Reduction In Gastrointestinal Toxicity Research Articles

Effectiveness of Nutritional Intervention in Reduction of Gastrointestinal Toxicity during External Beam Radiotherapy in Women with Gynecological Tumors

Effectiveness of Nutritional Intervention in Reduction of Gastrointestinal Toxicity during External Beam Radiotherapy in Women with Gynecological Tumors

The Brown University Oncology Group Experience With FOLFOX + Nab-paclitaxel [FOLFOX-A] for Metastatic and Locally Advanced Pancreatic, BrUOG-292 and BrUOG-318.

Objectives:To evaluate response rate, toxicity, and efficacy of the novel combination of nab-paclitaxel, oxaliplatin, 5-fluorouracil, and leucovorin [FOLFOX-A] in patients with advanced pancreatic ductal adenocarcinoma [PDAC].Methods:BrUOG-292 and BrUOG-318 were two concurrently run, prospective, single-arm phase II studies evaluating FOLFOX-A as first-line therapy in patients with metastatic and locally advanced/borderline resectable PDAC respectively. The FOLFOX-A regimen consisted of 5-fluorouracil, 1200 mg/m2/d as a continuous intravenous (IV) infusion over 46 hours, leucovorin 400 mg/m2 IV, oxaliplatin 85 mg/m2 IV, and nab-paclitaxel 150 mg/m2 IV on day 1 every 14 days up to a maximum of 12 cycles. Patients with locally advanced or borderline resectable disease were permitted to stop treatment after 6 cycles and receive radiation therapy and/or surgical exploration if feasible. The primary end point was overall response rate [ORR]. Secondary end points were median progression-free survival [PFS], median overall survival [OS], and safety.Results:Seventy-eight patients with previously untreated PDAC were enrolled between June 2014 and November 2019; 76 patients were evaluable. The median follow-up was 40 months and 32 months, respectively. overall response rate was 34%. Among the patients enrolled on BrUOG-292 [48 patients], the PFS was 5 months and OS was 11 months, respectively. For those enrolled on BrUOG 318 [28 patients], the PFS was 11 months and OS was 22 months. Treatment-related toxicities included grade 3 fatigue [40%], diarrhea [14%], and neuropathy [2%].Conclusions:The combination of FOLFOX-A has promising activity in PDAC and may represent an alternative to FOLFIRINOX when reduction of gastrointestinal toxicity is required.

Simulated Cone-Beam Computed Tomography Based Online Adaptive Radiotherapy of Anal Cancer — Potential Dosimetric Benefit

To evaluate the dosimetric benefit of cone beam computed tomography (CBCT) based online adaptive radiotherapy (oART) with full re-optimization on the anatomy of the day, for patients with anal cancer.CBCT-based oART was simulated using a novel commercial solution in research mode. Twenty-three consecutive patients with anal cancer, treated with radiotherapy from January to November 2020, were retrospectively included. Treatments were delivered in 30 fractions with a prescribed dose of 60 and 48 Gy to the primary and elective targets, respectively. Sixteen patients were also prescribed 60 Gy to positive lymph nodes. Two reference treatment plans were generated based on the planning CT for each patient; one with clinically used clinical target volume (CTV) to planning target volume (PTV) margins for image guided radiotherapy (non-ART) and one with expected clinical oART CTV-PTV margins. The oART margins were reduced 5 mm isotropically and 5 mm anteriorly for the positive lymph nodes and elective target, respectively, compared to non-ART; corresponding to a 50 % reduction from non-ART. Treatment sessions were simulated on six weekly CBCT images for one of the patients. Bladder, rectum and bowel cavity structures were automatically delineated and manually adjusted to match the anatomy on the CBCT. For non-ART, the reference plan was re-calculated on the anatomy of the day with rigidly propagated targets. For oART, the plan was re-optimized using targets that were either deformed or rigidly propagated, according to the expected clinical workflow. The volume of bowel cavity receiving 30 and 45 Gy (V30Gy and V45Gy, respectively) was evaluated and compared between the two workflows.For the reference treatment plans, the CTV-PTV margin reduction in oART resulted in a median reduction (interquartile range) for bowel cavity V30Gy and V45Gy of 6.4 (3.8 - 8.5) % and 11.4 (9.7 - 14.0) %, respectively. This corresponded to 39.4 (17.9 - 80.2) cc and 48.5 (35.6 - 61.3) cc, respectively. Re-optimizing the plan to the anatomy of the six CBCT images lead to a median reduction [minimum; maximum] for bowel cavity V30Gy and V45Gy of 9.2 [7.5; 12.3] % and 13.1 [10.8; 15.3] %, respectively, corresponding to 58.0 [46.5; 86.0] cc and 56.9 [46.4; 70.3] cc.Simulated oART of anal cancer resulted in reduced dose to the bowel cavity, indicating potential reduction in gastrointestinal toxicity. Early results demonstrated that the superiority of oART compared to non-ART was consistent during the course of treatment. Further oART sessions of other patients are planned to be simulated before the ASTRO conference. A single-arm phase II trial to investigate the clinical impact has been developed and awaits approval.

Normal Tissue Complication Probability for Hematologic and Gastrointestinal Toxicity in Postoperative Whole Pelvic Radiotherapy for Gynecologic Malignancies using Intensity Modulated Proton Therapy with Robust Optimization

Hematologic toxicity (HT) and gastrointestinal toxicity (GI) are often observed in the postoperative whole pelvic radiotherapy (WPRT) for gynecologic malignancies since the irradiation field contains large volume of the bone marrow (BM) and bowel bag (BB). Although proton beam therapy with single field uniform dose optimization has a potential of the risk reduction of HT compared with intensity modulated X-ray therapy (IMXT), the risk reduction of GI has not been previously described. Thus, the aim of this in silico study was to evaluate the risk of HT and GI using intensity modulated proton therapy with robust optimization (robust IMPT). This dosimetric planning study included 9 patients who had previously undergone hysterectomy and WPRT at our institution from 2008 to 2020. For robust IMPT planning, we used two posterior oblique fields and a 3.5% beam specific margin from the distal and proximal edges of clinical target volume (CTV) in water equivalent space to discern the range uncertainty. The prescribed dose was 45 GyE in 25 fractions for 99% of the CTV (CTV D99). We evaluated CTV coverage using following indicators, CTV D99, conformity index (CI), homogeneity index (HI); dose volume statistics of BM received 10 and 20 GyE (BM V10 and BM V20), and BB received 40 GyE (BB V40); the planning robustness for CTV by shifting each 5 mm for six axes; and the risk of HT and GI using the Lyman-Kutcher-Burman normal tissue complication probability (LKB-NTCP) model. The parameters of LKB-NTCP model were determined to calculate the risk of grade ≥ 3 acute HT and chronic GI such as obstruction or perforation. We performed the comparative evaluation of NTCP value for HT and GI between robust IMPT and IMXT prescribed 45 GyE in 25 fractions for 95% of the planning target volume with 7-fields step and shoot technique. The Wilcoxon signed rank test was used for all statistical comparisons. In the LKB-NTCP modeling analysis, the NTCP values for robust IMPT were significantly lower than IMXT (HT: 0.06±0.02 for robust IMPT and 0.19±0.03 for IMXT, p<0.05, and GI: 0.01±0.004 for robust IMPT and 0.03±0.01 for IMXT, p<0.05, respectively). Moreover, robust IMPT was excellent CTV coverage; the mean and standard deviation of CTV D99, CI, and HI was 45.63±0.21 GyE, 1.00±0.001, and 0.03±0.01, respectively. The dose volume statistics for BM V10, BM V20 and BB V40 were 61.41±4.47%, 53.12±4.75%, and 17.77±3.45%, respectively. Changes in the mean value of CTV D99 in the shifted plan were within 2%, except for the anterior shift plan (left: -1.05%, right: -0.91%, superior: -0.97%, inferior: -1.17%, anterior: -2.59%, and posterior: -0.10%). Robust IMPT for WPRT reduced the risk of HT and GI without compromising CTV coverage, compared with IMXT. These results indicate that robust IMPT has a clinical advantage in reducing the risk of HT and GI in the treatment of gynecologic malignances.

Reduction in Gastrointestinal Toxicity with Interstitial Hydrogel Spacer during Prostate Proton Therapy

Interstitial hydrogel provides both rectal immobilization and spacing between the prostate and rectum during prostate radiotherapy and reduces the incidence and severity of rectal toxicity. Its use during prostate proton therapy has not yet been evaluated. Patients with localized prostate cancer were treated with definitive proton beam therapy at a single institution on a multi-institutional registry protocol (PCG GU-002). Patients were treated to a dose of 79.2 Gy(RBE) in 44 fractions (762 patients), 70 Gy(RBE) in 28 fractions (102 patients) or 38 Gy(RBE) in 5 fractions (51 patients). Patients were treated in consecutive cohorts with rectal water (RW), rectal balloon (RB) or hydrogel spacer (HS), and followed prospectively for late (>90 days after treatment) adverse events. Toxicity was assessed using CTCAE version 4.0 and compared between cohorts using pairwise chi-square tests. 947 patients treated from 10/10 through 2/17, with median follow-up of 4.4 years and minimum follow-up of 1.5 years. RW was used in 385 patients, RB in 342 patients, and HS in 220 patients. Grade≥3 toxicity did not occur in the HS cohort and was rare in the RW and RB cohorts (<1%). Grade≥2 overall GI toxicity rates were lower for HS (2.2%) relative to RW (14.8%, p<0.001) and RB (17.3%, p<0.001). Grade 2 rectal bleeding was lower for HS (2.2%) relative to RW (10.4%, p<0.001) and RB (12.3%, p<0.001). Interstitial hydrogel spacer during proton therapy reduces the risk of gastrointestinal toxicities and rectal bleeding.

A novel dynamic arc treatment planning solution to reduce dose to small bowel in preoperative radiotherapy for rectal cancer

Preoperative radiotherapy or combined chemoradiotherapy for locally advanced rectal cancer (LARC) can cause acute and late gastrointestinal (GI) side-effects. There is thought to be a dose-volume relationship between small bowel irradiation and the development of these effects. A planning study was undertaken to compare small bowel sparing for a range of 3D conformal and dynamic arc planning solutions. A planning study was carried out for 20 LARC patients. Organs at risk (OAR) contoured included bowel loops and peritoneal space (PS). For each of the 20 patients, 5 plans were created: (1) standard 3D conformal plan; (2) standard dual dynamic arc plan; (3) dual dynamic arc plan with 90° avoidance sector through the anterior portion of the patient; (4) dual dynamic arc plan with an anterior avoidance structure in the optimizer; (5) dual dynamic arc plan with both an anterior avoidance structure and an avoidance sector. The prescription was 50.4 Gy in 28 fractions to the planning target volume (PTV). Five Dose Volume Levels (DVLs; V15 Gy, V20 Gy, V25 Gy, V35 Gy, V40 Gy, and V50.4 Gy) for bowel and PS were selected. The DVLs were compared between the plans using Friedman Tests and Wilcoxon Signed Rank Tests. Comparison of the 5 plans revealed that a dual dynamic arc plan containing both an anterior avoidance sector and structure significantly improved the dose to the bowel compared to a standard 3D conformal plan and to a standard dual dynamic arc plan. This improvement was achieved while maintaining PTV coverage. This novel dual dynamic arc planning technique that uses both an avoidance sector and structure reduces the dose to the bowel and PS, which may lead to a reduction in GI toxicity.

Effectiveness of a nutritional intervention in the reduction of gastrointestinal toxicity during teletherapy in women with gynaecological tumours

ObjectiveTo evaluate whether nutritional intervention through a diet low in oligosaccharides, disaccharides, monosaccharides and fermentable polyols reduces acute gastrointestinal toxicity by pelvic teletherapy in patients with gynaecological tumours. Material and methodsA prospective unicentric randomised clinical trial comparing patients on a diet low in oligosaccharides, disaccharides, monosaccharides and fermentable polyols versus a standard Mexican diet, designed to detect a decrease from 80% of grade 1–2 acute gastrointestinal toxicity in the normal diet group versus a 25% of acute gastrointestinal toxicity grade 1–2 in patients assigned to a diet low in oligosaccharides, disaccharides, monosaccharides and fermentable polyols. ResultsThirteen patients were recruited per group, with a higher gastrointestinal toxicity in the normal diet group, grade 1–2 (85% vs 77%) and 3 (23% vs 0%) compared to the diet low in oligosaccharides, disaccharides, monosaccharides and fermentable polyols (p 0.16). The diet low in oligosaccharides, disaccharides, monosaccharides and fermentable polyols group had a lower symptom score at the end of treatment in the quality of life questionnaire of patients with cervical cancer (1.41 vs 1.85, p 0.01) and a lower mean deterioration in performance status (0.61 of 0.5 vs 0.23 of 0.43, p 0.049). 85% of the patients had an excellent attachment to the diet. No significant factors associated with the presence of grade 3 gastrointestinal toxicity were found. ConclusionThe implementation of a diet low in oligosaccharides, disaccharides, monosaccharides and fermentable polyols during treatment with pelvic teletherapy is a low cost and high attachment intervention, which decreases the deterioration of functional status and symptomatology at the end of treatment in patients with cervical cancer.

Tumour regression and improved gastrointestinal tolerability from controlled release of SN-38 from novel polyoxazoline-modified dendrimers

Irinotecan is used clinically for the treatment of colorectal cancer; however, its utility is limited by its narrow therapeutic index. We describe the use of a generation 5 l-lysine dendrimer that has been part-modified with a polyoxazoline as a drug delivery vehicle for improving the therapeutic index of SN-38, the active metabolite of irinotecan. By conjugating SN-38 to the dendrimer via different linker technologies we sought to vary the release rate of the drug to generate diverse pharmacokinetic profiles. Three conjugates with plasma release half-lives of 2.5h, 21h, and 72h were tested for efficacy and toxicity using a mouse SW620 xenograft model. In this model, the linker with a plasma release half-life of 21h achieved sustained SN-38 exposure in blood, above the target concentration. Control over the release rate of the drug from the linker, combined with prolonged circulation of the dendrimer, enabled administration of an efficacious dose of SN-38, achieving significant regression of the SW620 tumours. The conjugates with 2.5 and 72h release half-lives did not achieve an anti-tumour effect. Intraperitoneal dosing of the clinically used prodrug irinotecan produces high initial and local concentrations of SN-38, which are associated with gastrointestinal toxicity. Administration of the 21h release dendrimer conjugate did not produce a high initial Cmax of SN-38. Consequently, a marked reduction in gastrointestinal toxicity was observed relative to irinotecan treatment. Additional studies investigating the dose concentrations and dose scheduling showed that a weekly dosing schedule of 4mg SN-38/kg was the most efficacious regimen. After 4 doses at weekly intervals, the survival period of the mice extended beyond 70 days following the final dose. These extensive studies have allowed us to identify a linker, dose and dosing regimen for SN-38 conjugated to polyoxazoline-modified dendrimer that maximised efficacy and minimised adverse side effects.

Reduction in gastrointestinal toxicity by gastric secretion inhibitors during S-1 monotherapy for patients with gastric cancer.

The purpose of this study was to retrospectively examine the effect of concomitant administration of gastric secretion inhibitors or gastrectomy on the frequency of gastrointestinal toxicity caused by 5-fluorouracil (5-FU) in gastric cancer patients receiving chemotherapy with S-1. In 62 gastric cancer patients treated with S-1 alone, data relating to the occurrence of gastrointestinal toxicity (diarrhea, vomiting, and nausea) and possible contributing factors were retrospectively collected, and logistic regression analysis was performed. Time-to-event data relating to the occurrence of gastrointestinal toxicity were also collected, and the effect of gastric secretion inhibitors on the time-to-event profiles was examined using a log-rank test. Logistic regression analysis suggested that the frequency of gastrointestinal toxicity was significantly reduced by the administration of gastric secretion inhibitors (p=0.01; odds ratio, 0.197; 95% confidence interval (CI), 0.056-0.694) and that gastrointestinal toxicity correlated with the estimated glomerular filtration rate (p=0.04; odds ratio, 0.956; 95% CI, 0.916-0.997). The median time-to-event of gastrointestinal toxicity was 85 d for patients that received gastric secretion inhibitors, which was significantly different from the 42 d for patients that did not receive the inhibitors (p=0.02, log-rank test). No clear effect of gastrectomy was found in the present study. The prophylactic use of gastric secretion inhibitors in gastric cancer patients treated with S-1 may decrease and delay the occurrence of gastrointestinal toxicity.

Polyamidoamine dendrimer and dextran conjugates: preparation, characterization, and in vitro and in vivo evaluation

AbstractAmide and ester conjugates of aceclofenac with polyamidoamine (PAMAM-G0) dendrimer zero generation and dextran (40 kDa) polymeric carrier, respectively, are presented. The prepared conjugates were characterized by UV, TLC, HPLC, IR, and 1H NMR spectroscopy. The average degrees of substitution of amide and ester conjugates were determined and found to be (12.5 ± 0.24) % and (7.5 ± 0.25) %, respectively. The in vitro hydrolysis studies showed that dextran ester conjugate hydrolyzed faster in a phosphate buffer solution of pH 9.0 as compared to PAMAM dendrimer G0 amide conjugate, and followed the first order kinetics. No amount of the drug was regenerated at pH 1.2 in simulated gastric fluid. The dextran conjugate showed short half-life as compared to the PAMAM dendrimer conjugate. Anti-inflammatory and analgesic activities of the dendrimer conjugate were found to be similar to those of the standard drug. Results of chronic ulceroginic activity showed deep ulceration and high ulcer index for aceclofenac, whereas lower ulcer index was found for the PAMAM dendrimer and dextran (40 kDa) conjugates. Experimental data suggest that PAMAM dendrimer and dextran (40 kDa) can be used as carriers for the sustained delivery of aceclofenac along with a remarkable reduction in gastrointestinal toxicity.

Clinical Pharmacokinetic and Pharmacodynamic Profile of Etoricoxib

The NSAID etoricoxib is a selective inhibitor of cyclo-oxygenase 2 (COX-2), approved for treatment of patients with chronic arthropathies and musculoskeletal and dental pain. The rate of absorption of etoricoxib is moderate when given orally (the maximum plasma drug concentration occurs after approximately 1 hour), and the extent of absorption is similar with oral and intravenous doses. Etoricoxib is extensively protein bound, primarily to plasma albumin, and has an apparent volume of distribution of 120 L in humans. The area under the plasma concentration-time curve (AUC) of etoricoxib increases in proportion to increasing oral doses between 5 and 120 mg. The elimination half-life of approximately 20 hours in healthy subjects enables once-daily dosing. Etoricoxib is eliminated following biotransformation to carboxylic acid and glucuronide metabolites that are excreted in urine and faeces, with little of the drug (<1%) being eliminated unchanged in the urine. Etoricoxib is metabolized primarily by the cytochrome P450 (CYP) 3A4 isoenzyme. Plasma concentrations (AUC) of etoricoxib appear not to be different in patients with chronic renal insufficiency compared with individuals who have normal renal function. Compared with healthy subjects, it has been reported that the AUC is increased by approximately 40% in patients with moderate hepatic impairment. No inhibitory effects on CYP2C9, 2C19, 2D6, 2E1 or 3A4 are expected to occur with etoricoxib. Coadministration of etoricoxib with other drugs has been examined only to a limited extent, thus further assessment is necessary. Etoricoxib has been assessed for the management of several specific disease states, including pain, osteoarthritis, and rheumatoid arthritis, and has shown similar efficacy in comparison with traditional NSAIDs (including naproxen, diclofenac and ibuprofen) in these conditions. Etoricoxib has demonstrated a significant reduction in gastrointestinal toxicity compared with many traditional NSAIDs. The renal adverse effects of etoricoxib appear to be similar to those of other NSAIDs, and the cardiovascular adverse effects of this selective COX-2 inhibitor require further clinical scrutiny. Further study is necessary to delineate the relevance of the pharmacokinetic disposition in terms of the clinical benefits and risks of etoricoxib compared with other options in the clinical arsenal.

Reduction of 5-fluorouracil (5-FU) gastrointestinal (GI) toxicity resulting from the protection of thymidylate synthase (TS) in GI tissue by repeated simultaneous administration of potassium oxonate (Oxo) in rats.

An important cytotoxic effect of 5-fluorouracil (5-FU) is the inactivation of thymidylate synthase (TS) (EC 2.1.1.45) activity by the formation of a ternary complex consisting of covalently bound 5-fluorodeoxyuridine 5'-monophosphate (FdUMP), TS and 5,10-methylenetetrahydrofolate (CH2FH4). The gastrointestinal (GI) toxicity of 5-FU is also caused by its phosphorylation in the GI tract. Potassium oxonate (O(XO)) competitively inhibits pyrimidine phosphoribosyltransferase (EC 2.4.2.10), which converts 5-FU to 5-fluorouridine 5'-monophosphate (FUMP) in vitro. In this study the benefits of combining Oxo and tegafur (FT), which is a masked compound of 5-FU, in reducing the GI toxicity of 5-FU and in protecting the activity of TS in the normal GI tissues were evaluated. We administered orally a preparation of 1 M FT and 0.4 M 5-chloro-2,4-dihydroxypyridine (CDHP) with or without 1 M O(XO) (called S-1 and FT + CDHP, respectively) or vehicle only (control) to rats for ten consecutive days and compared the toxicity, the histopathological findings and the free TS activity in the GI tissues of the treated rats. During the experimental periods, the signs of toxicity, such as a decrease in body weight, diarrhea and death, were only observed in the rats treated with FT + CDHP. The histopathological findings in the ileum and colon samples from rats treated consecutively with S-1 on day 1, day 4, day 7 and day 10 were less frequent and more mild than in the samples from rats treated with FT + CDHP. Furthermore, the free TS activities in the ileum samples of rats given S-1 and FT + CDHP were significantly decreased compared with the activity in samples from the control rats throughout the experimental periods. The free TS activities in GI tissues of rats treated with S-1 were higher than the TS activities in tissues from rats treated with FT + CDHP daily from day 4 to day 10, although activities in S-1-treated rat were decreased to almost same low levels as in FT + CDHP-treated rats on day 1. Our results suggest that repeated simultaneous administration of Oxo and FT can effectively protect the activity of TS by decreasing FdUMP via FUMP from 5-FU in GI tissue, and may lead to a reduction in GI toxicity.

Acute morbidity reduction using 3DCRT for prostate carcinoma: a randomized study

Purpose: To study the effects on gastrointestinal and urological acute morbidity, a randomized toxicity study, comparing conventional and three-dimensional conformal radiotherapy (3DCRT) for prostate carcinoma was performed. To reveal possible volume effects, related to the observed toxicity, dose–volume histograms (DVHs) were used.Methods and Materials: From June 1994 to March 1996, 266 patients with prostate carcinoma, stage T1-4N0M0 were enrolled in the study. All patients were treated to a dose of 66 Gy (ICRU), using the same planning procedure, treatment technique, linear accelerator, and portal imaging procedure. However, patients in the conventional treatment arm were treated with rectangular, open fields, whereas conformal radiotherapy was performed with conformally shaped fields using a multileaf collimator. All treatment plans were made with a 3D planning system. The planning target volume (PTV) was defined to be the gross target volume (GTV) + 15 mm. Acute toxicity was evaluated using the EORTC/RTOG morbidity scoring system.Results: Patient and tumor characteristics were equally distributed between both study groups. The maximum toxicity was 57% grade 1 and 26% grade 2 gastrointestinal toxicity; 47% grade 1, 17% grade 2, and 2% grade > 2 urological toxicity. Comparing both study arms, a reduction in gastrointestinal toxicity was observed (32% and 19% grade 2 toxicity for conformal and conventional radiotherapy, respectively; p = 0.02). Further analysis revealed a marked reduction in medication for anal symptoms: this accounts for a large part of the statistical difference in gastrointestinal toxicity (18% vs. 14% [p = ns] grade 2 rectum/sigmoid toxicity and 16% vs. 8% [p < 0.0001] grade 2 anal toxicity for conventional and conformal radiotherapy, respectively). A strong correlation between exposure of the anus and anal toxicity was found, which explained the difference in anal toxicity between both study arms. No difference in urological toxicity between both treatment arms was found, despite a relatively large difference in bladder DVHs.Conclusions: The reduction in gastrointestinal morbidity was mainly accounted for by reduced toxicity for anal symptoms using 3DCRT. The study did not show a statistically significant reduction in acute rectum/sigmoid and bladder toxicity.