a ≥Grade 3 treatment related adverse event, most commonly hypertension (6 patients, 21%). Two patients (7%) discontinued all study treatments due to toxicity. Conclusions: Preliminary results from this study show promising efficacy with the combination of atezolizumab, bevacizumab and cobimetinib in platinum resistant HGSC. Duration of response, progression free survival data and translational data exploring molecular characteristics will be presented as data matures. Clinical trial information: NCT03363867 . [Table: see text]

Correlations between first cycle toxicity and overall survival in patients with rare cancers treated with immune checkpoint inhibitors (NCI/SWOG S1609).

2655 Background: Associations between immune-related adverse events (irAEs) from checkpoint inhibitor therapy and outcomes have been previously evaluated, with most prior research finding a positive association between toxicity incidence and overall survival. This prior research has generally reported on more common tumor types. We use a unique data resource of a federally funded basket trial (NCT02834013) for patients with rare cancers to evaluate associations between irAEs and overall survival (OS) and progression-free survival (PFS) in a cohort of patients treated with combination checkpoint inhibitor therapy. Methods: We evaluated irAEs observed in the first cycle (6 weeks) of therapy that were possibly, probably, or definitely related to treatment; irAE grade was based on CTCAEv5. Patients received ipilimumab [1mg/kg intravenously (IV) every 6 weeks] plus nivolumab (240mg IV every 2 weeks). Landmarks methods were used to avoid immortal-time bias; PFS and OS were analyzed from day 43 with patients who died or progressed before that date excluded from analyses. Cox regression analyses were used to evaluate covariate associations. Results: We found that grade 1-2 treatment-related irAEs in the first cycle of therapy were associated with longer OS (multivariable hazard ratio, 95% confidence interval, p-value: 0.61, 0.49-0.75, p&lt;0.001) compared to no treatment-related irAE in the first cycle, while grade 3-4 irAEs were associated with shorter OS (HR=1.41, 95% CI=1.04-1.90, p=0.025). Similar, but weaker, associations were observed with PFS, grade 1-2 treatment-related irAEs: HR=0.83, 95% CI=0.67-1.01, p=0.067 and grade 3-4: HR=1.35, 95% CI=1.02-1.78, p=0.037 compared to no treatment-related irAE in the first cycle. Grade 1-2 dermatologic toxicity were associated with improved OS compared to other grade 1-2 toxicities (HR=0.67, 95% CI=0.52-0.85, p=0.002). There were no significant differences between OS among patients with Grade 1-2 gastrointestinal, metabolic, hepatic, endocrine, and thyroid toxicities and fatigue and other Grade 1-2 toxicities. Conclusions: In this large cohort of patients with rare tumors receiving ipilimumab and nivolumab grade of irAE in the first cycle of therapy was prognostic for survival.

Examining the risk of immune checkpoint inhibitor-related toxicity among patients with melanoma and their history of cannabis use.

e21539 Background: With cannabis use rising due to better availability for recreational and medicinal uses, there is a need for studies examining cannabinoids interactions. Immune Checkpoint Inhibitors have been increasing in popularity among metastatic cancer patients like those with melanoma. The biological impact of cannabis is mediated in part by the CB1 and CB2 receptors present in the endocannabinoid system that is present in the immune system. ICI therapy also targets the immune system through manipulating PD-1/PD-L1 receptors to induce cancer cell death. Therefore, concurrent cannabis use with ICI therapy could have potentiating effects on toxicities and negatively impact efficacy. There is limited information in the literature examining this and therefore the goal was to examine the impact of ICI toxicity risk among melanoma patients on any form of ICI therapy. Methods: A retrospective cohort study was conducted using TriNetX, a multicenter database comprised of ~100 million patients across 84 healthcare organizations. Adults ( &gt; 17 years) from 2012-2023 were identified based on ICI-therapy initiation within 1 month of malignant melanoma diagnosis. Patients were then stratified by history of those with and without cannabis use disorder. ICI toxicity categories were determined a priori and included cardiac, nephrological, gastrointestinal, endocrine, respiratory, ocular, hematological, hepatological, musculoskeletal, and neurological toxicities. 1:1 propensity score matching was conducted to control for comorbidities and demographics. Adjusted hazard ratios (aHR) with 95% CI were calculated at 1-year follow-up after therapy initiation for ICI toxicities between the cohorts. aHR was estimated using the Cox proportional hazard model. Results: A total 14589 melanoma patients who underwent ICI therapy were identified where 2.3% had history of cannabis use. Matching revealed two balanced cohorts of 344 patients. Melanoma patients with a history of cannabis use did not have any significant differences with controls for cardiotoxicity (aHR[95%CI] = 0.94[0.54,1.6]), Nephrotoxicity (0.86[0.51,1.5]), GI toxicity (1.44[0.95,2.2]), endocrine toxicity (1.2[0.82,1.8]), respiratory toxicity (0.93[0.55,1.6]), ocular toxicity (0.63[0.25,1.6]), hematologic toxicity (1.04[0.7,1.6]), neurotoxicity (1.04[0.6,1.7]), liver toxicity (1.41[0.78,2.5]), or musculoskeletal toxicity (1.53[0.62,3.8]). Conclusions: With cannabis use rising due in part to recreational use and in part to medical marijuana, the implications of use must be a topic of research. Cannabis use among melanoma patients did not provide any significant differences in risk of developing ICI-therapy-related toxicities. Additional studies are needed to validate this finding.

Current status of PD-(L)1 inhibitor usage in advanced or metastatic non-small cell lung cancer: A national survey of oncologists in China.

e20559 Background: The aim of the present study conducted by Chinese Society of Clinical Oncology Expert Committee on Immunotherapy was to obtain real-world information on the use of PD-(L)1 inhibitors for non-small cell lung cancer (NSCLC) in different regions of China via a national questionnaire survey for oncologists. Methods: This survey was distributed online to cancer-related medical departments in 202 first-tier to fourth-tier cities of China between March to April 2023. The national survey consisted of four sections regarding oncologists’ concerns about immunotherapy as follows: treatment choice, response assessment, treatment duration, and management of immune-related adverse events (irAEs). Results: A total of 2,018 oncologists completed this survey. For advanced squamous (SQ) and non-squamous (NSQ) NSCLC without targetable genetic alterations, PD-(L)1 inhibitor-based regimens were the most widely used first-line treatment regimen (SQ: 52%, NSQ: 46%), followed by chemotherapy alone (SQ: 37%, NSQ: 37%) and other regimens (SQ: 11%, NSQ: 17%). The average treatment duration of 1L PD-(L)1 inhibitor-based regimens in SQ NSCLC and NSQ NSCLC were 6.4 and 6.2 cycles, respectively. 67% of oncologists may discontinue immunotherapy or change regimens when the first radiographic tumor assessment was SD per RECIST 1.1. Other reasons for early discontinuation of PD-(L)1 inhibitors before PD or unacceptable toxicity included economic reasons (78%) and patients’ low willingness to continue immunotherapy even they reached CR/PR (62%). Oncologists in the second-tier cities and below were more likely to discontinue immunotherapy when the tumors were stable, with shorter treatment duration of 5.7 cycles versus 7.1 cycles in the first-tier cities. The most common irAEs included dermatologic, endocrine, pulmonary, gastrointestinal, and hepatic toxicities. Conclusions: PD-(L)1 inhibitor-based regimens have become the priority choice for advanced NSCLC in China, however, the status of standardized continuous use of immunotherapy is obviously insufficient. There is a gap between clinical practice and clinical trials regarding PD-(L)1 inhibitor usage, which need more attention. [Table: see text]

TOPOLOGY: A phase II study to evaluate the efficacy and toxicities of PLX038, in patients with locally advanced or metastatic triple-negative breast cancer.

TPS1142 Background: Sacituzumab govitecan (SG) is an anti-TROP2 antibody-drug conjugate (ADC) with an SN-38 payload (topoisomerase I inhibitor) that was recently approved for use in advanced triple-negative breast cancer (TNBC). The rapid spontaneous linker hydrolysis in sacituzumab-govitecan releases a very large amount of SN-38 cargo systemically, which may in part contribute to efficacy and also in part be responsible for systemic side effects (1). PLX038 is a 40 kDa 4-arm PEG-SN38 conjugate with a half-life of 5 days. It has a controlled, slow-release rate which allows high SN-38 exposure over an extended period of time with a low Cmax, and very low levels of SN-38-glucuronide. The PLX038 nanomolecule also penetrates large pores of tumor vasculature, and accumulates and is retained in the tumor for long periods. The prolonged exposure of tumors to SN-38 may result in increased efficacy without resulting in severe gastrointestinal toxicity. We hypothesize that PLX038 may be effective in patients with advanced TNBC who have been previously treated with standard chemotherapy regimens. Methods: This is an open label, multi-centric phase II study designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of PLX038 in locally advanced or metastatic TNBC previously treated with at least two prior cytotoxic chemotherapy regimens for locally advanced or metastatic breast cancer including an anthracycline, taxane and sacituzumab govitecan. Patients will be treated at a dose of 1730mg/m2 IV infusion on Day 1 of each cycle Q3W (every 21 days, 1 cycle = 1 injection) after at least a first cycle at 1300mg/m2. At the discretion of the treating physician, the PLX038 dose will be increased to 1730 mg/m2 for patients who tolerate at least 1 cycle. All included patients will receive PLX038 as single agent as long as study is ongoing or until progression of disease, unacceptable toxicity, patient withdrawal of consent, Investigator decision, lost to follow-up, death, patient non-compliance, or study termination by Sponsor. The primary endpoint is the best tumor response (defined as partial or complete response in the first 6 months of treatment) assessed by investigators per RECIST v1.1 criteria, with tumor assessments every 8 weeks (± 7 days). Secondary endpoints include i) efficacy criteria (time to response, duration of response, progression-free survival, overall survival), ii) toxicity criteria (AE/SAEs), iii) association between PLX038 efficacy and biomarkers (homologous recombination defect, replication stress-related biomarkers such as SFLN11 expression, RB1 loss), iv) PK/PD analysis. A Simon's two-stage optimum design will be used, and a maximum of N=44 patients will be included, 1. Santi et al., Biodrugs 2024. Clinical trial information: NCT06162351 .

Selected phytocannabinoids inhibit SN-38- and cytokine-evoked increases in epithelial permeability and improve intestinal barrier function in vitro

Irinotecan use is linked to the development of gastrointestinal toxicity and inflammation, or gastrointestinal mucositis. Selected phytocannabinoids have been ascribed anti-inflammatory effects in models of gastrointestinal inflammation, associated with maintaining epithelial barrier function. We characterised the mucoprotective capacity of the phytocannabinoids: cannabidiol, cannabigerol, cannabichromene and cannabidivarin in a cell-based model of intestinal epithelial stress occurring in mucositis.Transepithelial electrical resistance (TEER) was measured to determine changes in epithelial permeability in the presence of SN-38 (5 μM) or the pro-inflammatory cytokines TNFα and IL-1β (each at 100 ng/mL), alone or with concomitant treatment with each of the phytocannabinoids (1 μM). The DCFDA assay was used to determine the ROS-scavenging ability of each phytocannabinoid following treatment with the lipid peroxidant tbhp (200 μM).Each phytocannabinoid provided significant protection against cytokine-evoked increases in epithelial permeability. Cannabidiol, cannabidivarin and cannabigerol were also able to significantly inhibit SN-38-evoked increases in permeability. None of the tested phytocannabinoids inhibited tbhp-induced ROS generation.These results highlight a novel role for cannabidiol, cannabidivarin and cannabigerol as inhibitors of SN-38-evoked increases in epithelial permeability and support the rationale for the further development of novel phytocannabinoids as supportive therapeutics in the management of irinotecan-associated mucositis.

6:2 Cl-PFESA, a proposed safe alternative for PFOS, diminishes the gemcitabine effectiveness in the treatment of pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC)/pancreatic cancer, is a highly aggressive malignancy with poor prognosis. Gemcitabine-based chemotherapy remains the cornerstone of PDAC treatment. Nonetheless, the development of resistance to gemcitabine among patients is a major factor contributing to unfavorable prognostic outcomes. The resistance exhibited by tumors is modulated by a constellation of factors such as genetic mutations, tumor microenvironment transforms, environmental contaminants exposure. Currently, comprehension of the relationship between environmental pollutants and tumor drug resistance remains inadequate. Our study found that PFOS/6:2 Cl-PFESA exposure increases resistance to gemcitabine in PDAC. Subsequent in vivo trials confirmed that exposure to PFOS/6:2 Cl-PFESA reduces gemcitabine’s efficacy in suppressing PDAC, with the inhibition rate decreasing from 79.5 % to 56.7 %/38.7 %, respectively. Integrative multi-omics sequencing and molecular biology analyses have identified the upregulation of ribonucleotide reductase catalytic subunit M1 (RRM1) as a critical factor in gemcitabine resistance. Subsequent research has demonstrated that exposure to PFOS and 6:2 Cl-PFESA results in the upregulation of the RRM1 pathway, consequently enhancing chemotherapy resistance. Remarkably, the influence exerted by 6:2 Cl-PFESA exceeds that of PFOS. Despite 6:2 Cl-PFESA being regarded as a safer substitute for PFOS, its pronounced effect on chemotherapeutic resistance in PDAC necessitates a thorough evaluation of its potential risks related to gastrointestinal toxicity.

Conditional Risk and Predictive Factors Associated With Late Toxicity in Patients With Prostate Cancer Treated With External Beam Radiation Therapy Alone in the Randomized Trial RTOG 0126

The objective of this study was to characterize the conditional risk of developing grade 2+ urinary or gastrointestinal (GI) toxicity for patients treated with external beam radiation therapy in Radiation Therapy Oncology Group 0126. A secondary objective was to analyze baseline patient and treatment characteristics and determine their relevance in predicting toxicity both at the time of trial enrollment and at later points of follow-up. One thousand five hundred thirty-two patients with localized prostate cancer were enrolled between March 2002 and August 2008, of whom 1499 were eligible and included in data analysis with a median follow-up of 8.4 years (range, 0.02-13 years). Patients were treated with either 3-dimensional conformal radiation therapy or intensity-modulated radiation therapy according to institutional practice without the addition of androgen deprivation and randomized to receive either standard-dose radiation therapy of 70.2 Gy or dose-escalated radiation therapy of 79.2 Gy of radiation therapy to the prostate only with standard fractionation. Univariate and multivariate analyses were performed to determine whether initial factors were predictive of late toxicity at the time of treatment and at later time points. As patients proceed further from completion of radiation therapy without the development of toxicity, the subsequent risk of both grade 2+ genitourinary (GU) and GI toxicity decreases with time. At the time of enrollment, the risk of developing grade 2+ toxicity over the next 5 years was 9.57% and 17.89%, respectively. After 5 years of toxicity-free survival, the risk of developing grade 2+ GU or GI toxicity in the subsequent 5 years was 3.02% and 1.54%, respectively. Baseline treatment and patient-related factors predicted late toxicity both at trial enrollment and after 2 years of toxicity-free survivorship. Baseline urinary dysfunction and dose-escalated radiation therapy were associated with increased late GU toxicity. Acute GI toxicity and dose-escalated radiation therapy were associated with increased risk of late GI toxicity. Treatment with intensity-modulated radiation therapy was associated with reduced risk of either toxicity. The conditional risk of grade 2+ toxicities decreases as patients proceed further from treatment, with most toxicities occurring in the first few years after treatment completion. Baseline patient and treatment characteristics remain relevant at both enrollment and later time points.

Treatment patterns and survival outcomes of patients admitted to the intensive care unit due to immune-related adverse events of immune checkpoint inhibitors.

Severe immune-related adverse events (irAEs) due to immune checkpoint inhibitors (ICIs) can lead to admission to the intensive care unit (ICU). In this retrospective study, we determined the incidence, treatment patterns and survival outcomes of this patient population at a comprehensive cancer center. All patients admitted to the ICU due to irAEs from ICI treatment between January 2015 and July 2022 were included. Descriptive statistics were reported on patient characteristics and treatment patterns during hospital admission. Overall survival (OS) from the time of ICU discharge to death was estimated using the Kaplan-Meier method. Over the study period, 5561 patients received at least one ICI administration, of which 32 patients (0.6%) were admitted to the ICU due to irAEs. Twenty patients were treated with anti-PD-1 plus anti-CTLA-4 treatment, whereas 12 patients were treated with ICI monotherapy. The type of irAEs were de novo diabetes-related ketoacidosis (n = 8), immune-related gastrointestinal toxicity (n = 8), myocarditis or myositis (n = 10), nephritis (n = 3), pneumonitis (n = 2), and myelitis (n = 1). The median duration of ICU admission was 3 days (interquartile range: 2-6 days). Three patients died during ICU admission. The median OS of the patients who were discharged from the ICU was 18 months (95% confidence interval, 5.0-NA). The incidence of irAEs leading to ICU admission in patients treated with ICI was low in this study. ICU mortality due to irAEs was low and a subset of this patient population even had long-term survival.

Preliminary results of adjuvant image-guided vaginal brachytherapy alone for early stage endometrial carcinoma

ObjectiveThis retrospective study evaluated the preliminary outcomes of image-guided vaginal brachytherapy (IG-VBT) in the adjuvant treatment of high intermediate risk endometrial cancer. Materials and MethodsData were collected from 48 patients who underwent adjuvant IG-VBT between 2019 and 2022 at the Division of Radiation Oncology, Department of Radiology, Faculty of Medicine, Chiang Mai University. The vaginal cuff clinical target volume (CTV-VC) is composed of a 4-mm-thick band around vaginal cylinder at the upper 3 cm of the vaginal cuff. A total dose of 21 Gy in three fractions was delivered to the CTV-VC, and the dose to the bladder and rectum were evaluated. Treatment details, patient characteristics, and outcomes were analyzed. Descriptive statistics were used for analysis, and Kaplan-Meier method was employed for survival analysis. ResultsThe mean age was 62 years, with mainly endometrioid carcinoma pathology (96 %). All patients were at stage I, with 87.5 % receiving complete surgical staging. Mean total treatment time was 10 days with mean D90 of CTV-VC was 29.7 Gy, and D2cc of bladder, rectum, and sigmoid were 24.6 Gy, 21.0 Gy, and 7.7 Gy, respectively. At a median follow-up of 37 months, 3-year local control, disease-free survival, and overall survival rates were 100 %, 100 %, and 97.9 %. respectively. Two patients (4.2 %) experienced grade 1–2 gastrointestinal toxicity, while no genitourinary toxicity or serious adverse events were observed. ConclusionsThe preliminary results of IG-VBT in endometrial cancer demonstrated favorable outcomes in terms of vaginal control and toxicity. Further studies with larger cohorts and longer follow-up durations are warranted.

#1304 Clinical characteristics of acute kidney injury caused by Phytolaccaceae ingestion

Abstract Background and Aims Phytolaccaceae is a poisonous plant that is associated with cardiac and gastrointestinal toxicity. However, there are limited data about acute kidney injury (AKI) in patients with Phytolaccaceae ingestion. We conducted this study to investigate the clinical characteristics of AKI by Phytolaccaceae overdose. Method From 2010 to 2022, 15 patients with Phytolaccaceae ingestion were enrolled in this study. The incidence, clinical characteristics, and severity of AKI were compared between AKI (N=8) and non-AKI (N=7) groups according to the RIFLE classification. Results Of the 15 patients, 8 patients experienced AKI during hospitalization period. There is no difference in age (54.3 ± 7.2 years vs. 67.1 ± 13.5 years, P=0.057) and comorbidities such as hypertension and diabetes (37.5% vs 28.5%, P=0.563) between two groups. In addition, there is also no difference in total leukocyte count (10.8 × 103/mL vs. 11.4 × 103/mL, P=0.84) and serum albumin level (4.5 ± 2.6 vs 4.3 ± 0.5, P=0.498). Compared to patients without AKI, the estimated glomerular filtration rate was lower in the AKI group (57 ± 12 ml/min/1.73 m2 vs. 77 ± 24 ml/min/1.73 m2, p&amp;lt;0.05) on admission. The AKI group had a significantly longer hospital stay (9.7 ± 6.2 vs 6.1 ± 3.1 days, p&amp;lt;0.001). The overall AKI incidence was 61.5%, of which 46.1% and 15.4% cases were classified as risk and injury, respectively. All patients recovered baseline renal function without renal replacement therapy following antibiotics therapy and supportive care. Conclusion The incidence of AKI in patient with Phytolaccaceae ingestion is 61.5%. Most patients with AKI had a mild type of AKI during admission period. In cases of AKI patients with Phytolaccaceae ingestion, aggressive supportive care including hydration is very important.