Severe Gastrointestinal Toxicity Research Articles

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 .

Abstract 5266: Deciphering the systemic immune effects of abemaciclib in recurrent metastatic breast cancer: A multicenter, prospective study

Abstract Background: Abemaciclib, a CDK4/6 inhibitor, stands as a cornerstone for managing hormone receptor-positive, HER2-negative advanced or metastatic recurrent breast cancer. It is known to modulate the tumor immune microenvironment, enhancing anti-tumor responses. Yet, its systemic immunological impact remains to be elucidated. This investigation aims to delineate the influence of abemaciclib on both the gut microbiota and the systemic immune landscape in patients with breast cancer. Methods: A multicenter, prospective clinical trial was conducted involving 40 patients with hormone receptor-positive, HER2-negative advanced or metastatic recurrent breast cancer, scheduled for abemaciclib therapy. The trial's primary objectives were to evaluate the duration of treatment efficacy and the severity of gastrointestinal toxicity. Secondary objectives included assessing the interplay between circulating immune profiles, gut microbiota, and clinical outcomes. Patient samples, including peripheral blood mononuclear cells (PBMCs) for single-cell RNA sequencing and stool for 16S rRNA gene analysis, were collected at baseline and after 90 days of treatment initiation. Results: This interim report presents findings from 39 patients. We examined 75 PBMC samples and 78 stool samples. Preliminary analysis indicated that abemaciclib precipitated an upregulation of cytokines pivotal for anti-tumor immunity, notably IL-7 and IP-10, alongside an activation of circulating innate immune cells such as CD4-positive T cells and dendritic cells. Concurrently, gut microbiota analysis revealed a post-treatment reduction in alpha diversity, with notable shifts in microbial populations implicated in innate immune activation. Discussion: This study presents novel insights into the systemic immunomodulatory effects of abemaciclib. Our results suggest that abemaciclib's therapeutic efficacy may partially derive from its ability to alter the circulating immune profile and gut microbiota. These findings could pave the way for innovative immunotherapeutic approaches, integrating gut microbiome considerations into the treatment of hormone receptor-positive, HER2-negative breast cancer. Citation Format: Yukiko Fukui, Kosuke Kawaguchi, Yurina Maeshima, Yuri Fujimoto, Hiroshi Ishiguro, Kazuhiko Yamagami, Sachiko Takahara, Hirofumi Suwa, Masae Torii, Shigenori Nagai, Yasuaki Sagara, Wakako Tsuji, Hiroyasu Yamashiro, Takeshi Kotake, Shinji Fukuda, Kuniaki Saito, Yasuko Yamamoto, Masako Kataoka, Yuki Himoto, Atsushi Yonezawa, Yuki Nakamura, Wei Li, Sunao Tanaka, Satoshi Morita, Masahiro Takada, Masakazu Toi. Deciphering the systemic immune effects of abemaciclib in recurrent metastatic breast cancer: A multicenter, prospective study [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 5266.

Dose-escalated SBRT for borderline and locally advanced pancreatic cancer. Feasibility, safety and preliminary clinical results of a multicenter study

BackgroundPancreatic Stereotactic Body Radiotherapy (SBRT) allows for the administration of a higher biologically effective doses (BED), that would be essential to achieve durable tumor control. Escalating treatment doses need a very accurate tumor positioning and motion control during radiotherapy.The aim of this study to assess the feasibility and safety of a Simultaneous Integrated Boost (SIB) dose-escalated protocol at 45 Gy, 50 Gy and 55 Gy in 5 consecutive daily fractions, in Border Line Resectable Pancreatic Cancer (BRCP) /Locally Advanced Pancreatic Cancer (LAPC) by means of a standard LINAC platform. MethodsPatients diagnosed of BRPC/LAPC, candidates for neoadjuvant chemotherapy and SBRT, in four university hospitals of the province of Las Palmas (Canary Islands, Spain) were included in this prospective study. Radiotherapy was administered using standard technology (LINACS) with advanced positioning (Lipiodol® and metallic stent used as fiducial markers) and tumor motion control (4D, DBH, Calypso®). There were 3 planned dose-escalated SIB groups, 45 Gy/5f (9 patients) 50 Gy/5f (9 + 9 patients) and 55 Gy/5f (9 patients). The defined primary end points of the study were the safety and feasibility of the proposed treatment protocol. Secondary endpoints included radiological tumor response after SBRT, local control and survival. ResultsFrom June 2017 to December 2022, sixty-two patients were initially assessed for eligibility in the study in the four participating centers, and 49 were candidates for chemotherapy (CHT). Forty-one were referred to radiotherapy after CHT and 33 finally were treated by escalated-dose SIB, 45 Gy (9 patients) 50 Gy (16 patients), 55 Gy(8 patients). All patients completed the scheduled treatment and no acute or late severe (≥grade3) gastrointestinal toxicity was observed.Local response was analyzed by CT/MRI two months after the end of SBRT. Ten patients (31,25 %) achieved objective response (2/9:45 Gy, 5/15:50 Gy, 3/8:55 Gy). Follow-up was closed as July 2023. Freedom from local progression at 1-2y were 89,3% (95 %CI:83,4–95,2%) and 66 % (95 %CI:54,6–77,4%) respectively. The 1-2y survival rates were 95,7% (95 %CI:91,4–100 % and 48,6% (95 %CI:37,7–59,5%) respectively. ConclusionThese promising results should be confirmed by further studies with larger sample size and extended follow-up period.

Selective mPGES-1 Inhibitor Ameliorated Adjuvant-Induced Arthritis in the Rat Model

Endogenous prostaglandin E2 (PGE2) plays an important role in maintaining the homeostasis conditions. However, the overexpression of PGE2 in response to various inflammatory stimulations is an important target of anti-inflammatory drugs. Both inducible COX-2 (cyclooxygenase-2) and mPGES-1 (microsomal prostaglandin E2 synthase-1) enzymes are responsible for the inflammatory overexpressed PGE2 production. Among them, mPGES-1 is regarded as a more promising ideal target for anti-inflammatory drugs without the gastrointestinal and cardiovascular side effects. As our continuous research for the discovery of novel mPGES-1 inhibitors, we have characterized MPO-0144 as a selective mPGES-1 inhibitor with a selectivity index of >270 over COX-1 and >25 over COX-2, respectively. Herein, we evaluated the anti-inflammatory effect of MPO-0144 in an adjuvant-induced arthritis rat model. MPO-0144 attenuated the inflammatory responses without severe gastrointestinal side effects and organ toxicities. These overall data suggest a possibility that MPO-0144 downregulates PGE2 production by potent mPGES-1 and weak COX-2 inhibitory activities, thus attenuating the paw swelling in AIA (adjuvant-induced arthritis) rat models. MPO-0144 also exhibited favorable ADMET profiles. However, MPO-0144 did not show any inhibitory effects on human mPGES-1 enzyme at a high concentration. Therefore, MPO-0144 represents a valuable pharmacological tool for the study of regulation of inducible mPGES-1 in an inflammatory arthritis rat model.

Gut microbiome in association with chemotherapy-induced toxicities among patients with breast cancer.

Little research has focused on the relationship between gut microbiome and chemotherapy-induced toxicity. This prospective study involves 301 patients with breast cancer who had prechemotherapy stool samples collected. Gut microbiome was sequenced by shotgun metagenomics; associations with chemotherapy-induced toxicities during first-line treatment by gut microbial diversity, composition, and metabolic pathways with severe (i.e., grade ≥3) hematological and gastrointestinal toxicities were evaluated via multivariable logistic regression. High prechemotherapy α-diversity was associated with a significantly reduced risk of both severe hematological toxicity (odds ratio [OR]=0.94; 95% CI, 0.89-0.99; p=.048) and neutropenia (OR=0.94; 95% CI, 0.89-0.99; p=.016). A high abundance of phylum Synergistota, class Synergistia, and order Synergistales were significantly associated with a reduced risk of severe neutropenia; conversely, enrichment of phylum Firmicutes C, class Negativicutes, phylum Firmicutes I, and class Bacilli A, order Paenibacillales were significantly associated with an increased risk of severe neutropenia (p range: 0.012-2.32×10-3; false discovery rate <0.1). Significant positive associations were also observed between severe nausea/vomiting and high Chao1 indexes, β-diversity (p<.05), 20 species belonging to the family Lachnospiraceae, Oscillospiraceae, and Ruminococcaceae (p value range: 6.14×10-3 to 1.33×10-5; false discovery rate <0.1), and three metabolic pathways involved in reductive tricarboxylic acid cycle I and cycle II, and an incomplete reductive tricarboxylic acid cycle (p<.01). Conversely, a high abundance of species Odoribacter laneus and the pathway related to the L-proline biosynthesis II were inversely associated with severe nausea/vomiting. Our study suggests that gut microbiota may be a potential preventive target to reduce chemotherapy-induced toxicity.

Adaptive ultra-hypofractionated whole-pelvic radiotherapy in high-risk and very high-risk prostate cancer on 1.5-Tesla MR-Linac: Estimated delivered dose and early toxicity results.

Magnetic resonance (MR)-guided ultra-hypofractionated radiotherapy with whole-pelvic irradiation (UHF-WPRT) is a novel approach to radiotherapy for patients with high-risk (HR) and very high-risk (VHR) prostate cancer (PCa). However, the inherent complexity of adaptive UHF-WPRT might inevitably result in longer on-couch time. We aimed to estimate the delivered dose, study the feasibility and safety of adaptive UHF-WPRT on a 1.5-Tesla MR-Linac. Ten patients with clinical stage T3a-4N0-1M0-1c PCa, who consecutively received UHF-WPRT, were enrolled prospectively. The contours of the target and organ-at-risks on the position verification-MR (PV-MR), beam-on 3D-MR(Bn-MR), and post-MR (after radiotherapy delivery) were derived from the pre-MR data by deformable image registration. The physician then manually adjusted them, and dose recalculation was performed accordingly. GraphPad Prism 9 (GraphPad Prism Software Inc.) was utilized for conducting statistical analyses. In total, we collected 188 MR scans (50 pre-MR, 50 PV-MR, 44 Bn-MR, and 44 post-MR scans). With median 59 min, the mean prostate clinical target volume (CTV)-V100% was 98.59% ± 2.74%, and the mean pelvic CTVp-V100% relative percentages of all scans was 99.60% ± 1.18%. The median V29 Gy change in the rectal wall was -2% (-18% to 20%). With a median follow-up of 9 months, no patient had acute Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or more severe genitourinary (GU) or gastrointestinal (GI) toxicities (0%). UHF-RT to the prostate and the whole pelvis with concomitant boost to positive nodes using an Adapt-To-Shape (ATS) workflow was technically feasible for patients with HR and VHR PCa, presenting only mild GU and GI toxicities. The estimated target dose during the beam-on phase was clinically acceptable based on the 3D-MR-based dosimetry analysis. Chinese Clinical Trial Registry ChiCTR2000033382.

PAZEC: a Dutch Gynaecological Oncology Group open-label, multicenter, phase II study of pazopanib in metastatic and locally advanced hormone-resistant endometrial cancer

ObjectiveThere is a continued need for improvement of second-line systemic treatment for metastatic and/or recurrent endometrial cancer.MethodsIn this phase II, open-label study, eligible patients had histologically or cytologically confirmed endometrial...

Bifidobacterium longum SX-1326 ameliorates gastrointestinal toxicity after irinotecan chemotherapy via modulating the P53 signaling pathway and brain-gut axis

BackgroundColorectal cancer (CRC) is a prevalent malignant malignancy affecting the gastrointestinal tract that is usually treated clinically with chemotherapeutic agents, whereas chemotherapeutic agents can cause severe gastrointestinal toxicity, which brings great pain to patients. Therefore, finding effective adjuvant agents for chemotherapy is crucial.MethodsIn this study, a CRC mouse model was successfully constructed using AOM/DSS, and the treatment was carried out by probiotic Bifidobacterium longum SX-1326 (B. longum SX-1326) in combination with irinotecan. Combining with various techniques of modern biomedical research, such as Hematoxylin and Eosin (H&E), Immunohistochemistry (IHC), Western blotting and 16S rDNA sequencing, we intend to elucidate the effect and mechanism of B. longum SX-1326 in improving the anticancer efficacy and reducing the side effects on the different levels of molecules, animals, and bacteria.ResultsOur results showed that B. longum SX-1326 enhanced the expression of Cleaved Caspase-3 (M vs. U = p < 0.01) and down-regulated the expression level of B-cell lymphoma-2 (Bcl-2) through up-regulation of the p53 signaling pathway in CRC mice, which resulted in an adjuvant effect on the treatment of CRC with irinotecan. Moreover, B. longum SX-1326 was also able to regulate the gut-brain-axis (GBA) by restoring damaged enterochromaffin cells, reducing the release of 5-hydroxytryptamine (5-HT) in brain tissue (I vs. U = 89.26 vs. 75.03, p < 0.05), and further alleviating the adverse effects of nausea and vomiting. In addition, B. longum SX-1326 reversed dysbiosis in CRC model mice by increasing the levels of Dehalobacterium, Ruminnococcus, and Mucispirillum. And further alleviated colorectal inflammation by downregulating the TLR4/MyD88/NF-κB signaling pathway.ConclusionsIn conclusion, our work reveals that B. longum SX-1326 has a favorable effect in adjuvant irinotecan for CRC and amelioration of post-chemotherapy side effects, and also provides the theoretical basis and data for finding a safe and efficient chemotherapeutic adjuvant.

A Multicenter Phase2 Trial of Linperlisib in Relapsed or Refractory Peripheral T/NK Cell Lymphomas

Introduction Peripheral T/NK cell lymphomas (PTCLs) are a group of aggressive heterogeneous non-Hodgkin's lymphomas where in relapsed or refractory (r/r) disease, the approved standard therapies are limited with a median progression free survival (mPFS) of only 3-4 months. PI3Kdelta inhibitors have demonstrated clinical activities in T-cell and B-cell lymphomas, owing to the multiple cellular activities in the T, B, and myeloid cell tumor microenvironment. However, application of these agents has been hampered by poor tolerabilities, particularly with toxicities such as diarrhea/colitis, hepatotoxicity, pneumonitis, hyperglycemia, and rash. As a new PI3Kdelta-selective oral agent, linperlisib was shown to be efficacious and indicated a favorable safety profile in phase 1 and 2 clinical trials in r/r Follicular Lymphoma (FL) and PTCL. Linperlisib received marketing approval in China in 2022 for r/r FL patients (pts) with 2 prior systemic therapies. Here we report the efficacy and safety findings for linperlisib in a pivotal phase 2 trial in r/r PTCL. Methods Ninety-eight pts were enrolled in the open-label phase 2 registration trial (CTR20210333) from May 2021 to October 2022 at 25 sites in China. The trial had a representation of different PTCL subtypes: AITL (48 pts), PTCL-NOS (24 pts), NKT (8 pts), ALCL (2 pts), MEITL (2 pts), Other (4 pts), and 10pt did not qualify as PTCL confirmed by independent pathology review, yielding a Full Analysis Set (FAS) of 88 pts for efficacy evaluation. Linperlisib was orally dosed at 80 mg QD (RP2D) continuously until disease progression, intolerable toxicity, or study withdrawal. Tumor assessments performed every 2 treatment cycles (28-day cycle) were evaluated with Lugano 2014 criteria by an Independent Review Committee. Safety was evaluated according to CTCAE v5.0. Results In this phase 2 study, the median age was 57 years, ECOG 0-1 (100%). Most patients were diagnosed with Lugano 2014 Stage III (29 pts, 33%), or IV (49pts, 56%) diseases, and were refractory or relapsed to a median of 2 prior systemic therapies. Sixty-four pts (73%) had refractory diseases, 59 pts (67%) had relapsed diseases, and 35 pts (40%) were with both r/r. Treatment related adverse events (TRAE) were observed in 94 pts (95.9%) , with the most common TRAEs (≥10%) being neutropenia (59%), leukopenia (47%), thrombocytopenia (32%), anaemia (24%), elevated alanine aminotransferase (23%), elevated aspartate aminotransferase (20%), pneumonia (20%), lymphocytopenia (17%), hypertriglyceridemia (15%), fever (15%), diarrhea (14%), elevated lipase (13%), hyperuricemia (13%), rash (13%), hypercholesterolemia (12%), hyponatremia (11%), elevated lactate dehydrogenase (10%), elevated creatinine (10%). AEs of ≥Grade 3 (≥5%) were neutropenia (32%), pneumonia (14%), leukopenia (10%), anaemia (6%), thrombocytopenia (5%), upper respiratory tract infection (5%) and lymphocytopenia (5%). The most frequent Serious Adverse Event (drug-related) was pneumonia (11%). Twenty-two pts (22.4%) had dose reductions, and 9 pts (9.2%) discontinued from the study due to AEs. The safety profile was consistent with all previously reported in linperlisib clinical studies. Among the 88 FAS pts, the objective response rate (ORR) was 48%, including 30% (26 pts) complete response, 18% (16 pts) partial response, and 20% (18 pts) stable disease. The disease control rate was 68%. Responses were demonstrated in all subtypes, including AITL, PTCL-NOS, NKT, and others. As of April 24, 2023, the median duration of response had not been reached (95%CI: 7.8, NR), and mPFS was 5.5 months (95%CI: 3.5, 15.6). All pts had ≥6 months of follow-up as of the safety and efficacy analysis data cut off (April 24, 2023); median follow-up was 13.9 months. The 6-month OS rate was 75% (95% CI: 64.51%, 82.74%), the median OS was 14.2 months (95%CI: 7.9, NR), 16 pts continued to receive linperlisib treatment. Conclusions Linperlisib, as a new PI3Kdelta-selective oral agent, showed a well-tolerated safety profile with low levels of severe gastrointestinal and liver toxicities seen with other PI3K agents. In r/r PTCL, linperlisib had promising durable efficacies, with 48% ORR (30% CR) and a median duration of response that was not reached. As in previous lymphoma studies with linperlisib, a high proportion of responses were CRs, and responses were observed across almost all PTCL subtypes. A phase 2 r/r PTCL and CTCL trial in the US/EU is ongoing.

Molecular Characteristics of Cisplatin-Induced Ototoxicity and Therapeutic Interventions.

Cisplatin is a commonly used chemotherapeutic agent with proven efficacy in treating various malignancies, including testicular, ovarian, cervical, breast, bladder, head and neck, and lung cancer. Cisplatin is also used to treat tumors in children, such as neuroblastoma, osteosarcoma, and hepatoblastoma. However, its clinical use is limited by severe side effects, including ototoxicity, nephrotoxicity, neurotoxicity, hepatotoxicity, gastrointestinal toxicity, and retinal toxicity. Cisplatin-induced ototoxicity manifests as irreversible, bilateral, high-frequency sensorineural hearing loss in 40-60% of adults and in up to 60% of children. Hearing loss can lead to social isolation, depression, and cognitive decline in adults, and speech and language developmental delays in children. Cisplatin causes hair cell death by forming DNA adducts, mitochondrial dysfunction, oxidative stress, and inflammation, culminating in programmed cell death by apoptosis, necroptosis, pyroptosis, or ferroptosis. Contemporary medical interventions for cisplatin ototoxicity are limited to prosthetic devices, such as hearing aids, but these have significant limitations because the cochlea remains damaged. Recently, the U.S. Food and Drug Administration (FDA) approved the first therapy, sodium thiosulfate, to prevent cisplatin-induced hearing loss in pediatric patients with localized, non-metastatic solid tumors. Other pharmacological treatments for cisplatin ototoxicity are in various stages of preclinical and clinical development. This narrative review aims to highlight the molecular mechanisms involved in cisplatin-induced ototoxicity, focusing on cochlear inflammation, and shed light on potential antioxidant and anti-inflammatory therapeutic interventions to prevent or mitigate the ototoxic effects of cisplatin. We conducted a comprehensive literature search (Google Scholar, PubMed) focusing on publications in the last five years.

Comparison of Low Dose Rate and High Dose Rate Brachytherapy Boost Techniques in Prostate Cancer: Evaluation of Toxicity.

The ASCENDE-RT trial has been criticized for higher rates of chronic severe toxicity (18% genitourinary (GU)) than expected with a low dose rate (LDR) boost technique. We compared clinical outcomes of LDR and high dose rate (HDR) boost in the acute and chronic setting from a large single institution experience over a continuous 20-year period, with a focus on GU and gastrointestinal (GI) toxicity during treatment of prostate cancer. We retrospectively reviewed patients treated with LDR boost (2003 - 2013) and HDR boost (2014 - 2018). Clinical and treatment-related prognostic factors including age, stage, androgen deprivation therapy (ADT), dosimetry details, and toxicity data were recorded. Toxicity was scored according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Multi-variable analysis (MVA) was performed to evaluate variables associated with toxicity. A total of 184 men were evaluated (87 LDR and 97 HDR) with a median follow-up of 7.1 years and 4.0 years, respectively. Most patients (92% LDR and 57% HDR) received ADT in addition to BT. The median EBRT dose was 46 Gy for LDR and 45 Gy for HDR (range 25 - 50 Gy). Prostate D90% was similar at 104% and 105% in the LDR and HDR groups, respectively. Urethra D10% and Rectum V100% were both higher with LDR compared to HDR with 155% vs 119% and 0.436% vs 0.073%, respectively. Severe (grade 3+) toxicity was rare (Table 1), with 3.4% of LDR patients experiencing grade 3 chronic GU toxicity. With HDR, 3.1% and 1% of patients experienced acute and chronic grade 3 GU toxicity, respectively. Although non-severe GU toxicity (grade 1-2) was similar between groups (95% LDR vs 89% HDR, p = 0.16), LDR patients experienced more grade 2 GU events (80.5% acute; 82.8% chronic) compared to HDR patients (45.4% acute; 57.7% chronic). There were no severe GI toxicities in the acute or chronic period. Non-severe acute GI toxicity was more common with HDR, while non-severe chronic GI toxicity was more common with LDR. On MVA, acute GU toxicity (any grade) was associated with short term ADT (p = 0.01) and Urethra D10% (p < 0.05); Chronic GU toxicity (any grade) was associated with age (p = 0.09) and Prostate V150cc (p = 0.07) but not BT boost technique. This comparative retrospective analysis of BT boost techniques reveals the overall rate of severe GU and GI toxicity to be low with both LDR and HDR. HDR boost appears to have a slightly more favorable ratio of Grade 1 to Grade 2 GU toxicity and improved urethra/rectum dosimetry. Our analysis suggests that the dosimetric advantages of HDR may deliver small reductions in GU toxicity.

Adaptive Ultra-Hypofractionated Whole-Pelvic Radiotherapy in High-Risk and Very High-Risk Prostate Cancer on 1.5-1.5 MR Linac: The Estimated Delivered Dose and Early Toxicity Results

To study the feasibility and safety for patients with high-risk (HR) and very high-risk (VHR) prostate cancer treated with adaptive ultra-hypofractionated whole-pelvic radiotherapy (UHF-WPRT) on 1.5 magnetic resonance (MR)-Linac. Sevenpatients with clinical stage T3a-4N0-1M0-1c consecutively treated with UHF-WPRT on a 1.5-T MR-Linac were recruited prospectively in a phase II trial (NCT05183074, ChiCTR2000033382). A 36.25 Gy dose in five fractions was delivered every other day with a boost of 40 Gy to the whole prostate, as well as 25 Gy to whole pelvic nodal area with a concomitant boost of 35 Gy to metastatic regional nodes. To estimate the delivered dose, we collected data by 3D-MR for the following stages: pre-MR, position verification-MR (PV-MR) in the Adapt-To-Shape (ATS) workflow, and 3D-MR during the beam-on phase (Bn-MR) and at the end of RT (post-MR). The target and organ-at-risk contours in the PV-MR, Bn-MR, and post-MR stages were projected from the pre-MR data by deformable image registration and manually adapted by the physician, followed by dose recalculation for the ATS plan. The cumulative acute genitourinary (GU) and gastrointestinal (GI) toxicities were evaluated as per NCI-CTCAE 5.0 criteria. The primary endpoints were acute ≥grade 3 genitourinary (GU) and gastrointestinal (GI) toxicities during the first 3 months. Overall, 133 MR scans were collected (35 pre-MR, 35 PV-MR, 31 Bn-MR and 32 post-MR scans). With a median on-couch time of 61 minutes, the mean prostate and pelvic planning target volume (PTV)-V95% of all scans was 96.98 ± 3.06% and 96.44 ± 2.85%, respectively. The corresponding mean prostate clinical target volume (CTV)-V100% was 99.89 ± 0.32%, 98.71 ± 1.90%, 97.77 ± 2.89%, and 98.56 ± 1.72%, and the mean pelvic CTV-V100% was 97.57% ± 3.70%, 96.54 ± 3.80%, 95.43 ± 4.31%, and 94.39 ± 4.47% on pre-MR, PV-MR, Bn-MR and post-MR scans, respectively. For the 4 patients with positive nodes, the mean V100% of metastatic regional nodes was 99.89 ± 0.81%. The median V29 Gy change in the rectal wall was -1% (-18%-20%). The V29 Gy of the rectal wall increased by >15% was observed in one scan. A slight increase in the high dose of bladder wall was noted due to gradual bladder growth during the workflow. With median follow-up time of 7.3 (4.6-12.2) months, all patients were followed-up for more than 3 months. No patient was observed with acute CTCAE grade 2 or more severe GU or GI toxicities (0%). UHF-RT to prostate and pelvic with ATS workflow is well tolerated by patients with HR and VHR prostate cancer, with only mild GU and GI toxicities. The 3D-MR-based dosimetry analysis demonstrated clinically acceptable estimated dose coverage of target volumes during the beam-on period.

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.

CDK4/6 inhibition confers protection of normal gut epithelia against gemcitabine and the active metabolite of irinotecan

ABSTRACT Cancer chemotherapy relies on a high ratio of toxicity toward cancer cells vs. nonmalignant cells, making it desirable to protect normal cells. Among the nonmalignant cells, epithelia of the gut belong to the most vulnerable ones toward chemotherapeutics. Here, we use a murine intestinal organoid model to assess a strategy for protecting such epithelia against chemotherapy. Cell cycle progression was first stalled by palbociclib, a clinically established cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. Washout of the drug allowed subsequent outgrowth of gut organoids. This transient cell cycle arrest conferred near-complete protection of the cells toward the nucleoside analogue gemcitabine. Moreover, pre-treatment with palbociclib protected the organoids against SN-38, the topoisomerase I-inhibiting metabolite of irinotecan, which is otherwise known for its severe gastrointestinal toxicities. In contrast, RB1-mutated cancer cells were not protected against gemcitabine or SN-38 when pre-treated with palbociclib. Taken together, these results outline a strategy for protecting nonmalignant cells against the toxicities of chemotherapeutics commonly used to treat advanced colorectal and pancreatic cancer. We propose that this strategy is particularly promising to protect the gut when treating RB1-deficient tumors that fail to arrest the cell cycle in response to CDK4/6 inhibitors.

Severe Gastrointestinal Toxicity Following the Use of Gilteritinib: A Case Series and Analysis of Postmarketing Surveillance Data.

Gilteritinib has been approved as monotherapy in adults with acute myeloid leukemia (AML) FLT3 mutated with relapsed or refractory disease, in light of its advantages in terms of survival and the favorable safety profile. Hepatobiliary disorders and musculoskeletal and connective tissue disorders represent the most frequent adverse reactions associated with gilteritinib, whereas the most frequent serious adverse reaction is acute kidney injury. In the summary of product characteristics, gastrointestinal (GI) events are indicated as very common, in particular diarrhea, nausea and stypsis. Furthermore, serious GI disorders have been observed with gilteritinib in clinical trials, including GI hemorrhage, GI perforation and GI obstruction. However, the association with the FLT3 inhibitor has not been confirmed. Nevertheless, serious GI AEs have been recognized as an important potential risk to be monitored in postmarketing surveillance. We present three cases of serious self-limiting GI events observed in patients on gilteritinib treatment for AML, and an analysis of relevant available postmarketing surveillance data.

Local salvage of radiorecurrent prostate cancer.

Locally recurrent prostate cancer following primary external beam radiotherapy without distant metastasis is a challenging problem, with no current consensus on the optimal management of these patients. Traditional whole-gland salvage treatments offered up to a 50% 5-year disease-free survival rate but with troubling levels of risk for significant complications. Recent progress in advanced imaging techniques has allowed a more accurate selection of patients with local-only recurrence and a selection of patients that may be suitable for newer partial-gland salvage treatments that may reduce late complications. This article reviews advances in patient selection and provides an overview of whole- and partial-gland salvage results from selected recent meta-analyses, multi-institutional series, and studies from centers of excellence for these treatment approaches. Salvage radical prostatectomy produces 5-year relapse-free survival (RFS) rates in the 50%-60% range with severe gastrointestinal (GI) toxicity in < 2% but severe genitourinary (GU) toxicity in 15%-23% of patients. The whole-gland options of high and low dose rate brachytherapy and stereotactic body radiation therapy appear to offer similar 5-year control rates, with low severe GU and GI toxicity rates of 4%-8% and <2%, respectively. Cryotherapy and high-intensity focused ultrasound (HIFU) offer similar 5-year RFS rates but carry significant risks for severe GU and GI toxicity in the range of 10%-27% and <2%, respectively. Early results of partial-gland salvage techniques in selected patients appear promising, with 3-year RFS rates of 48%-72% and rare grade 3 toxicity. It is important to understand the relative effectiveness and risks of the various treatment options to effectively counsel patients who face this distressing clinical situation. Whole-gland salvage options offer the possibility of long-term control but with significant risks of severe toxicity. Emerging data for the partial-gland salvage options in appropriately selected patients may offer hope of reasonable control rates with reduced severe toxicity.

Evaluation of gastrointestinal complications in Egyptian patients after autologous stem cell transplantation using melphalan-based regimens

BackgroundAutologous stem cell transplantation (ASCT) is a curative treatment for patients with hematological malignancies. Melphalan either alone or in combination with other chemotherapeutic agents is a widely used pre-transplant conditioning regimen with known gastrointestinal (GI) complications. We retrospectively evaluate the incidence and severity of GI toxicities, the possible risk factors, and their impact on transplant outcomes in 47 patients who received ASCT using melphalan-based conditioning.ResultsMedian age was 50 years. Among our patients, 48.9% received melphalan at 200 mg/m2. Mucositis was developed in 93.6% of patients, nausea in 87.2% and grade 2 vomiting in 36.2% of patients. Grade 3 diarrhea was detected in 42.6%. Severe GI toxicities were associated with significantly delayed engraftment, longer hospital stay, and increased transfusion requirements but overall survival (OS) and transplant-related mortality (TRM) were not affected by the severity of GI symptoms.ConclusionDespite using prophylactic and supportive care, some patients developed severe GI complications following different doses of melphalan with a negative effect on some transplant outcomes. Melphalan dose or disease type was not identified as a risk factor for severe GI toxicity. Additional larger prospective studies with higher doses, different formulations, and better prophylactic measures are warranted to evaluate potential risk factors and their impact on GI toxicities.

Abstract 3928: Therapeutic targeting of NOTCH1 and neddylation pathway in T cell acute lymphoblastic leukemia

Abstract T-cell Acute Lymphoblastic Leukemia (T-ALL) is hematologic tumor characterized by the diffuse infiltration of the bone marrow by malignant hematopoietic cells expressing immature T cell markers. Although T-ALL currently has better cure rates primarily due to multiagent or intensified chemotherapy, the prognosis for patients who are resistant or develop relapse to therapy remains very poor. Aberrant Notch homolog-1 (NOTCH1) signaling is a major driver of T-ALL pathogenesis as more than 60% of T-ALL cases harbor activating mutations in the NOTCH1 gene. Gamma Secretase Inhibitors (GSIs) which effectively block the activation of oncogenic protein NOTCH1 are potential candidates for the treatment of T-ALL. However, the clinical application of GSIs is hampered by severe gastrointestinal toxicity due to the inhibition of NOTCH1 signaling in the gut. Here we demonstrate that combination therapy of GSIs and a small molecule inhibitor of the neddylation pathway circumvents the GSI-induced gut toxicity in vitro and in vivo. Genome-wide CRISPR loss-of-function screen in LS174T adenocarcinoma cells revealed neddylation pathway as a main regulator of massive goblet cell differentiation upon NOTCH1 inhibition. Genetic and pharmacologic inhibition of the neddylation pathway in LS174T cells rescued GSI-induced differentiation and cell death. Mechanistically, neddylation inhibition increases the protein stability of Hairy and enhancer of split-1 (HES1), a known regulator of absorptive and secretory cell fate decisions. Combination treatment of GSI and neddylation inhibitor in C57/BL6 mice showed a profound decrease in the number of goblet cells and maintained HES1 protein levels in the intestinal epithelium compared to GSI treatment alone. Remarkably, combined treatment of GSI and neddylation inhibitor in NOTCH1-induced T-ALL mice showed leukemia regression and improved overall survival without any associated gut toxicity. Overall, these results substantiate the potential of targeting NOTCH1 and neddylation pathway in the treatment of NOTCH1-induced T-ALL. Citation Format: Carla Bertulfo, Pablo Perez-Duran, Teresa Palomero, Adolfo Ferrando. Therapeutic targeting of NOTCH1 and neddylation pathway in T cell acute lymphoblastic leukemia. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3928.

Dose-escalated radiotherapy for clinically localized and locally advanced prostate cancer.

Dose-escalated radiotherapy for clinically localized and locally advanced prostate cancer.

Opioid-induced microbial dysbiosis disrupts irinotecan (CPT-11) metabolism and increases gastrointestinal toxicity in a murine model.

Opioids are commonly used for the management of cancer-associated pain and chemotherapy-induced diarrhoea. The chemotherapeutic irinotecan (CPT-11) causes severe gastrointestinal (GI) toxicity due to deconjugation of inactive metabolite SN-38 glucuronide (SN-38G) by bacterial β-glucuronidases to the active 7-ethyl-10-hydroxycamptothecin (SN-38). Opioids are known to cause gut microbial dysbiosis, this study evaluated whether CPT-11 anti-tumour efficacy and GI toxicity are exacerbated by opioid co-administration. Eight-week-old C57BL/6 male mice were co-administration with CPT-11 ± opioid. 16S rRNA sequencing was used for gut microbiome analysis. LC-MS analyses of plasma and intestinal extracts were performed to investigate the pharmacokinetic profile of CPT-11. Histological analysis and quantitative real-time polymerase chain reaction were used to determine the severity of intestinal tissue damage. Human liver microsome In vitro assay was performed to confirm the effects of opioids on CPT-11 metabolism. Gut microbiome analysis showed that morphine treatment induced enrichment of β-glucuronidase-producing bacteria in the intestines of CPT-11-treated mice, resulting in SN-38 accumulation and exacerbation of GI toxicity in the small intestine. Oral administration of both antibiotics and glucuronidase inhibitor protected mice against GI toxicity induced with CPT-11 and morphine co-administration, implicating a microbiome-dependent mechanism. Additionally, morphine and loperamide decreased the plasma concentration of SN-38 and compromised CPT-11 anti-tumour efficacy, this seemed to be microbiome independent. Gut microbiota play a significant role in opioid and chemotherapeutic agent drug-drug interactions. Inhibition of gut microbial glucuronidase may also prevent adverse GI effects of CPT-11 in patients on opioids.