Gastrointestinal Toxic Effects Research Articles

Adjuvant Chemotherapy for Upper Tract Urothelial Carcinoma: A Real-World, Retrospective Study.

The aim of this retrospective study was to evaluate the efficacy of adjuvant cisplatin-based chemotherapy in patients with locally-advanced upper tract urothelial carcinoma (UTUC), administered following radical nephroureterectomy. Patients with UTUC, arising from renal pelvis or ureter, staged pT3/T4 or N+ were treated with adjuvant chemotherapy following surgery. The chemotherapy consisted of gemcitabine 1,000 mg/m2 on days 1 and 8, cisplatin 70 mg/m2 on day 1. Treatment was repeated every 3 weeks for up to 4 cycles. Endpoints included disease-free survival (DFS), metastasis-free survival (MFS), and safety. Among 89 eligible patients, 85 (96%) completed at least 3 cycles of adjuvant chemotherapy. Chemotherapy was well tolerated, the main toxicities being mild-to-moderate gastrointestinal toxic effects and pruritus. With a median follow-up of 37 months, median DFS was 30 months (95% CI, 22 to 39), and the median MFS was not reached. The 3-year DFS and MFS were 44% and 56%, respectively. Multivariate analyses revealed that the main factor associated with DFS and MFS was the lymph node involvement, whereas age, T stage, grade, or the primary site of UTUC were not significantly associated with DFS or MFS. Adjuvant cisplatin-based chemotherapy after radical surgery of pT3/T4 or N+ UTUC was feasible and may demonstrate benefits in DFS and MFS. Whether novel agents added to the chemotherapy regimen, as a concurrent combination or maintenance, impacts on survival or reduces the development of metastases remains to be studied.

Accelerated Hypofractionated Chemoradiation Followed by Stereotactic Ablative Radiotherapy Boost for Locally Advanced, Unresectable Non–Small Cell Lung Cancer

Intrathoracic progression remains the predominant pattern of failure in patients treated with concurrent chemoradiation followed by a consolidation immune checkpoint inhibitor for locally advanced, unresectable non-small cell lung cancer (NSCLC). To determine the maximum tolerated dose (MTD) and use of hypofractionated concurrent chemoradiation with an adaptive stereotactic ablative radiotherapy (SABR) boost. This was an early-phase, single-institution, radiation dose-escalation nonrandomized controlled trial with concurrent chemotherapy among patients with clinical stage II (inoperable/patient refusal of surgery) or III NSCLC (American Joint Committee on Cancer Staging Manual, seventh edition). Patients were enrolled and treated from May 2011 to May 2018, with a median patient follow-up of 18.2 months. Patients advanced to a higher SABR boost dose if dose-limiting toxic effects (any grade 3 or higher pulmonary, gastrointestinal, or cardiac toxic effects, or any nonhematologic grade 4 or higher toxic effects) occurred in fewer than 33% of the boost cohort within 90 days of follow-up. The current analyses were conducted from January to September 2023. All patients first received 4 Gy × 10 fractions followed by an adaptive SABR boost to residual metabolically active disease, consisting of an additional 25 Gy (low, 5 Gy × 5 fractions), 30 Gy (intermediate, 6 Gy × 5 fractions), or 35 Gy (high, 7 Gy × 5 fractions) with concurrent weekly carboplatin/paclitaxel. The primary outcome was to determine the MTD. Data from 28 patients (median [range] age, 70 [51-88] years; 16 [57%] male; 24 [86%] with stage III disease) enrolled across the low- (n = 10), intermediate- (n = 9), and high- (n = 9) dose cohorts were evaluated. The protocol-specified MTD was not exceeded. The incidences of nonhematologic acute and late (>90 days) grade 3 or higher toxic effects were 11% and 7%, respectively. No grade 3 toxic effects were observed in the intermediate-dose boost cohort. Two deaths occurred in the high-dose cohort. Two-year local control was 74.1%, 85.7%, and 100.0% for the low-, intermediate-, and high-dose cohorts, respectively. Two-year overall survival was 30.0%, 76.2%, and 55.6% for the low-, intermediate-, and high-dose cohorts, respectively. This early-phase, dose-escalation nonrandomized controlled trial showed that concurrent chemoradiation with an adaptive SABR boost to 70 Gy in 15 fractions with concurrent chemotherapy is a safe and effective regimen for patients with locally advanced, unresectable NSCLC. ClinicalTrials.gov Identifier: NCT01345851.

Gastrointestinal Degradation and Toxicity of Disinfection Byproducts in Drinking Water Using In Vitro Models and the Roles of Gut Microbiota.

Disinfection byproducts (DBPs) in drinking water are mainly exposed to the human body after oral ingestion and degradation in the gastrointestinal tract. The role of gastrointestinal degradation in the toxic effects of DBPs still needs further investigation. In this study, the degradation of five categories of DBPs (22 DBPs) in the stomach and small intestine was investigated based on a semicontinuous steady-state gastrointestinal simulation system, and 22 DBPs can be divided into three groups based on their residual proportions. The degradation of chloroacetonitrile (CAN), dibromoacetic acid (DBAA), and tetrabromopyrrole (FBPy) was further analyzed based on the Simulator of the Human Intestinal Microbial Ecosystem inoculating the gut microbiota, and approximately 60% of CAN, 45% of DBAA, and 80% of FBPy were degraded in the stomach and small intestine, followed by the complete degradation of remaining DBPs in the colon. Meanwhile, gastrointestinal degradation can reduce oxidative stress-mediated DNA damage and apoptosis induced by DBPs in DLD-1 cells, but the toxicity of DBPs did not disappear with the complete degradation of DBPs, possibly because of their interferences on gut microbiota. This study provides new insights into investigating the gastrointestinal toxic effects and mechanisms of DBPs through oral exposure.

Hyaluronic Acid Spacer for Hypofractionated Prostate Radiation Therapy

Hypofractionated radiation therapy (RT) for prostate cancer has been associated with greater acute grade 2 gastrointestinal (GI) toxic effects compared with conventionally fractionated RT. To evaluate whether a hyaluronic acid rectal spacer could (1) improve rectal dosimetry and (2) affect acute grade 2 or higher GI toxic effects for hypofractionated RT. This randomized clinical trial was conducted from March 2020 to June 2021 among 12 centers within the US, Australia, and Spain, with a 6-month follow-up. Adult patients with biopsy-proven, T1 to T2 prostate cancer with a Gleason score 7 or less and prostate-specific antigen level of 20 ng/mL or less (to convert to μg/L, multiply by 1) were blinded to the treatment arms. Of the 260 consented patients, 201 patients (77.3%) were randomized (2:1) to the presence or absence of the spacer. Patients were stratified by intended 4-month androgen deprivation therapy use and erectile quality. For the primary outcome, we hypothesized that more than 70% of patients in the spacer group would achieve a 25% or greater reduction in the rectal volume receiving 54 Gy (V54). For the secondary outcome, we hypothesized that the spacer group would have noninferior acute (within 3 months) grade 2 or higher GI toxic effects compared with the control group, with a margin of 10%. Of the 201 randomized patients, 8 (4.0%) were Asian, 26 (12.9%) Black, 42 (20.9%) Hispanic or Latino, and 153 (76.1%) White; the mean (SD) age for the spacer group was 68.6 (7.2) years and 68.4 (7.3) years for the control group. For the primary outcome, 131 of 133 (98.5%; 95% CI, 94.7%-99.8%) patients in the spacer group experienced a 25% or greater reduction in rectum V54, which was greater than the minimally acceptable 70% (P < .001). The mean (SD) reduction was 85.0% (20.9%). For the secondary outcome, 4 of 136 patients (2.9%) in the spacer group and 9 of 65 patients (13.8%) in the control group experienced acute grade 2 or higher GI toxic effects (difference, -10.9%; 95% 1-sided upper confidence limit, -3.5; P = .01). The trial results suggest that rectal spacing with hyaluronic acid improved rectal dosimetry and reduced acute grade 2 or higher GI toxic effects. Rectal spacing should potentially be considered for minimizing the risk of acute grade 2 or higher toxic effects for hypofractionated RT. ClinicalTrials.gov Identifier: NCT04189913.

Outcomes and Prognostic Factors for Locally Recurrent Rectal Cancer Treated With Proton Beam Therapy

Our objective was to report the outcome and prognostic factors for patients with locally recurrent rectal cancer (LRRC) treated with proton beam therapy (PBT) at our institution. The study included PBT-treated patients with LRRC between December 2008 and December 2019. Treatment response was stratified using an initial imaging test after PBT. Overall survival (OS), progression-free survival (PFS), and local control (LC) were estimated using the Kaplan-Meier method. Each outcome's prognostic factors were verified using the Cox proportional hazards model. Twenty-three patients were enrolled (median follow-up, 37.4 months). There were 11 patients with complete response (CR) or complete metabolic response (CMR), 8 with partial response or partial metabolic response, 2 with stable disease or stable metabolic response, and 2 with progressive disease or progressive metabolic disease. Three- and 5-year OS, PFS, and LC were 72.1% and 44.6%, 37.9% and 37.9%, and 55.0% and 47.2%, respectively, with 54.4 months' median survival time. The maximum standardized uptake value of fluorine-18-fluorodeoxyglucose-positron emission tomography-computed tomography (18F-FDG-PET/CT) before PBT (cutoff value, 10) showed significant differences in OS (P=.03), PFS (P=.027), and LC (P=.012). The patients who achieved CR or CMR after PBT had significantly better LC than those with non-CR or non-CMR (hazard ratio, 4.49; 95% confidence interval, 1.14-17.63; P=.021). Older patients (aged ≥65 years) had significantly higher LC and PFS rates. Patients with pain before PBT and larger tumors (≥30 mm) also had significantly lower PFS. Of 23 patients, 12 (52%) experienced further local recurrence after PBT. One patient developed grade 2 acute radiation dermatitis. Regarding late toxicity, grade 4 late gastrointestinal toxic effects were recorded in 3 patients, in 2 of whom reirradiation was associated with further local recurrence after PBT. The results showed that PBT may have potential to be a good treatment option for LRRC. 18F-FDG-PET/CT before and after PBT may be useful for assessing tumor response and predicting outcomes.

Magnetic Resonance Imaging–Guided vs Computed Tomography–Guided Stereotactic Body Radiotherapy for Prostate Cancer

Magnetic resonance imaging (MRI) guidance offers multiple theoretical advantages in the context of stereotactic body radiotherapy (SBRT) for prostate cancer. However, to our knowledge, these advantages have yet to be demonstrated in a randomized clinical trial. To determine whether aggressive margin reduction with MRI guidance significantly reduces acute grade 2 or greater genitourinary (GU) toxic effects after prostate SBRT compared with computed tomography (CT) guidance. This phase 3 randomized clinical trial (MRI-Guided Stereotactic Body Radiotherapy for Prostate Cancer [MIRAGE]) enrolled men aged 18 years or older who were receiving SBRT for clinically localized prostate adenocarcinoma at a single center between May 5, 2020, and October 1, 2021. Data were analyzed from January 15, 2021, through May 15, 2022. All patients had 3 months or more of follow-up. Patients were randomized 1:1 to SBRT with CT guidance (control arm) or MRI guidance. Planning margins of 4 mm (CT arm) and 2 mm (MRI arm) were used to deliver 40 Gy in 5 fractions. The primary end point was the incidence of acute (≤90 days after SBRT) grade 2 or greater GU toxic effects (using Common Terminology Criteria for Adverse Events, version 4.03 [CTCAE v4.03]). Secondary outcomes included CTCAE v4.03-based gastrointestinal toxic effects and International Prostate Symptom Score (IPSS)-based and Expanded Prostate Cancer Index Composite-26 (EPIC-26)-based outcomes. Between May 2020 and October 2021, 156 patients were randomized: 77 to CT (median age, 71 years [IQR, 67-77 years]) and 79 to MRI (median age, 71 years [IQR, 68-75 years]). A prespecified interim futility analysis conducted after 100 patients reached 90 or more days after SBRT was performed October 1, 2021, with the sample size reestimated to 154 patients. Thus, the trial was closed to accrual early. The incidence of acute grade 2 or greater GU toxic effects was significantly lower with MRI vs CT guidance (24.4% [95% CI, 15.4%-35.4%] vs 43.4% [95% CI, 32.1%-55.3%]; P = .01), as was the incidence of acute grade 2 or greater gastrointestinal toxic effects (0.0% [95% CI, 0.0%-4.6%] vs 10.5% [95% CI, 4.7%-19.7%]; P = .003). Magnetic resonance imaging guidance was associated with a significantly smaller percentage of patients with a 15-point or greater increase in IPSS at 1 month (6.8% [5 of 72] vs 19.4% [14 of 74]; P = .01) and a significantly reduced percentage of patients with a clinically significant (≥12-point) decrease in EPIC-26 bowel scores (25.0% [17 of 68] vs 50.0% [34 of 68]; P = .001) at 1 month. In this randomized clinical trial, compared with CT-guidance, MRI-guided SBRT significantly reduced both moderate acute physician-scored toxic effects and decrements in patient-reported quality of life. Longer-term follow-up will confirm whether these notable benefits persist. ClinicalTrials.gov Identifier: NCT04384770.

Acute and Late Adverse Effects of Prostate-Only or Pelvic Stereotactic Radiation Therapy in Prostate Cancer: A Comparative Study

To compare the urinary and gastrointestinal adverse effects with or without the inclusion of pelvic nodal regions in patients treated with extreme hypofractionated stereotactic radiation therapy (SBRT) for prostate cancer. Patients treated with definitive SBRT for nonmetastatic adenocarcinoma prostate were identified from prospectively maintained institutional database, and details of radiation therapy volume, dose, acute, and late adverse effects were analyzed. Symptoms of acute (within 90 days of completing SBRT) and late gastrointestinal and urinary toxic effects were graded using Common Terminology Criteria for Adverse Effects version 5.0. Each symptom was scored according to the worst reported grading during treatment and the follow-up period. Cumulative rates of adverse effects between prostate-only SBRT (PO-SBRT) and whole pelvic SBRT (WP-SBRT) were compared using the χ2 test. Univariable and multivariable analysis was performed for possible factors affecting acute gastrointestinal and late urinary toxic effects. A total of 220 patients were analyzed (PO-SBRT = 118, WP-SBRT = 102), with a median follow-up of 28 months (interquartile range, 14-40). Most patients had locally advanced disease (PO-SBRT 60% high risk and 40% intermediate risk, WP-SBRT 79% node positive, and 21% high risk). The median SBRT dose was 36.25Gy (interquartile range, 35-36.25) to the prostate (2-Gy equivalent, EQD2 = 90.6Gy, a/b = 1.5Gy) and simultaneous integrated 25Gy to the pelvis (EQD2 = 46.3Gy) in 5 fractions on alternate days. No grade 3 to 4 acute adverse effects were observed except 1 grade 3 urinary obstruction (PO-SBRT). WP-SBRT was associated with a significantly higher rate of acute grade 2 gastrointestinal toxic effects (29.4% vs 14.7%, P = .008) and late grade 2 urinary adverse effects (45.6% vs 25.0%, P = .003). Both groups had low incidence of late grade 3 adverse effects (urinary 2.5%, gastrointestinal 1%). WP-SBRT was associated with significantly higher acute gastrointestinal and late urinary adverse effects compared with PO-SBRT, although overall incidence of severe adverse effects was low.

28-Year-Old Man With Joint Pain

28-Year-Old Man With Joint Pain

Meta-analysis of Elective Pelvic Nodal Irradiation Using Moderate Hypofractionation for High-Risk Prostate Cancer

Despite several advances in planning and delivery of radiation therapy (RT) for prostate cancer, the role of elective pelvic nodal irradiation (EPNI) remains controversial for high-risk disease. We performed a meta-analysis to evaluate the outcomes of patients treated with moderate hypofractionated RT (MHF-RT) with EPNI using modern RT techniques. Eligible studies were identified on MEDLINE, Embase, the Cochrane Library, and proceedings of annual meetings through October 2021. We followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) and MOOSE (Meta-analyses of Observational Studies in Epidemiology) guidelines. A metaregression analysis was performed to assess a possible correlation between selected variables and outcomes. A P value <.05 was considered significant. Eighteen studies with a total of 1745 patients (median follow-up, 61 months) treated with EPNI using MHF-RT were included. The biochemical relapse-free survival at 5, 7, and 10 years was 90% (95% confidence interval [CI], 88%-94%), 83% (95% CI, 78%-91%), and 78% (95% CI, 68%-88%). The 5-year prostate cancer-specific survival, disease-free survival, distant metastases-free survival, and overall survival were 98% (95% CI, 97%-99%), 88.7% (95% CI, 85%-93%), 91.2% (95% CI, 88%-92%), and 93% (95% CI, 90%-96%), respectively. The rates of local, pelvic, and distant recurrence were 0.38% (95% CI, 0%-2%), 0.13% (95% CI, 0%-1.5%), and 7.35% (95% CI, 2%-12%), respectively. The rate of late grade ≥2 gastrointestinal and genitourinary toxic effects were 6.7% (95% CI, 4%-9%) and 11.3% (95% CI, 7.6%-15%), with heterogeneity, but with rare cases of grade 3 to 5 toxic effects. EPNI with concomitant MHF-RT provides satisfactory biochemical relapse-free survival in long-term follow-up, with low rates of genitourinary and gastrointestinal severe toxic effects and minimal pelvic and local failure.

Quality-of-Life Outcomes and Toxic Effects Among Patients With Cancers of the Uterus Treated With Stereotactic Pelvic Adjuvant Radiation Therapy

Adjuvant radiation plays an important role in reducing locoregional recurrence in patients with uterine cancer. Although hypofractionated radiotherapy may benefit health care systems and the global community while decreasing treatment burden for patients traveling for daily radiotherapy, it has not been studied prospectively nor in randomized trials for treatment of uterine cancers, and the associated toxic effects and patient quality of life are unknown. To evaluate acute genitourinary and bowel toxic effects and patient-reported outcomes following stereotactic hypofractionated adjuvant radiation to the pelvis for treatment of uterine cancer. The Stereotactic Pelvic Adjuvant Radiation Therapy in Cancers of the Uterus (SPARTACUS) phase 1/2 nonrandomized controlled trial of patients accrued between May 2019 and August 2021 was conducted as a multicenter trial at 2 cancer centers in Ontario, Canada. In total, 61 patients with uterine cancer stages I through III after surgery entered the study. Stereotactic adjuvant pelvic radiation to a dose of 30 Gy in 5 fractions administered every other day or once weekly. Assessments of toxic effects and patient-reported quality of life (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires C30 and endometrial EN24) were collected at baseline, fractions 3 and 5, and at 6 weeks and 3 months of follow-up. Descriptive analysis was conducted, calculating means, SDs, medians, IQRs, and ranges for continuous variables and proportions for categorical variables. Univariate generalized linear mixed models were generated for repeated measurements on the quality-of-life scales. A total of 61 patients were enrolled (median age, 66 years; range, 51-88 years). Tumor histologic results included 39 endometrioid adenocarcinoma, 15 serous or clear cell, 3 carcinosarcoma, and 4 dedifferentiated. Sixteen patients received sequential chemotherapy, and 9 received additional vault brachytherapy. Median follow-up was 9 months (IQR, 3-15 months). Of 61 patients, worst acute gastrointestinal tract toxic effects of grade 1 were observed in 33 patients (54%) and of grade 2 in 8 patients (13%). For genitourinary worst toxic effects, grade 1 was observed in 25 patients (41%) and grade 2 in 2 patients (3%). One patient (1.6%) had an acute grade 3 gastrointestinal tract toxic effect of diarrhea at fraction 5 that resolved at follow-up. Only patient-reported diarrhea scores were both clinically (scores ≥10) and statistically significantly worse at fraction 5 (mean [SD] score, 35.76 [26.34]) compared with baseline (mean [SD] score, 6.56 [13.36]; P < .001), but this symptom improved at follow-up. Results of this phase 1/2 nonrandomized controlled trial suggest that stereotactic hypofractionated radiation was well tolerated at short-term follow-up for treatment of uterine cancer. Longer follow-up and future randomized studies are needed to further evaluate this treatment. ClinicalTrials.gov Identifier: NCT04866394.

Multiagent Chemotherapy and Stereotactic Body Radiation Therapy in Patients with Unresectable Pancreatic Adenocarcinoma: A Prospective Nonrandomized Controlled Trial

PurposeIn a prospective multicenter study, gemcitabine monotherapy followed by stereotactic body radiation therapy (SBRT) was well tolerated with outcomes comparable to chemoradiation for locally advanced pancreatic cancer (LAPC). Recent trials have reported improved survival with multiagent chemotherapy (MA-CTX) alone. This prospective trial explored whether SBRT could be safely delivered after MA-CTX. Herein, we report the long-term outcomes of adding SBRT after MA-CTX in LAPC patients and evaluate whether genetic profiles of specimens obtained before SBRT influence outcomes. Methods and MaterialsThis prospective nonrandomized controlled phase 2 trial enrolled 44 LAPC and 4 locally recurrent patients after multidisciplinary evaluation between 2012 and 2015 at a high-volume pancreatic cancer center. For induction CTX, most received modified FOLFIRINOX (mFFX), or gemcitabine and nab-paclitaxel (GnP) followed by 5-fraction SBRT for all. During fiducial placement, biopsies were obtained with DNA extracted for targeted sequencing using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets platform. ResultsMedian induction CTX duration was ≥4 months, and 31 patients received mFFX (65%). Among 44 LAPC patients, 17 (39%) were surgically explored, and 12 of 16 (75%) achieved a R0 resection. Median overall survival (mOS) was 20.2 and 14.6 months from diagnosis and SBRT, respectively. One- and 2-year OS from SBRT was 58% and 28%. The mOS after resection was 28.6 and 22.4 months from diagnosis and SBRT, respectively. Median local progression-free survival was 23.9 and 15.8 months from diagnosis and SBRT, respectively. The mOS for pre-SBRT CA 19-9 ≤180 U/mL versus >180 was 23.1 and 11.3 months, respectively (hazard ratio, 0.53; P = .04). Only 1 patient (2.1%) had late grade ≥2 gastrointestinal toxic effects attributable to SBRT. Despite significant pretreatment with chemotherapy, 88% of tumor specimens were effectively sequenced; survival outcomes were not significantly associated with specific mutational patterns. Quality of life was prospectively collected pre- and post-SBRT with the EORTC QLQ-C30 and PAN26 questionnaires showing no significant change. ConclusionsSBRT was safely administered with MA-CTX with minimal toxicity. A high proportion of LAPC patients underwent R0 resection with favorable survival outcomes.

Magnetic Resonance–Guided Prostate Stereotactic Body Radiation Therapy With Daily Online Plan Adaptation: Results of a Prospective Phase 1 Trial and Supplemental Cohort

PurposeStereotactic magnetic resonance (MR)–guided adaptive radiation therapy (SMART) for prostate cancer allows for MR-based contouring, real-time MR motion management, and daily plan adaptation. The clinical and dosimetric benefits associated with prostate SMART remain largely unknown. Methods and MaterialsA phase 1 trial of prostate SMART was conducted with primary endpoints of safety and feasibility. An additional cohort of patients similarly treated with prostate SMART were included in the analysis. SMART was delivered to 36.25 Gy in 5 fractions to the prostate ± seminal vesicles using the MRIdian linear accelerator system (ViewRay, Inc). Rates of urinary and gastrointestinal toxic effects and patient-reported outcome measures were assessed. Dosimetric analyses were conducted to evaluate the specific benefits of daily plan adaptation. ResultsThe cohort included 22 patients (n = 10 phase 1, n = 12 supplemental) treated in 110 fractions. Median follow-up was 7.9 months. Acute grade 2 urinary and gastrointestinal toxic effects were observed in 22.7% and 4.5%, respectively, and 4.5% and 0%, respectively, at last follow-up. No grade 3+ events were observed. Expanded Prostate Cancer Index-26 urinary obstructive scores decreased during SMART (mean, 9.3 points; P = .03) and returned to baseline by 3 months. No other significant changes in patient-reported outcome measures were observed. One-hundred percent of fractions required plan adaptation owing to exceeding organ-at-risk metrics (68%) or suboptimal target coverage (33%) resulting from anatomic changes. Minimum acceptable planning target volume, rectal, bladder, and urethra/bladder neck metrics were violated in 24%, 20%, 24%, and 33% of predicted plans, respectively; 0% of reoptimized plans violated metrics. Underlying causes for deficient dosimetry before reoptimization included changes in bladder filling, seminal vesicle position, prostate volume (median 4.7% increase by fraction 3; range, 0%-56%), and hotspots shifting into urethra/bladder neck. ConclusionsProstate SMART results in low risk of acute toxic effects with improvements in target and organ-at-risk dosimetry. The clinical benefits resulting from daily plan adaptation, including urethra/bladder neck protection, warrant further investigation.

Comparison of 3 Paclitaxel-Based Chemoradiotherapy Regimens for Patients With Locally Advanced Esophageal Squamous Cell Cancer

Multiple paclitaxel-based regimens are widely used in chemoradiation therapy against esophageal cancer, including regimens combining paclitaxel with fluorouracil, cisplatin, and carboplatin. However, which among these 3 regimens provides the best prognosis with minimum adverse events is still unknown. To compare the efficacy and adverse events of fluorouracil, cisplatin, and carboplatin in definitive chemoradiotherapy in patients with esophageal squamous cell carcinoma (ESCC). This randomized clinical trial of patients with ESCC was conducted in 11 treatment centers in China. Eligible patients were aged 18 to 75 years and had histologically confirmed ESCC stages IIa to IVa with no prior treatment, Eastern Cooperative Oncology Group performance status of 2 or lower, and adequate organ functions. The study was conducted between July 2015 and February 2018, and the cutoff date for data analysis was August 31, 2020. Patients with locally advanced ESCC were randomly assigned (1:1:1) to groups combining paclitaxel treatment with fluorouracil, cisplatin, or carboplatin. Patients in the cisplatin group were treated with 2 cycles of concurrent chemoradiotherapy followed by 2 cycles of consolidation chemotherapy with monthly paclitaxel plus cisplatin. For the fluorouracil group, patients were administered 6 cycles of weekly paclitaxel plus fluorouracil in concurrent chemoradiotherapy followed by 2 cycles of monthly paclitaxel plus fluorouracil in consolidation chemotherapy. Patients in the carboplatin group were treated with 6 cycles of weekly paclitaxel plus carboplatin in concurrent chemoradiotherapy followed by 2 cycles of monthly paclitaxel plus carboplatin in consolidation chemotherapy. All patients received radiotherapy of 61.2 Gy delivered in 34 fractions. The primary end point was overall survival (OS). The secondary end points were progression-free survival and adverse events. Overall, 321 patients (median [IQR] age, 64 years [59-69 years]; 248 [77.3%] men) with ESCC from 11 centers were randomized into fluorouracil, cisplatin, or carboplatin groups between July 2015 and February 2018. Over a median (IQR) follow-up time of surviving patients of 46.0 months (36.6-53.0 months), the 3-year OS rates were 57.2% in the fluorouracil group, 60.1% in the cisplatin group, and 56.5% in the carboplatin group, respectively (fluorouracil vs cisplatin: HR, 1.06; 95% CI, 0.71-1.60; P = .77; fluorouracil vs carboplatin: HR, 0.94; 95% CI, 0.63-1.40; P = .77). The cisplatin group had significantly higher incidences of acute grade 3 or 4 neutropenia (69 events [60.8%] vs 19 [17.8%] for fluorouracil and 37 [34.6%] carboplatin; P < .001), thrombocytopenia (14 events [13.1%] vs 4 [3.7%] for fluorouracil and 5 [4.7%] for carboplatin; P = .01), anemia (50 events above grade 2 [46.7%] vs 25 [23.4%] for fluorouracil and 37 [34.6%] for carboplatin; P = .35), fatigue (11 events [10.3%] vs 2 [1.9%] for fluorouracil and 1 [0.9%] carboplatin; P = .007), and vomiting (17 events above grade 2 [15.9%] vs 3 [2.8%] for fluorouracil and 5 [4.7%] for carboplatin; P < .001) than the other 2 groups. In this randomized clinical trial, paclitaxel plus fluorouracil did not show OS superiority over paclitaxel plus cisplatin or paclitaxel plus carboplatin regimens in definitive chemoradiation in patients with locally advanced ESCC. Higher rates of hematologic and gastrointestinal toxic effects were reported in the cisplatin group compared with those in the fluorouracil or carboplatin groups. ClinicalTrials.gov Identifier: NCT02459457.

Bullet for periodontal disease in future: Chemically modified tetracyclines

Chronic periodontitis is nowadays popularly regarded as Dysbiosis, [1] which causes destruction of tissues rich in collagen like periodontal ligament, alveolar bone and gingival connective tissue. The oral biofilm comprises many periodontal pathogens better regarded as ‘triggers’ in causing chronic periodontitis. Since, not everyone will be affected in the same manner due to periodontal pathogens. Some might not elicit a host response while, the others might have exaggerated response. So, host modulation therapy came into existence to counteract the exaggerated host response. The chemically modified tetracyclines (CMTs) have emerged to inhibit the inflammatory response or to reduce the collagenolytic activity of host. Though a derivative of tetracyclines, it still lacks an antimicrobial action and hence, can be used for periodontitis for longer duration with no adverse effects of gastrointestinal toxicity which parent tetracyclines have.

ALK inhibitors for ALK-altered paediatric malignancies.

The phase 1 dose-escalation trial bfy Matthias Fischer and colleagues1 published in The Lancet Oncology shows high response rates obtained with ceritinib, a second-generation ALK inhibitor, in 83 children with ALK-positive anaplastic large cell lymphoma (ALCL), inflammatory myofibroblastic tumors (IMT), and a subgroup of those with ALK-altered neuroblastomas, confirming and expanding results previously reported with crizotinib2–5 and other ALK inhibitors.6,7 The study results showed that ceritinib is tolerable in children, with mild and manageable gastrointestinal and hepatic toxic effects, and a safety profile consistent with that observed in adult patients.

Folpet induces mitochondrial dysfunction and ROS-mediated apoptosis in mouse Sertoli cells

Folpet is a phthalimide type of fungicide and has been used to control several crop diseases. Although it has adverse effects on the gastrointestinal tract, its mechanism and toxic effects on testis have not been demonstrated. In the present study, we elucidated the cytotoxic effect of folpet on the mouse Sertoli cell line, TM4. Our results revealed that folpet suppressed viability and proliferative capacity of TM4 cells and further inhibited 3D spheroid formation. Moreover, folpet impeded appropriate cell cycle progression and induced apoptotic cell death in TM4 cells. It disrupted the electrochemical gradient of mitochondria and calcium homeostasis in TM4 cells. Furthermore, endoplasmic reticulum stress-related proteins were activated in folpet-treated TM4 cells, and relative reactive oxygen species (ROS) production was also increased. N-acetylcysteine (NAC) treatment reinstated the folpet-induced ROS generation in TM4 cells. Additionally, NAC restored the proliferative capacity and reduced the apoptotic cells in folpet-treated TM4 cells. Collectively, we demonstrated that folpet causes ROS-mediated apoptotic cell death with mitochondrial dysfunction and calcium dysregulation in TM4 cells.

Safety and Efficacy of Virtual Prostatectomy With Single-Dose Radiotherapy in Patients With Intermediate-Risk Prostate Cancer

Ultra-high single-dose radiotherapy (SDRT) represents a potential alternative to curative extreme hypofractionated stereotactic body radiotherapy (SBRT) in organ-confined prostate cancer. To compare toxic effect profiles, prostate-specific antigen (PSA) responses, and quality-of-life end points of SDRT vs extreme hypofractionated SBRT. The PROSINT single-institution phase 2 randomized clinical trial accrued, between September 2015 and January 2017, 30 participants with intermediate-risk prostate cancer to receive SDRT or extreme hypofractionated SBRT. Androgen deprivation therapy was not permitted. Data were analyzed from March to May 2020. Patients were randomized in a 1:1 ratio to receive 5 × 9 Gy SBRT (control arm) or 24 Gy SDRT (test arm). The primary end point was toxic effects; the secondary end points were PSA response, PSA relapse-free survival, and patient-reported quality of life measured with the International Prostate Symptom Score (IPSS) and Expanded Prostate Cancer Index Composite (EPIC)-26 questionnaires. A total of 30 men were randomized; median (interquartile range) age was 66.3 (61.2-69.9) and 73.6 (64.7-75.9) years for the SBRT and SDRT arms, respectively. Time to appearance and duration of acute and late toxic effects were similar in the 2 trial arms. Cumulative late actuarial urinary toxic effects did not differ for grade 1 (hazard ratio [HR], 0.41; 90% CI, 0.13-1.27) and grade 2 or greater (HR, 1.07; 90% CI, 0.21-5.57). Actuarial grade 1 late gastrointestinal (GI) toxic effects were comparable (HR, 0.37; 90% CI, 0.07-1.94) and there were no grade 2 or greater late GI toxic effects. Declines in PSA level to less than 0.5 ng/mL occurred by 36 months in both study arms. No PSA relapses occurred in favorable intermediate-risk disease, while in the unfavorable category, the actuarial 4-year PSA relapse-free survival values were 75.0% vs 64.0% (HR, 0.76; 90% CI, 0.17-3.31) for SBRT vs SDRT, respectively. The EPIC-26 median summary scores for the genitourinary and GI domains dropped transiently at 1 month and returned to pretreatment scores by 3 months in both arms. The IPSS-derived transient late urinary flare symptoms occurred at 9 to 18 months in 20% (90% CI, 3%-37%) of patients receiving SDRT. In this randomized clinical trial among patients with intermediate-risk prostate cancer, SDRT was safe and associated with low toxicity, and the tumor control and quality-of-life end points closely match the SBRT arm outcomes. Further studies are encouraged to explore indications for SDRT in the cure of prostate cancer. ClinicalTrials.gov Identifier: NCT02570919.

Elucidation of gastrointestinal dysfunction in response to irradiation using metabolomics

Gastrointestinal toxicity is frequently observed secondary to accidental or therapeutic radiation exposure. However, the variation in the intestinal metabolites after abdominal radiation exposure remains ambiguous. In the present study, C57BL/6 mice were exposed to 0, 2, and 20 Gy irradiation dose. The Head and chest of each mouse were covered with a lead shield before x-ray irradiation. 24 h post-irradiation treatment, intestinal tissue of each mouse was excised and prepared for metabolites measurement using gas chromatography-mass spectrometry (GC-MS). Our comprehensive analysis of metabolites in the intestinal tissues detected 44 metabolites after irradiation, including amino acids, carbohydrates, organic acids, and sugars. Amino acid levels in the intestinal tissue gradually rose, dependent on the radiation dose, perhaps as an indication of oxidative stress. Our findings raise the possibility that amino acid metabolism may be a potential target for the development of treatments to alleviate or mitigate the harmful effects of oxidative stress-related gastrointestinal toxicity due to radiation exposure.

Efficacy and Safety of Locoregional Radiotherapy With Chemotherapy vs Chemotherapy Alone in De Novo Metastatic Nasopharyngeal Carcinoma

The role of locoregional radiotherapy in patients with de novo metastatic nasopharyngeal carcinoma (mNPC) is unclear. To investigate the efficacy and safety of locoregional radiotherapy in de novo mNPC. Patients with biopsy-proven mNPC, who demonstrated complete or partial response (RECIST v1.1) following 3 cycles of cisplatin and fluorouracil chemotherapy, were enrolled. Eligible patients were randomly assigned (1:1) to receive either chemotherapy plus radiotherapy or chemotherapy alone. Overall, 126 of 173 patients screened were eligible to the study, and randomized to chemotherapy plus radiotherapy (n = 63) or chemotherapy alone (n = 63). Median (IQR) follow-up duration was 26.7 (17.2-33.5) months. The chemotherapy regimens were fluorouracil continuous intravenous infusion at 5 g/m2 over 120 hours and 100 mg/m2 intravenous cisplatin on day 1, administered every 3 weeks for 6 cycles. Patients assigned to the chemotherapy plus radiotherapy group received intensity-modulated radiotherapy (IMRT) after chemotherapy. The primary end point of the study was overall survival (OS). The secondary end point was progression-free survival (PFS) and safety. Overall, 126 patients were enrolled (105 men [83.3%] and 21 women [16.7%]; median [IQR] age, 46 [39-52] years). The 24-month OS was 76.4% (95% CI, 64.4%-88.4%) in the chemotherapy plus radiotherapy group, compared with 54.5% (95% CI, 41.0%-68.0%) in the chemotherapy-alone group. The study met its primary end point of improved OS (stratified hazard ratio [HR], 0.42; 95% CI, 0.23-0.77; P = .004) in favor of chemotherapy plus radiotherapy. Progression-free survival was also improved in the chemotherapy plus radiotherapy group compared with the chemotherapy-alone group (stratified HR, 0.36; 95% CI, 0.23-0.57). No significant differences in acute hematological or gastrointestinal toxic effects were observed between the treatment arms. The frequency of acute grade 3 or higher dermatitis, mucositis, and xerostomia was 8.1%, 33.9%, and 6.5%, respectively, in the chemotherapy plus radiotherapy group. The frequency of late severe grade 3 or higher hearing loss and trismus was 5.2% and 3.4%, respectively, in the chemotherapy plus radiotherapy group. In this randomized clinical trial, radiotherapy added to chemotherapy significantly improved OS in chemotherapy-sensitive patients with mNPC. ClinicalTrials.gov Identifier: NCT02111460.

Evaluation of analgesic activity of the methanol extract from the galls of Quercus infectoria alone and as an adjuvant in wistar rats

Background: Non-steroidal anti-inflammatory drugs and opioids are the most preferred drugs for pain relief. Considering the gastrointestinal toxicity, dependence and other side effects, search for better analgesic drug continues. Quercus infectoria (QI) is from the family Fagaceae. The galls of QI are comprised of tannin (36 to 60%), gallic acid, ellagic acid, and syringic acid. They possess antioxidant, anti-inflammatory, antimicrobial, and anti-diabetic properties. In India, galls of QI have been used for the treatment of toothache, diarrhoea, sore throat and inflammatory diseases as a home remedy. This study was conducted to evaluate the analgesic activity of methanolic extract of galls of QI on wistar rats using tail-flick and Eddy’s hot-plate methods. The objective of the study was to evaluate the analgesic activity of methanolic extract of galls of QI alone and as an adjuvant with tramadol on Wistar rats.Methods: Total of 24 wistar rats were included in the study and divided into 4 groups. They received drugs intra-peritoneally as follows. In group 1, normal saline, in group 2, tramadol, in group 3, methanolic extract of galls of QI and in group 4, tramadol with methanolic extract of galls of QI was available.Results: Methanolic extract of galls of QI produced significant maximal possible analgesia (&lt;0.001) at 30 and 60 minutes in tail-flick method whereas it failed to produce analgesia in hot-plate method during all time intervals.Conclusions: Methanolic extract of galls of QI showed analgesic activity in tail-flick method indicating that its possible mechanism of action is spinally mediated.