Lower Gastrointestinal Toxicity Research Articles

A pivotal phase 2 single-arm study of glecirasib (JAB-21822) in patients with NSCLC harboring KRAS G12C mutation.

468214 Background: KRAS G12C mutation occurs in approximately 4% of non-small cell lung cancers (NSCLC) in China. Glecirasib (Jacobio, Beijing, PRC) is a potent and highly selective covalent oral inhibitor of KRAS G12C. Methods: This phase 2 single-arm study (NCT05009329) of glecirasib was conducted in China at 43 sites, enrolling participants with locally advanced or metastatic KRAS G12C mutated NSCLC. Subjects must have received prior platinum-based therapy and an immune checkpoint inhibitor (ICI) as well as appropriate targeted agents for any actionable mutations per local standards. Primary study objective is overall response rate (ORR) assessed by independent review committee (IRC). The secondary study objectives include duration of response (DOR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Here we report topline results from this pivotal study. Results: A total of 119 patients with NSCLC harboring KRAS G12C mutation were enrolled and treated with single agent glecirasib at 800mg daily (median follow up 10.4 months). The median age was 62 years, 79% was male and 21% was female, and 80.7% had ECOG PS 1. The prior lines of therapy include 1-3, with 94.1% (112/119) patients having received prior platinum-based therapy and ICI. Confirmed ORR was 47.9% (56/117; 95% CI, 38.5%-57.3%) and confirmed DCR was 86.3% (101/117; 95% CI, 78.7%-92%) assessed by IRC. Median PFS per IRC was 8.2 months (95% CI, 5.5 – 13.1), and median OS was 13.6 months (95% CI, 10.9 – NE). Median DOR has not been reached (95% CI, 7.2 – NE ). Overall, treatment-related adverse events (TRAEs) of any grade were observed in 97.5% of subjects. Most common TRAEs [≥15%] were anemia (56.3%), blood bilirubin increased (48.7%), alanine aminotransferase increased (35.3%), aspartate aminotransferase increased (35.3%), hypertriglyceridemia (28.6%) and γ-Glutamyl transferase increased (15.1%). Grade 3 and 4 TRAEs were observed in 39.5%. No grade 5 TRAEs occurred. Most of patients can stay on the treatment and 5.0% patients discontinued the treatment due to TRAE. In contrast to other FDA approved KRAS G12C inhibitor, Gleciasib has 6.7% of nausea, 7.6% vomiting, 3.4% diarrhea in which only one grade 3 nausea is reported. Conclusion: The pivotal phase 2 study of Glecirasib has met the primary endpoints and demonstrates impressive ORR and PFS with promising clinical activity for patients with KRAS G12C mutated advanced NSCLC. Glecirasib is well tolerated, with an extremely low gastrointestinal toxicity profile, which may improve patient compliance with oral therapy. Clinical trial information: NCT05009329 .

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.

The evidence framework of traditional Chinese medicine injection (Aidi injection) in controlling malignant pleural effusion: A clustered systematic review and meta-analysis

IntroductionAidi injection (Aidi), a traditional Chinese medicine injection, is often practiced to control malignant pleural effusion (MPE). ObjectivesWe performed a registered systematic review and meta-analysis (PROSPERO: CRD42022337611) to clarify the clinical role of Aidi in MPE, reveal optimal combinations of Aidi and chemical agents, their indications, therapeutic route and usage, and demonstrate their clinical effectiveness and safety. MethodologyAll randomized controlled trials (RCTs) about Aidi in controlling MPE were collected from Chinese and English databases (up to October 2022). We clustered them into multiple homogenous regimens, evaluated the risk-of-bias at outcome level using a RoB 2, extracted and pooled the data using meta-analysis or descriptive analysis, and finally summarized their evidence quality. ResultsAll 56 studies were clustered into intrapleural administration with Aidi alone or plus chemical agents, and intravenous administration with Aidi for MPE. Intrapleural administration with Aidi alone displayed similar clinical responses on Cisplatin (DDP) alone. Only administration with Aidi plus DDP significantly improved complete response and quality of life, and displayed a low pleurodesis failure, disease progression, hematotoxicity, gastrointestinal and hepatorenal toxicity. For patients with moderate to massive effusion, Karnofsky Performance Status score ≥ 50 or anticipated survival time ≥3 months, Aidi (50 ml to 80 ml each time, one time each week and three to eight times) plus DDP (20 to 30 mg, 40 to 50 mg, or 60 to 80 mg each time) significantly improved clinical responses. Most results had moderate to low quality. ConclusionsCurrent evidences indicate that Aidi, a pleurodesis agent, plays an interesting clinical role in controlling MPE. Aidi plus DDP perfusion is a most commonly used regimen, which shows a significant improvement in clinical responses. These findings also provide an indication and possible optimal usage for rational drug use.

Paclitaxel combined with platinum (PTX) versus fluorouracil combined with cisplatin (PF) in the treatment of unresectable esophageal cancer: a systematic review and meta-analysis of the efficacy and toxicity of two different regimens.

Chemotherapy plays an important role in definitive chemoradiotherapy strategies. However, the most optimal concurrent chemotherapy scheme is still controversial. This study aimed to systematically evaluate the efficacy and toxicity of paclitaxel/docetaxel combined with platinum (PTX) and fluorouracil combined with cisplatin (PF) in the concurrent chemoradiotherapy (CCRT) of unresectable esophageal cancer. The PubMed, China National Knowledge Infrastructure (CNKI), Google Scholar and Embase databases were searched by combining subject words and free words through December 31, 2021. The inclusion criteria were pathologically confirmed esophageal cancer studies using CCRT, where the chemotherapy regimen only compared PTX and PF. Quality evaluation and data extraction of studies that met the inclusion criteria were carried out independently. Stata 11.1 software was used to perform the meta-analysis. The begger analysis and egger analysis were used to assess publication bias, and the robustness of the pooled results further assessed by the Trim and Fill analysis. After screening, 13 randomized controlled trials (RCTs) were included. A total of 962 cases were enrolled, including 480 (49.9%) in the PTX group and 482 (50.1%) in the PF group. The gastrointestinal reaction to the PF regimen was the most serious [relative risk (RR) =0.54, 95% confidence interval (CI): 0.36-0.80, P=0.003]. The complete remission (CR) rate, objective response rate (ORR), and disease control rate (DCR) of the PTX group were higher than those of the PF group (RR =1.35, 95% CI: 1.03-1.76, P=0.030; RR =1.12, 95% CI: 1.03-1.22, P=0.006; RR =1.05, 95% CI: 1.01-1.09, P=0.022). In terms of the overall survival (OS) rate, the 2-year survival rates of the PTX group were higher than those of the PF group (P=0.005). There was no significant difference in the 1-, 3-, and 5-year survival rates between the two regimens (P=0.064, 0.144, and 0.341, respectively). There may be publication bias for ORR and DCR, and the results are reversed after applying the Trim and Fill method, so the combined results are not robust. PTX may be the preferred regimen for CCRT of esophageal squamous cell carcinoma, with better short-term therapeutic effect and 2-year OS rate and lower gastrointestinal toxicity.

PO23 Presentation Time: 7:40 AM: Dosimetric Effects of Model-Based TG-186 Vaginal Cylinder Treatment Plans

<h3>Purpose</h3> The vaginal cuff is the main location of relapse after curative surgery for early-stage endometrial cancer. Adjuvant vaginal cylinder brachytherapy is increasingly used to decrease the risk of postoperative recurrence due to low vaginal cuff recurrence rates and low gastrointestinal toxicity. Current clinical treatment planning follows TG-43 guidance, which assumes that all material is water. Cylinder composition can vary substantially from water equivalent materials, highlighting the importance of investigations into the dosimetric impact of cylinder composition. In the present study, we evaluated dosimetric characteristics of plans utilizing TG-186, which provides a model-based calculation approach to account for heterogeneities in cylinder configuration. <h3>Materials and Methods</h3> Ten graphically planned vaginal cylinder plans were retrospectively evaluated in this study. Each patient was fitted with an Elekta cylinder (part# 084350) comprised primarily of polysulfone (PSU, 1.29g/cc) and secondarily of stainless steel (8.00g/cc) for the stem and rings. Cylinder diameters ranged from 2.5cm to 3.5cm, and treatment lengths from 4.0cm to 7.5cm. Dose prescription was 7Gy/fx x 3fx at 5mm depth for the most proximal 2cm of the cylinder and at cylinder surface for the remainder of the treatment length. Treatment planning was conducted in Oncentra Brachy 4.5.3. The original TG-43 plans (which assume a water-equivalent material, 1.00g/cc) were recalculated using Oncentra's Advanced Collapsed-Cone Engine (ACE) according to TG-186's guidance to account for differences in density. Dwell times were unchanged, so heterogeneity correction accounts for any dosimetric changes. Points placed at the middle of the 5mm depth portion and the middle of the surface depth portion - prescription dose for TG-43 - were compared, as were rectum points. In addition, all isodose lines were converted to contours and compared for the following metrics: percent volume change, Hausdorff distance (HD), mean distance to agreement (MDA), and Dice coefficient. A paired Wilcoxon signed-rank test assessed for significance. <h3>Results</h3> Recalculated TG-186 plans were found to have consistently and statistically significantly (p<0.05) less dose: 5mm depth: -10.5% +/- 2.4%, surface: -15.9% +/- 3.5%, and rectum: -12.1% +/- 3.4% average dose reduction. Compared to TG-43, the TG-186 100% isodose lines as contours show an average volume decrease of 22.2% +/- 2.5%, HD 4.6mm +/- 1.2mm, MDA 1.5mm +/- 0.3mm, and Dice 0.87 +/- 0.02. The high dose region as defined by 150% of prescription (25.7% volume decrease, HD 4.4mm, MDA 1.3mm) and the low dose region of 50% prescription (19.5% volume decrease, HD 8.2mm, MDA 1.9mm) show similar trends. <h3>Conclusions</h3> Ten TG-43 graphical vaginal cylinder plans were recalculated using TG-186 to account for the material composition of the cylinders. ACE calculations show that the dose delivered to target prescription points and to OARs may be less than originally planned, although the impact on treatment efficacy is presently unclear. Further studies on other cylinder models will be useful to evaluate the generalizability of these findings, as well as any potential effect on treatment.

Image-Guided Versus Conventional Brachytherapy for Locally Advanced Cervical Cancer: Experience of Single Institution with the Same Practitioner and Time Period.

This study aimed to compare treatment outcomes and toxicity profile between imaged-guided brachytherapy (IGBT) versus conventional brachytherapy (CBT) performed by the same practitioner during the same time period. Medical records of 104 eligible patients who underwent brachytherapy for locally advanced cervical cancer were retrospectively reviewed. Fifty patients (48.1%) underwent IGBT, and 54 (51.9%) patients underwent CBT. All patients underwent concurrent chemoradiation with cisplatin. High-dose-rate intracavitary brachytherapy with dose prescription of 25-30 Gy in 4-6 fractions was performed for all patients. Late lower gastrointestinal (GI) and urinary toxicities occurred more than 3 months after the end of brachytherapy were included for comparative and dosimetric analyses. The median follow-up period was 18.33 months (range, 3.25 to 38.43 months). There were no differences in oncologic outcomes between the two groups. The IGBT group had lower rate of actuarial grade ≥ 3 toxicity than the CBT group (2-year, 4.5% vs. 25.7%; p=0.030). Cumulative equieffective D2cc of sigmoid colon was significantly correlated with grade ≥ 2 lower GI toxicity (p=0.033), while equieffective D2cc of rectum (p=0.055) and bladder (p=0.069) showed marginal significance with corresponding grade ≥ 2 toxicities in the IGBT group. Half of grade ≥ 3 lower GI toxicities impacted GI tract above the rectum. Optimal thresholds of cumulative D2cc of sigmoid colon and rectum were 69.7 Gy and 70.8 Gy, respectively, for grade ≥ 2 lower GI toxicity. IGBT showed superior toxicity profile to CBT. Evaluating the dose to the GI tract above rectum by IGBT might prevent some toxicities.

Design and Development of Pharmacosome Loaded with Piroxicam to Improve Oral Bioavailability

The design of the present investigation was to prepare Piroxicam bounded pharmacosomes to improve the water solubility, bioavailability and to minimize the gastrointestinal toxicity of Piroxicam. Pharmacosome is a potential approach in vesicular drug delivery systems which exhibits several advantages over conventional vesicular drug delivery systems. Pharmacosomes are phospholipid complexes with a potential to improve bioavailability of poorly water soluble as well as poorly lipophilic drugs. Piroxicam was complexed with soya phosphatidylcholine in various ratios using conventional solvent evaporation technique. In our study, Pharmacosomes thus prepared were subjected to drug solubility, drug content evaluation, surface morphology (by scanning electron microscopy), crystallinity (by X- ray powder diffraction), quality control tests for capsules and in-vitro dissolution study. Solubility profile of the prepared complexes was found to be much better than Piroxicam pure drug. This improvement in solubility of the prepared pharmacosomes may result in improved dissolution and lower gastrointestinal toxicity. Drug content was found to be 96.84%w /W for the optimized Piroxicam phospholipid complex, F1 (Piroxicam: lecithin ratio of 1:1). The pharmacosomes were found to be disc shaped in scanning electron microscopy. X-ray powder diffraction data confirmed the formation of phospholipid complexes. The formulation F1 showed 94.69% drug release while the free Piroxicam showed a total of only 60.42% at the end of 10-hour dissolution study. Thus the solubility and hence the bioavailability of Piroxicam can be increased to a greater extent by complexing it with soya phosphatidylcholine.

PB2085: UPFRONT TREATMENT OF MANTLE CELL LYMPHOMA (MCL) WITH R-HDAC (RITUXIMAB-HIGH DOSE CYTARABINE + DEXAMETHASONE) IN YOUNG, HIGH RISK PATIENTS IS WELL TOLERATED AND LEADS TO DURABLE RESPONSES.

Background: MCL commonly presents as aggressive disease with a low cure rate and multiply relapsing/remitting course. Treatment of classical MCL with upfront intensive chemoimmunotherapy (CIT) consolidated with an autologous stem cell transplant (ASCT) is considered best practice in younger patients. There is no gold standard intensive CIT regimen. Common approaches include alternating RCHOP/RDHAP (Nordic) and R-Hyper-CVAD.(1) The addition of high dose Cytarabine (HDAC) has been shown to improve time to treatment failure (TTF), complete response (CR) rates and progression free survival (PFS). Aims: There is little published on the efficacy of R-HDAC in treatment-naive MCL, however a 2013 case series (Forbes et al) reported good early efficacy (CR in 16/18), with no detriment to harvest success. We describe tolerability and efficacy of upfront R-HDAC in a high risk cohort of younger patients with MCL. Methods: We identified 28 patients who received upfront R-HDAC in 3 UK centres from 2010–2021. Data were collected, anonymized and transferred centrally for analysis using Kaplan-Meier survival curves. Results: For baseline characteristics see Table 1. Treatment regimen: Dexamethasone 40mg d1-d4, Rituximab 500mg d1, Cytarabine 3000mg/m2 BD d2-d3 in 21day cycles. 22/28 (79%) completed their planned quota of 4-6cycles; 6/28 (21%) did not. Of these n=5 had progressive disease (PD), n=1 ceased with toxicity. 4/28 incurred cycle delays. 1 patient developed PD after completing R-HDAC. Haematological toxicity ≥ Grade 3 CTCAE: Anaemia 71%; Thrombocytopenia 93%; Neutropenia 93%. Fatigue (57%), Nausea 25%, Vomiting 7%, Constipation 21%, Diarrhoea 11%, Cardiac toxicity 11%, Pulmonary toxicity 18%, Rash 11%. 20/28 (71%) underwent stem cell transplant consolidation of which 19 had an ASCT. The median CD34+ stem cell harvest was 8.3x109^L/Kg (2.56-40.9) with no harvest failures. One patient underwent an allogeneic SCT. Of those who didn’t undergo transplant: 1/8 declined; 1/8 was ineligible; 6/8 had PD and switched to 2nd line therapy. Overall Response Rate (ORR) (RECIST) was 78%, CR 41%; PR (Partial response) 37%; and PD 22%. The median PFS was 3.39years (95% CI 0-7.937). 5y OS was 64.3% (95% CI 44.9-83.7%), median OS 8.7years (95% CI 2.634 – 14.894). Image:Summary/Conclusion: Our cohort showed higher rates of haematological toxicity, but lower gastrointestinal toxicity than those reported with the Nordic approach.(1) There were no incidents of treatment related mortality (TRM). More intensive regimens e.g. R-Hyper-CVAD have documented TRM rates of up to 8%. Only 1 patient in our cohort ceased treatment because of toxicity. Whilst our ORR is lower than those published in trial data on commonly used regimens (78% vs MCL Younger trial ORR: RCHOP arm 90%/Cytarabine arm 94%) our cohort’s baseline demographics are comparably much higher risk: MIPIb High 53% vs 25/20%; Blastoid disease 25% vs 9/8%. Of those with PD in our cohort, 4/6 had high MIPIb and blastoid disease. Despite this disparity, R-HDAC retains a comparable CR rate (41% vs 38%) and 5y OS (64.3% vs 65%). Whilst this observational retrospective study has limitations, it has shown that R-HDAC is an option for younger patients with high risk MCL. Using fewer CIT drugs could reduce toxicity and reserve more agents for use in future relapse.

Efficacy and Safety of Ceritinib 450 mg/day with Food and 750 mg/day in Fasted State in Treatment-Naïve Patients with ALK+ Non-Small Cell Lung Cancer: Results from the ASCEND-8 Asian Subgroup Analysis.

Previous report from the ASCEND-8 trial showed consistent efficacy with less gastrointestinal (GI) toxicity in patients with anaplastic lymphoma kinase-rearranged (ALK+) advanced/metastatic non-small cell lung cancer (NSCLC) treated with ceritinib 450-mg with food compared with 750-mg fasted. In this subgroup analysis, we report outcomes in Asian patients of the ASCEND-8 trial. Key efficacy endpoints were blinded independent review committee (BIRC)-assessed overall response rate (ORR) and duration of response (DOR) evaluated per Response Evaluation Criteria in Solid Tumors v1.1. Other efficacy endpoints were investigator-assessed ORR and DOR; BIRC- and investigator-assessed progression-free survival (PFS) and disease control rate; overall survival (OS). Safety was evaluated by frequency and severity of adverse events. At final data cutoff (6 March 2020), 198 treatment-naïve patients were included in efficacy analysis, of which 74 (37%) comprised the Asian subset; 450-mg fed (n=29), 600-mg fed (n=19), and 750-mg fasted (n=26). Baseline characteristics were mostly comparable across study arms. At baseline, more patients in 450-mg fed arm (44.8%) had brain metastases than in 750-mg fasted arm (26.9%). Per BIRC, patients in the 450-mg fed arm had a numerically higher ORR, 24-month DOR rate and 24-month PFS rate than the 750-mg fasted arm. The 36-month OS rate was 93.1% in 450-mg fed arm and 70.9% in 750-mg fasted arm. Any-grade GI toxicity occurred in 82.8% and 96.2% of patients in the 450-mg fed and 750-mg fasted arms, respectively. Asian patients with ALK+ advanced/metastatic NSCLC treated with ceritinib 450-mg fed showed numerically higher efficacy and lower GI toxicity than 750-mg fasted patients.

Clinicopathologic Features, Treatment Response, and Outcomes of Immune Checkpoint Inhibitor-Related Esophagitis.

Although immune checkpoint inhibitors (ICIs) have provided practice-changing outcomes in treating many cancers, ICI-related gastrointestinal toxicity can limit their use. Upper gastrointestinal toxicity is not common nor as well described as lower gastrointestinal toxicity. We aimed to characterize the clinical presentation, endoscopic and histologic features, treatment response, and outcomes of ICI-related esophagitis. We retrospectively studied patients at The University of Texas MD Anderson Cancer Center in whom esophagitis developed after receiving ICIs from June 2011 through January 2020. We included patients with endoscopic evidence of esophagitis and excluded those with other obvious causes of esophagitis. A chi-square test was used to assess associations between categorical variables. The Mann-Whitney U test was used to compare differences between continuous variables. Of 657 consecutive patients who underwent esophagogastroduodenoscopy (EGD) during or within 6 months of completing ICI-based therapy, 21 (3%) had esophagitis deemed to be from ICIs. Of these patients, 1 (5%) received an inhibitor of CTLA-4 alone, 15 (71%) received anti-PD-1 or PD-L1 monotherapy, and 5 (24%) received a combination of these. Median time from ICI initiation to onset of esophagitis was 4 months. Upon evaluation with EGD, only 3 patients (14%) had isolated esophageal involvement; 18 (86%) had concurrent involvement of the stomach, duodenum, or both. Most patients (67%) were treated with proton pump inhibitors, and 4 (19%) received steroids (prednisone or budesonide). The mortality rate was 38% (median follow-up, 15 months). Esophagitis associated with ICI use is rare. The diagnosis is one of exclusion because its clinical presentation appears similar to that of inflammation resulting from other causes. It often occurs in conjunction with other upper gastrointestinal toxicity. Symptoms are mild and respond well to nonimmunosuppressive treatment, with few severe complications.

Postoperative or Salvage Proton Radiotherapy for Prostate Cancer After Radical Prostatectomy.

PurposePostprostatectomy radiation improves disease control, but limited data exist regarding outcomes, toxicities, and patient-reported quality of life with proton therapy.Method and MaterialsThe first 102 patients who were enrolled on an outcome tracking protocol between 2006 and 2017 and treated with double-scattered proton therapy after prostatectomy were retrospectively reviewed. Eleven (11%) received adjuvant radiation, while 91 (89%) received salvage radiation. Seventy-four received double-scattered proton therapy to the prostate bed only. Twenty-eight received a double-scattered proton therapy prostate-bed boost after prostate-bed and pelvic-node treatment. Eleven adjuvant patients received a median dose of 66.6 GyRBE (range, 66.0-70.2). Ninety-one salvage patients received a median dose of 70.2 GyRBE (range, 66.0-78.0). Forty-five patients received androgen deprivation therapy for a median 9 months (range, 1-30). Toxicities were scored using Common Terminology Criteria for Adverse Events v4.0 criteria, and patient-reported quality-of-life data were reviewed.ResultsThe median follow-up was 5.5 years (range, 0.8-11.4 years). Five-year biochemical relapse-free and distant metastases-free survival rates were 72% and 91% for adjuvant patients, 57% and 97% for salvage patients, and 57% and 97% overall. Acute and late grade 3 or higher genitourinary toxicity rates were 1% and 7%. No patients had grade 3 or higher gastrointestinal toxicity. Acute and late grade 2 gastrointestinal toxicities were 5% and 2%. The mean values and SDs of the International Prostate Symptom Score, International Index of Erectile Function, and Expanded Prostate Cancer Index Composite bowel function and bother were 7.5 (SD = 5.9), 10.2 (SD = 8.3), 92.8 (SD = 11.1), and 91.2 (SD = 6.4), respectively, at baseline, and 12.1 (SD = 9.1), 10.1 (SD = 6.7), 87.3 (SD = 18), and 86.7 (SD = 13.8) at the 5-year follow-up.ConclusionHigh-dose postprostatectomy proton therapy provides effective long-term biochemical control and freedom from metastasis, with low acute and long-term gastrointestinal and genitourinary toxicity.

Hypofractionated radiotherapy for hepatocellular carcinomas adjacent to the gastrointestinal tract.

Decisions regarding therapeutic plans for inoperable patients with hepatocellular carcinoma (HCC) adjacent to the gastrointestinal (GI) tract are challenging because radiofrequency ablation has the potential risk of thermal injury. Moreover, the response rate of transcatheter arterial chemoembolization is relatively low and stereotactic body radiotherapy (SBRT) is believed to be too toxic. We have applied hypofractionated radiotherapy (HFRT) for such lesions. This study investigated the outcomes and toxicities of this treatment. Among consecutive HCC patients treated with radiotherapy with curative intent at our institution between 2015 and 2019, we retrospectively extracted those outside of the indication for SBRT due to exceeding the constraint of the GI tract and who were treated using HFRT with a prescription dose of 42Gy in 14 fractions and prophylactic proton pump inhibitor administration for 6 months. The oncological outcomes and toxicities were investigated. A total of 66 patients with 73 lesions were eligible. The median follow-up period was 24.0 months. The local recurrence, intrahepatic recurrence, liver-related death, and overall survival rates at 2 years were 11.3%, 50.6%, 15.9%, and 60.4%, respectively. Six (9.1%) patients experienced Child-Pugh score deterioration ≥2 within 6 months following treatment. Two and one patient developed grades 2 and 3 gastroduodenal bleeding, respectively. HFRT can achieve good local control in patients with HCC adjacent to the GI tract, with low GI toxicity incidence. Our study demonstrated that HFRT can be a potentially curative treatment option for lesions.

S0451 Clinicopathologic Features, Treatment Response, and Outcomes of Immune Checkpoint Inhibitor-Related Esophagitis

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have shown practice-changing results in the treatment of many cancers, however, ICI-related gastrointestinal (GI) toxicity can limit their use. Upper GI toxicity is not as common nor as well described as lower GI toxicity. We aim to characterize esophagitis associated with ICIs by describing its clinical presentation, endoscopic features, histological findings, treatment response and outcomes. METHODS: This is a retrospective study of patients at a tertiary cancer center who developed esophagitis after receiving ICI between June 2011 and January 2020. The diagnosis of esophagitis was made based on esophagogastroduodenoscopy (EGD) findings. Patients with pre-existing gastro-esophageal disease, and recent head/neck/chest radiation were excluded. A χ2 test was used to determine associations between categorical variables. A Mann-Whitney U test was used to compare differences between continuous variables. RESULTS: Of the 657 consecutive patients who underwent EGD during or within 6 months of completing ICI therapy, 21 (3%) developed esophagitis of unclear etiology, which was deemed to be related to ICI. Of these patients, one (5%) received an inhibitor of cytotoxic T-lymphocyte associated antigen 4 alone, 15 (71%) received an inhibitor of programmed cell death protein 1 or its ligand alone, and 5 (24%) received a combination of the two classes (Table 1). The median time between the initiation of ICI and onset of esophagitis was 4 months. On EGD, isolated esophageal involvement was only seen in 3 patients (24%); distribution of esophagitis varied widely within the esophagus. Eighteen patients (86%) had concurrent involvement of the stomach, duodenum, or both. Histology showed signs of both acute and chronic inflammation (Figure 1). Proton pump inhibitors (PPIs) were used in 14 patients (67%). Steroids (prednisone or budesonide) were used in 4 patients (19%). Repeat endoscopy was only performed in 5 patients, 4 (75%) of which had complete resolution. There was a 38% mortality in our cohort during the study period (median follow up was 15 months) attributed to their underlying malignancy (Table 2). CONCLUSION: Esophagitis associated with ICI is rare. The diagnosis is one of exclusion since its clinical presentation appears similar to inflammation due to other causes. Symptoms are mild and respond well to non-immunosuppressive treatment with very few severe complications.Figure 1.: Endoscopic and histological features of ICI-related esophagitis. (A) Multiple large circumferential ulcers found in the middle third of the esophagus. (B) Inflammation noted in the gastro-esophageal junction (C) Non-bleeding erosions in the lower third of the esophagus. (D) Chronic active esophagitis, with increased neutrophils in squamous epithelium and lamina propria. Granulation tissue, clusters of lymphocytes and plasma cells in lamina propria (H&E, 20x). (E) Esophageal ulceration with underlying chronic active inflammation (H&E, 20x).Table 1.: Clinical information related to ICI and esophagitis (n = 21)Table 2.: Endoscopic findings, pathologic findings, treatment and outcomes (n = 21)

Acute Side Effects with High Dose Rate Computed Tomography-guided Three-dimensional Brachytherapy in Carcinoma Cervix.

To determine the frequency and grades of acute side effects with three-dimensional brachytherapy in carcinoma cervix using RTOG/EORTC acute radiation morbidity scoring criteria. Descriptive study. Department of Radiotherapy, Institute of Nuclear Medicine and Oncology (INMOL), Lahore, Pakistan from July 2016 to September 2017. A total of 55 histologically proven patients of squamous cell carcinoma of the cervix, aged between 16-70 years, were included. Patients with previous radiotherapy in pelvic area, inflammatory bowel diseases and known diabetics, were excluded. All patients were given a radiation dose of 7 Gray in 4 insertions through 3-dimensional conformal brachytherapy planning. Acute vaginal, gastrointestinal, and genitor-urinary side effects of brachytherapy were assessed. Mean age of the patient population was 47.09 ±13.10 years (Range: 21-68). Mean time to presentation was 5.65 ±2.32 months and mean tumor size was 3.67 ±1.47 cm. Majority, i.e. 18 (32.7%) patient presented in stage III. Most of the patients, 26 (47.3%), had ECOG-2 performance status. Grade-1 genitourinary toxicity was significantly high (p <0.001). In lower gastrointestinal toxicity, Grade-1 was the highest being 54.5%. Conversely, vaginal toxicities of grade-2 and 3 were most commonly seen. Stratification of acute side effectswith respect toage, stage and tumor size revealed no significant association except in mucosal membrane toxicity, which was affected by tumor size (p = 0.004). Three-dimensional brachytherapy in carcinoma cervix is a safe and tolerable procedure with minimal acute side effects. Key Words: Cervical cancer, Brachytherapy, Acute toxicities, Computed tomography.

Moderately hypofractionated carbon ion radiotherapy for prostate cancer; a prospective observational study \u201cGUNMA0702\u201d

BackgroundCarbon ion Radiotherapy for prostate cancer is widely used, however reports are limited from single institute or short follow up. We performed a prospective observational study (GUNMA0702) to evaluate the feasibility and efficacy of carbon ion radiotherapy for localized and locally advanced prostate cancer.MethodsBetween June 2010 and August 2013, 304 patients with localized prostate cancer were treated, with a median follow-up duration of 60 months. All patients received carbon ion radiotherapy with 57.6 Gy (RBE) in 16 fractions over 4 weeks. Hormonal therapy was given according to the risk group. Toxicity was reported according to the Common Toxicity Criteria for Adverse Event, Version 4.0 by the National Cancer Institute.ResultsThe overall 5-year biochemical relapse-free rate was 92.7%, with rates of 91.7, 93.4, and 92.0% in low-risk, intermediate-risk, and high-risk patients, respectively. The 5-year local control and overall survival rates were 98.4 and 96.6%, respectively. Acute grade 3 or greater toxicity was not observed. Late grade 2 and grade 3 genitourinary and gastrointestinal toxicity rates were 9 and 0.3%, and 0.3, and 0%, respectively.ConclusionsThe present protocol of carbon ion radiotherapy for prostate cancer provided low genitourinary and gastrointestinal toxicity with good biochemical control within 5 years.Trial registrationUniversity Medical Information Network Clinical Trial Registry number: UMIN000003827.

Role of Mediterranean diet in preventing platinum based gastrointestinal toxicity in gynecolocological malignancies: A single Institution experience.

BACKGROUNDGynecological malignancies represent a major cause of death in women and are often treated with platinum-based regimens. Patients undergoing chemotherapy suffer from alterations in nutritional status which may worsen gastrointestinal (GI) toxicities, quality of life and affect the overall prognosis. Indeed, assuring a good nutritional status and limiting toxicities during treatment are still major goals for clinicians.AIMTo assess the role of Mediterranean Diet (MD) in reducing GI toxicities in patients with gynecological cancers treated with platinum-based regimens.METHODSWe conducted an observational study on 22 patients with gynecological tumors treated with a platinum-based chemotherapy at Candiolo Cancer Institute FPO/IRCCS between January 2018 and June 2018. The food and frequency (FFQ) and the Patient-Reported Outcomes Common Terminology Criteria For Adverse Events (PRO-CTCAE) questionnaires were administered at baseline and at every Day 1 of each cycle. To evaluate the differences in GI toxicities the study population was divided in two groups according to the currently validated Mediterranean Diet Serving Score (MDSS) at baseline.RESULTSPatients with high MDSS reported a trend toward lower GI toxicities according to PRO-CTCAE at each timepoint (first evaluation: P = 0.7; second: P = 0.52; third: P = 0.01). In particular, difference in nausea frequency and gravity (P < 0.001), stomach pain frequency and gravity (P = 0.01 and P = 0.02), abdomen bloating frequency and gravity (P = 0.02 and P = 0.03), and interference with daily activities (P = 0.02) were highly statistically significant at the end of treatment. More than 60% of patients changed their food habits during chemotherapy mainly because of GI toxicities. A higher reduction of food intake, both in terms of caloric (P = 0.29) and of single nutrients emerged in the group experiencing higher toxicity.CONCLUSIONOur results show that adherence to MD possibly reduces GI toxicity and prevents nutritional status impairment during chemotherapy treatment. Bigger studies are needed to confirm our results.

Retreatment for Local Recurrence of Prostatic Carcinoma After Prior Therapeutic Irradiation: Efficacy and Toxicity of HDR-Like SBRT

We evaluated the use of high dose-rate-like stereotactic body radiation therapy (SBRT) retreatment for biopsy-proven local persistence in prostate postradiation therapy, evaluating efficacy and toxicity. From 2009 to 2018, 50 patients with biopsy-proven recurrent prostate cancer >2 years after prior treatment were retreated with a high dose-rate-like dose of 3400 cGy over 5 fractions. Previous radiation therapy dose measured 75.6 Gy (64.8-81.0) and median salvage interval was 8.1 years (32-241 mo.). Eighty-three percent of patients had Gleason score 7 or higher disease at retreatment. Those with preexisting toxicity >grade 1 from their prior course were excluded. The planning target volume was comprised of the clinical target volume (prostate + any contiguous extension only) with no additional expansion. Toxicity assessment used CTCAE v.3.0 criteria. Median follow-up was 44 months (3-110). Median pre-SBRT salvage baseline prostate specific antigen (PSA) of 3.97 ng/mL decreased to 0.6 ng/mL and 0.16 ng/mL at 1 and 5 years in nonrelapsed patients, respectively. Actuarial 5-year biochemical disease-free survival (DFS) measured 60%, with corresponding 5-year actuarial local, distant, and salvage androgen deprivation therapy free rates of 94%, 89%, and 69%, respectively. Actuarial 5-year biochemical DFS measured 78% if PSA at salvage was <6.92 ng/mL versus 12% with ≥6.92 ng/mL (P = .0001). Toxicity was primarily in the GU domain, with an 8% 5-year actuarial rate of grade 3+, 3% when limited to salvage of "conventional external beam only" local relapse. No gastrointestinal (GI) toxicity >grade 1 occurred. Of the 30% sexually potent at the time of salvage, 82% subsequently lost potency. SBRT salvage of local prostate recurrence in previously irradiated patients appears clinically feasible in this challenging group. It demonstrates favorable PSA and DFS response, typically deferring the need for salvage androgen deprivation therapy or other treatment by over 5 years, with low GU and GI toxicity.

Synthesis and Pharmacological Activity of S(-)-2-Amino-2-Methyl-3-Phenylpropanoic Acid

Taking into account the high efficacy of 2-arylpropionic acid derivatives among NSAIDs and based on their SARs, we have evaluated the anti-inflammatory, antinociceptive, and antiaggregant activity and ulcerogenic properties of a new synthesized non-protein amino acid (NPAA) derivative S(-)-2-amino-2-methyl-3-phenylpropanoic acid (NPAA-36). A new method of NPAA-36 synthesis was developed and experiments were carried out, which showed that this compound injected in a dose of 10 mg/kg (i.p.) inhibited xylene-induced ear oedema by about 31.1%, which proved its anti-inflammatory properties. The antinociceptive activity of NPAA-36 was assessed in tail-flick test by the ability to increase the tail cut-off latency by 36.78% within 60 min after injection at the same dose. Investigation of the ulcerogenic properties of NPAA-36 demonstrated that it exhibited lower gastrointestinal toxicity than a well-known arylpropionic acid derivative NSAID. Results of in vitro experiments showed the antiplatelet activity registered not in all (only in 41.2%) cases, which might imply lower bleeding. The obtained data indicate that the new NPAAderivative can be a potential basis for the development of new anti-inflammatory drugs with weak side effects.

Safety of Topical Non-steroidal Anti-Inflammatory Drugs in Osteoarthritis: Outcomes of a Systematic Review and Meta-Analysis.

ObjectiveWe aimed to assess the safety of topical non-steroidal anti-inflammatory drugs (NSAIDs) in the management of osteoarthritis (OA) in a systematic review and meta-analysis of randomized, placebo-controlled trials.MethodsA comprehensive literature search was undertaken in the MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and Scopus electronic databases. Randomized, double-blind, placebo-controlled, parallel-group trials that assessed adverse events (AEs) with topical NSAIDs in patients with OA were eligible for inclusion. Authors and/or study sponsors were contacted to obtain the full report of AEs. The primary outcomes were overall severe and serious AEs, as well as the following MedDRA System Organ Class (SOC)-related AEs: gastrointestinal, vascular, cardiac, nervous system, skin and subcutaneous tissue, musculoskeletal and connective tissue.ResultsThe search strategy identified 1209 records, from which 25 papers were included in the qualitative synthesis and 19 were included in the meta-analysis, after exclusions. Overall, more total AEs (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.04–1.29; I2 = 0.0%) and more withdrawals due to AEs (OR 1.49, 95% CI 1.15–1.92; I2 = 0.0%) were observed with topical NSAIDs compared with placebo. The same results were achieved with topical diclofenac, largely driven by an increase in skin and subcutaneous tissue disorders (OR 1.73, 95% CI 0.96–3.10), although the difference was not statistically significant compared with placebo. No significant difference in the odds for gastrointestinal disorders was observed between topical NSAIDs and placebo (OR 0.96, 95% CI 0.73–1.27).ConclusionsTopical NSAIDs may be considered safe in the management of OA, especially with regard to low gastrointestinal toxicity. The use of topical NSAIDs in OA should be considered, taking into account their risk: benefit profile in comparison with other anti-OA treatments.Electronic supplementary materialThe online version of this article (10.1007/s40266-019-00661-0) contains supplementary material, which is available to authorized users.

GST (Gefitinib as Salvage Treatment) in Pretreated Head and Neck Squamous Cell Cancer

Purpose: To determine the efficacy and safety profiles of GST (gefitinib as salavage therapy) in patients with advanced recurrent, residual and/or metastatic squamous cell cancer of the head and neck (HNSCC). Subjects and Methods: Patients with recurrent, residual, or metastatic (R/R/M) HNSCC, were treated with gefitinib 250mg orally daily for 3 weeks. Results and Conclusion: Partial response (PR) was noted in 10% of patients, median progression free survival (PFS) was 3.3 months. Anemia was observed in 16.7% of patients, toxicity related to total leucocyte count grade I,II &III toxicities were observed in 20%, 3.3% and 0%. Only grade I hepatic toxicity was observed in 20%. No case of renal toxicity was seen. Grade I-II upper gastrointestinal toxicity (nausea/ vomiting) was noted in 13.3% patients. Lower gastrointestinal toxicity (diarrhea) was observed in 46.7% of patients. Skin rash was graded and 8 (26.7%) patients demonstrated skin reactions. Overall survival (OS) was 4 months. Gefitinib was well tolerated in this heavily pretreated HNSCC population and produced prolonged disease stabilization.