Gastrointestinal Acute Radiation Syndrome: Mechanisms, Models, Markers, and Medical Countermeasures.

There have been a number of reported human exposures to high dose radiation, resulting from accidents at nuclear power plants (e.g., Chernobyl), atomic bombings (Hiroshima and Nagasaki), and mishaps in industrial and medical settings. If absorbed radiation doses are high enough, evolution of acute radiation syndromes (ARS) will likely impact both the bone marrow as well as the gastrointestinal (GI) tract. Damage incurred in the latter can lead to nutrient malabsorption, dehydration, electrolyte imbalance, altered microbiome and metabolites, and impaired barrier function, which can lead to septicemia and death. To prepare for a medical response should such an incident arise, the National Institute of Allergy and Infectious Diseases (NIAID) funds basic and translational research to address radiation-induced GI-ARS, which remains a critical and prioritized unmet need. Areas of interest include identification of targets for damage and mitigation, animal model development, and testing of medical countermeasures (MCMs) to address GI complications resulting from radiation exposure. To appropriately model expected human responses, it is helpful to study analogous disease states in the clinic that resemble GI-ARS, to inform on best practices for diagnosis and treatment, and translate them back to inform nonclinical drug efficacy models. For these reasons, the NIAID partnered with two other U.S. government agencies (the Biomedical Advanced Research and Development Authority, and the Food and Drug Administration), to explore models, biomarkers, and diagnostics to improve understanding of the complexities of GI-ARS and investigate promising treatment approaches. A two-day workshop was convened in August 2022 that comprised presentations from academia, industry, healthcare, and government, and highlighted talks from 26 subject matter experts across five scientific sessions. This report provides an overview of information that was presented during the conference, and important discussions surrounding a broad range of topics that are critical for the research, development, licensure, and use of MCMs for GI-ARS.

Comparison of gut toxicity and microbiome effects in zebrafish exposed to polypropylene microplastics: Interesting effects of UV-weathering on microbiome.

Weathered microplastics (MPs) exhibit different physicochemical properties compared to pristine MPs, thus, their effects on the environment and living organisms may also differ. In the present study, we investigated the gut-toxic effects of virgin polypropylene MPs (PP) and UV-weathered PP MPs (UV-PP) on zebrafish. The zebrafish were exposed to the two types of PP MPs at a concentration of 50 mg/L each for 14 days. After exposure, MPs accumulated primarily within the gastrointestinal tract, with UV-PP exhibiting a higher accumulation than PP. The ingestion of PP and UV-PP induced gut damage in zebrafish and increased the gene expression and levels of enzymes related to oxidative stress and inflammation, with no significant differences between the two MPs. Analysis of the microbial community confirmed alterations in the abundance and diversity of zebrafish gut microorganisms in the PP and UV-PP groups, with more pronounced changes in the PP-exposed group. Moreover, the Kyoto Encyclopedia of Genes and Genomes pathway analysis confirmed the association between changes in the gut microorganisms at the phylum and genus levels with cellular responses, such as oxidative stress, inflammation, and tissue damage. This study provides valuable insights regarding the environmental impact of MPs on organisms.

Secondary analysis of late major gastrointestinal and genitourinary toxicities in unfavorable-risk prostate cancer patients receiving docetaxel: Insights from a randomized trial.

BACKGROUND: This study sought to evaluate the late toxicity associated with neoadjuvant and concurrent docetaxel and radiation therapy in patients with prostate cancer. METHODS: A secondary analysis was performed of the phase 3 multicenter randomized trial (Dana-Farber Cancer Institute 05-043) including 350 patients with nonmetastatic unfavorable-risk prostate cancer. Patients were randomized 1:1 to receive androgen deprivation therapy, radiation therapy, and docetaxel versus androgen deprivation therapy and radiation therapy. The study assessed the cumulative incidence rates of grade 2 and grade 3 or higher gastrointestinal, genitourinary, and sexual toxicity. A multivariable Fine and Gray's competing risks regression model adjusted for age at randomization and pelvic lymph node radiation therapy was used to evaluate the treatment effect of docetaxel on time to late genitourinary and gastrointestinal toxicities. RESULTS: The study included 338 patients who primarily had minimal or no comorbidity (74.9%) and median age 66 years (interquartile range: 61,71). At a median follow-up of 10.2 years, docetaxel was not associated with increased risk of any grade 3 or higher (adjusted hazard ratio [AHR], 0.98; 95% confidence interval [CI], 0.36-2.67; p = .96) or grade 2 gastrointestinal (p = .75), genitourinary (p = .44), and sexual (p = .29) toxicity. Age was associated with increased grade 3 or higher (AHR, 1.08; 95% CI, 1.01-1.16; p = .03) and grade 2 gastrointestinal toxicity (AHR, 1.11; 95% CI, 1.03-1.20; p = .005). A nonsignificant trend (p = .09) toward increased late grade 3 or higher toxicity was observed for pelvic radiation therapy use. CONCLUSIONS: Docetaxel combined with radiotherapy has an acceptable long-term toxicity profile.

Probability of normal tissue complications for hematologic and gastrointestinal toxicity in postoperative whole pelvic radiotherapy for gynecologic malignancies using intensity-modulated proton therapy with robust optimization.

This retrospective treatment-planning study was conducted to determine whether intensity-modulated proton therapy with robust optimization (ro-IMPT) reduces the risk of acute hematologic toxicity (H-T) and acute and late gastrointestinal toxicity (GI-T) in postoperative whole pelvic radiotherapy for gynecologic malignancies when compared with three-dimensional conformal radiation therapy (3D-CRT), intensity-modulated X-ray (IMXT) and single-field optimization proton beam (SFO-PBT) therapies. All plans were created for 13 gynecologic-malignancy patients. The prescribed dose was 45 GyE in 25 fractions for 95% planning target volume in 3D-CRT, IMXT and SFO-PBT plans and for 99% clinical target volume (CTV) in ro-IMPT plans. The normal tissue complication probability (NTCP) of each toxicity was used as an in silico surrogate marker. Median estimated NTCP values for acute H-T and acute and late GI-T were 0.20, 0.94 and 0.58 × 10-1 in 3D-CRT; 0.19, 0.65 and 0.24 × 10-1 in IMXT; 0.04, 0.74 and 0.19 × 10-1 in SFO-PBT; and 0.06, 0.66 and 0.15 × 10-1 in ro-IMPT, respectively. Compared with 3D-CRT and IMXT plans, the ro-IMPT plan demonstrated significant reduction in acute H-T and late GI-T. The risk of acute GI-T in ro-IMPT plan is equivalent with IMXT plan. The ro-IMPT plan demonstrated potential clinical benefits for reducing the risk of acute H-T and late GI-T in the treatment of gynecologic malignances by reducing the dose to the bone marrow and bowel bag while maintaining adequate dose coverage to the CTV. Our results indicated that ro-IMPT may reduce acute H-T and late GI-T risk with potentially improving outcomes for postoperative gynecologic-malignancy patients with concurrent chemotherapy.

Natural-history Characterization of a Murine Partial-body Irradiation Model System: Establishment of a Multiple-Parameter Based GI-ARS Severity-Scoring System.

The purpose of this investigation was to characterize the natural history of a murine total-abdominal-irradiation exposure model to measure gastrointestinal acute radiation injury. Male CD2F1 mice at 12 to 15 weeks old received total-abdominal irradiation using 4-MV linear accelerator X-rays doses of 0, 11, 13.5, 15, 15.75 and 16.5 Gy (2.75 Gy/min). Daily cage-side (i.e., in the animal housing room) observations of clinical signs and symptoms including body weights on all animals were measured up to 10 days after exposure. Jejunum tissues from cohorts of mice were collected at 1, 3, 7 and 10 days after exposure and radiation injury was assessed by histopathological analyses. Results showed time- and dose-dependent loss of body weight [for example at 7 days: 0.66 (±0.80) % loss for 0 Gy, 6.40 (±0.76) % loss at 11 Gy, 9.43 (±2.06) % loss at 13.5 Gy, 23.53 (± 1.91) % loss at 15 Gy, 29.97 (±1.16) % loss at 15.75 Gy, and 31.79 (±0.76) % loss at 16.5 Gy]. Negligible clinical signs and symptoms, except body weight changes, of radiation injury were observed up to 10 days after irradiation with doses of 11 to 15 Gy. Progressive increases in the severity of clinical signs and symptoms were found after irradiation with doses >15 Gy. Jejunum histology showed a progressive dose-dependent increase in injury. For example, at 7 days postirradiation, the percent of crypts, compared to controls, decreased to 82.3 (±9.5), 69.2 (±12.3), 45.4 (±11.9), 18.0 (±3.4), and 11.5 (± 1.8) with increases in doses from 11 to 16.5 Gy. A mucosal injury scoring system was used that mainly focused on changes in villus morphology damage (i.e., subepithelial spaces near the tips of the villi with capillary congestion, significant epithelial lifting along the length of the villi with a few denuded villus tips). Peak levels of total-abdominal irradiation induced effects on the mucosal injury score were seen 7 days after irradiation for doses ≥15 Gy, with a trend to show a decline after 7 days. A murine multiple-parameter gastrointestinal acute-radiation syndrome severity-scoring system was established based on clinical signs and symptoms that included measures of appearance (i.e., hunched and/or fluffed fur), respiratory rate, general (i.e., decreased mobility) and provoked behavior (i.e., subdued response to stimulation), weight loss, and feces/diarrhea score combined with jejunum mucosal-injury grade score. In summary, the natural-history radio-response for murine partial-body irradiation exposures is important for establishing a well-characterized radiation model system; here we established a multiple-parameter gastrointestinal acute-radiation syndrome severity-scoring system that provides a radiation injury gastrointestinal tissue-based assessment utility.

Radioprotective potential of probiotics against gastrointestinal and neuronal toxicity: a preclinical study

Purpose Radiotherapy is a critical component of cancer treatment, along with surgery and chemotherapy. Approximately, 90% of cancer patients undergoing pelvic radiotherapy show gastrointestinal (GI) toxicity, including bloody diarrhea, and gastritis, most of which are associated with gut dysbiosis. In addition to the direct effect of radiation on the brain, pelvic irradiation can alter the gut microbiome, leading to inflammation and breakdown of the gut–blood barrier. This allows toxins and bacteria to enter the bloodstream and reach the brain. Probiotics have been proven to prevent GI toxicity by producing short-chain fatty acids and exopolysaccharides beneficial for protecting mucosal integrity and oxidative stress reduction in the intestine and also shown to be beneficial in brain health. Microbiota plays a significant role in maintaining gut and brain health, so it is important to study whether bacterial supplementation will help in maintaining the gut and brain structure after radiation exposure. Methods In the present study, male C57BL/6 mice were divided into control, radiation, probiotics, and probiotics + radiation groups. On the 7th day, animals in the radiation and probiotics + radiation groups received a single dose of 4 Gy to whole-body. Posttreatment, mice were sacrificed, and the intestine and brain tissues were excised for histological analysis to assess GI and neuronal damage. Results Radiation-induced damage to the villi height and mucosal thickness was mitigated by the probiotic treatment significantly (p < 0.01). Further, radiation-induced pyknotic cell numbers in the DG, CA2, and CA3 areas were substantially reduced with bacterial supplementation (p < 0.001). Similarly, probiotics reduced neuronal inflammation induced by radiation in the cortex, CA2, and DG region (p < 0.01) (AU)

The progression of radiation injury in a Wistar rat model of partial body irradiation with ∼5% bone marrow shielding.

PURPOSE: To describe the dose response relationship and natural history of radiation injury in the Wistar rat and its suitability for use in medical countermeasures (MCM) testing. MATERIALS & METHODS: In two separate studies, male and female rats were exposed to partial body irradiation (PBI) with 5% bone marrow sparing. Animals were X-ray irradiated from 7 to 12 Gy at 7-10 weeks of age. Acute radiation syndrome (ARS) survival at 30 days and delayed effects of acute radiation exposure (DEARE) survival at 182 days were assessed. Radiation effects were determined by clinical observations, body weights, hematology, clinical chemistry, magnetic resonance imaging of lung, whole-body plethysmography, and histopathology. RESULTS: Rats developed canonical ARS responses of hematopoietic atrophy and gastrointestinal injury resulting in mortality at doses ≥8Gy in males and ≥8.5 Gy in females. DEARE mortality occurred at doses ≥8Gy for both sexes. Findings indicate lung, kidney, and/or liver injury, and persistent hematological dysregulation, revealing multi-organ injury as a DEARE. CONCLUSION: The Wistar rat PBI model is suitable for testing MCMs against hematopoietic and gastrointestinal ARS. DEARE multi-organ injury occurred in both sexes irradiated with 8-9Gy, also suggesting suitability for polypharmacy studies addressing the combination of ARS and DEARE injury.

Gastrointestinal Brachytherapy.

Brachytherapy is a sophisticated and proven treatment technique of different GI localizations. Here the development of GI- brachytherapy of last 20 years, current position and the perspectives for next years are discussed. In summary: The GI-brachytherapy of different localizations is very effective, in experienced hands a safe technique and should be part of armamentarium of every radiation oncologist.

Gut metabolite Urolithin A mitigates ionizing radiation-induced intestinal damage.

Ionizing radiation (IR)-induced intestinal damage is the major and common injury of patients receiving radiotherapy. Urolithin A (UroA) is a metabolite of the intestinal flora of ellagitannin, a compound found in fruits and nuts such as pomegranates, strawberries and walnuts. UroA shows the immunomodulatory and anti-inflammatory capacity in various metabolic diseases. To evaluate the radioprotective effects, UroA(0.4, 2 and 10 mg/kg) were intraperitoneally injected to C57BL/6 male mice 48, 24, 1 h prior to and 24 h after 9.0Gy TBI. The results showed that UroA markedly upregulated the survival of irradiated mice, especially at concentration of 2 mg/kg. UroA improved the intestine morphology architecture and the regeneration ability of enterocytes in irradiated mice. Then, UroA significantly decreased the apoptosis of enterocytes induced by radiation. Additionally, 16S rRNA sequencing analysis showed the effect of UroA is associated with the recovery of the IR-induced intestinal microbacteria profile changes in mice. Therefore, our results determinated UroA could be developed as a potential candidate for radiomitigators in radiotherapy and accidental nuclear exposure. And the beneficial functions of UroA might be associated with the inhibition of p53-mediated apoptosis and remodelling of the gut microbes.

Personalized Radiation Attenuating Materials for Gastrointestinal Mucosal Protection.

Cancer patients undergoing therapeutic radiation routinely develop injury of the adjacent gastrointestinal (GI) tract mucosa due to treatment. To reduce radiation dose to critical GI structures including the rectum and oral mucosa, 3D-printed GI radioprotective devices composed of high-Z materials are generated from patient CT scans. In a radiation proctitis rat model, a significant reduction in crypt injury is demonstrated with the device compared to without (p < 0.0087). Optimal device placement for radiation attenuation is further confirmed in a swine model. Dosimetric modeling in oral cavity cancer patients demonstrates a 30% radiation dose reduction to the normal buccal mucosa and a 15.2% dose reduction in the rectum for prostate cancer patients with the radioprotectant material in place compared to without. Finally, it is found that the rectal radioprotectant device is more cost-effective compared to a hydrogel rectal spacer. Taken together, these data suggest that personalized radioprotectant devices may be used to reduce GI tissue injury in cancer patients undergoing therapeutic radiation.

Evaluation of sodium orthovanadate as a radioprotective agent under total-body irradiation and partial-body irradiation conditions in mice.

PURPOSE: Our previous study indicated that sodium orthovanadate (vanadate), a strong inhibitor of p53, effectively suppressed the lethality from the hematopoietic (HP) and gastrointestinal (GI) syndromes after 12 Gy total-body irradiation (TBI) in mice. This conclusion, however, was inconsistent with the fact that p53 plays a radioprotective role in the intestinal epithelium. The death after TBI of around 12 Gy was attributed to a combined effect of HP and GI syndromes. To verify the effect from prophylactic administration of p53 inhibitor on protection of HP and GI syndromes, in this study, the radioprotective effects from vanadate were investigated in TBI and lower half-body irradiation (partial-body irradiation: PBI) mouse models. METHODS: Female ICR mice were given a single injection of vanadate or vehicle, followed by a lethal dose of TBI or PBI. Radioprotective effects of vanadate against the irradiations were evaluated by analyzing survival rate, body weight, hematopoietic parameters, and histological changes in the bone marrow and intestinal epithelium. RESULTS: TBI-induced HP syndrome was effectively suppressed by vanadate treatment. After TBI, the vanadate-treated mice retained better bone marrow cellularity and showed markedly higher survival rate compared to the vehicle-treated animals. In contrast, vanadate did not relieve loss of intestinal crypts and failed to rescue mice from GI death after PBI. CONCLUSION: Vanadate is a p53 inhibitor that has been shown to be beneficial as a radiation protective agent against HP but was not effective in protecting against acute GI radiation injury.

Early morbidity and dose-volume effects in definitive radiochemotherapy for locally advanced cervical cancer: a prospective cohort study covering modern treatment techniques.

PURPOSE: Predicting morbidity for patients with locally advanced cervix cancer after external beam radiotherapy (EBRT) based on dose-volume parameters remains an unresolved issue in definitive radiochemotherapy. The aim of this prospective study was to correlate patient characteristics and dose-volume parameters to various early morbidity endpoints for different EBRT techniques, including volumetric modulated arc therapy (VMAT) and adaptive radiotherapy (ART). METHODS AND MATERIALS: The study population consisted of 48 patients diagnosed with locally advanced cervix cancer, treated with definitive radiochemotherapy including image-guided adaptive brachytherapy (IGABT). Multiple questionnaires (CTCAE 4.03, QLQ-C30 and EORTC QLQ-CX24) were assessed prospectively for patients treated with different EBRT techniques, including online adaptive VMAT. Contouring and treatment planning was based on the EMBRACE protocols. Acute toxicity, classified as general, gastrointestinal (GI) or genitourinary (GU) and their corresponding dose-volume histograms (DVHs) were first correlated by applying least absolute shrinkage and selection operator (LASSO) and subsequently evaluated by multiple logistic binomial regression. RESULTS: The treated EBRT volumes varied for the different techniques with ~2500 cm3 for 3D conformal radiotherapy (3D-CRT), ~2000 cm3 for EMBRACE­I VMAT, and ~1800 cm3 for EMBRACE-II VMAT and ART. In general, a worsening of symptoms during the first 5 treatment weeks and recovery afterwards was observed. Dose-volume parameters significantly correlating with stool urgency, rectal and urinary incontinence were as follows: bowel V40Gy < 250 cm3, rectum V40Gy < 80% and bladder V40Gy < 80-90%. CONCLUSION: This prospective study demonstrated the impact of EBRT treatment techniques in combination with chemotherapy on early morbidity. Dose-volume effects for dysuria, urinary incontinence, stool urgency, diarrhea, rectal bleeding, rectal incontinence and weight loss were found.

Toxicity at 1 Year After Stereotactic Body Radiation Therapy in 3 Fractions for Localized Prostate Cancer.

PURPOSE: To assess the toxicity profile of prostate cancer stereotactic body radiation therapy (SBRT) in 3 fractions. METHODS AND MATERIALS: This was a prospective, multicenter phase 2 toxicity study enrolling patients with low to favorable intermediate-risk prostate cancer. Before simulation, 3 to 4 fiducial markers along with a rectal spacer were placed. The target (prostate only) was prescribed 40 Gy, whereas the maximum dose to the urethra was limited to 33 Gy with the highest priority at planning; less stringent objectives were placed on the bladder, the filling of which was controlled via a Foley catheter. Treatment was delivered every other day. Toxicity was prospectively scored with Common Terminology Criteria for Adverse Events, and several patient-reported outcomes were collected. The maximum allowed prevalence rate of grade 2+ genitourinary (GU) toxicity at 1 year was set at 15%, and the study was sized accordingly. RESULTS: Between November 2015 and May 2019, 59 patients were enrolled by 3 participating institutions. Acute gastrointestinal toxicity was occasional and mild, whereas 11.9% of patients developed acute grade 2 GU toxicity and 1.7% developed acute grade 3 GU toxicity. No patient had persistent treatment-related grade 2+ GU toxicity at 12 months after SBRT; thus, the null hypothesis was rejected. We observed a clinically relevant worsening of both International Prostate Symptom Score (IPSS) and International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) scores at 12 months compared with baseline. Moreover, we found a strong association between all selected bladder dose/volume metrics at planning and ICIQ-SF worsening at 12 months, whereas for the IPSS, the correlation with bladder dose metrics was marginal. CONCLUSIONS: The results suggest that at 12 months after treatment, the toxicity profile of SBRT in 3 fractions is acceptable.

Surgical spacer placement for proton radiotherapy in locally advanced pancreatic body and tail cancers: initial clinical results.

BACKGROUND: Particle radiotherapy has increasingly gained acceptance for locally advanced pancreatic cancers owing to superior tumor conformity and dosimetry compared to conventional photon radiotherapy. However, the close proximity of the pancreas to the stomach and duodenum leads to radiation-induced gastrointestinal toxicities, which hinder the delivery of curative doses to the tumor. To overcome this problem, a surgical spacer was placed between the tumor and gastrointestinal tract, and subsequent proton radiotherapy was performed in this study. METHODS: Data from 9 patients who underwent surgical spacer placement and subsequent proton radiotherapy were analyzed. The safety and feasibility of the spacer placement surgery were evaluated; the impact of the spacer on dosimetry was also assessed using dose volume histogram (DVH) analyses, before and after surgical spacer placement. RESULTS: Surgical spacer placement and subsequent proton radiotherapy were successfully completed in all cases. Surgical spacer placement significantly improved the dose intensity covering 95%, mean, and minimum doses for the gross tumor volume, and the clinical and planning target volume based on the DVH, while respecting the dose constraints of the gastrointestinal tract. Based on the Common Terminology Criteria for Adverse Events, two patients (22.2%) developed gastrointestinal ulcer (Grade 2) at 1 and 35 months, and one patient (11.1%) developed gastric perforation (Grade 4) at 4 months after proton radiotherapy. CONCLUSIONS: Surgical spacer placement in the locally advanced pancreatic body and tail cancers is relatively safe and technically feasible. Comparing radiation plans, surgical spacer placement seems to improve the dose distribution in the locally advanced pancreatic body and tail cancers, which are close to the gastrointestinal tract.

Hypofractionated Radiation Therapy to the Prostate Bed With Intensity-Modulated Radiation Therapy (IMRT): A Phase 2 Trial.

PURPOSE: Postoperative radiation therapy (RT) is a common therapy used for patients with prostate cancer. Although clinical trials have established the safety and efficacy of hypofractionation as a primary therapy, there are limited data in a postoperative setting. We conducted a prospective trial to evaluate the safety and feasibility of postoperative hypofractionated RT to the prostate bed. METHODS AND MATERIALS: In this phase 2 trial, patients submitted to radical prostatectomy were treated with hypofractionated RT to the prostate bed (adjuvant or salvage). The prescribed dose was 51 Gy in 15 fractions (3.4 Gy per fraction), using intensity modulated and image guided radiation therapy techniques. The primary endpoint was the rate of acute genitourinary (GU) grade ≥2 toxicity. Secondary endpoints included acute gastrointestinal (GI) and late GU/GI toxicities, biochemical failure-free survival (BFFS), metastasis-free survival, cancer-specific survival, overall survival, and health-related quality of life. RESULTS: Of 64 enrolled patients, 61 received radiation therapy (57 salvage and 4 adjuvant radiation therapy). After a median follow-up of 16 months, 11.5% of patients experienced acute grade ≥2 GU symptoms and 13.1% experienced acute grade ≥2 GI symptoms. The late grade ≥2 GU toxicity rate was 8.2%, and 1 patient (1.6%) developed both acute and late grade 3 GU toxicity. The late grade ≥2 GI toxicity rate was 11.5%, and no grade 3 GI adverse events were reported. The short follow-up limits our ability to perform a robust oncologic endpoint assessment; however, the 2-year BFFS, use of subsequent salvage therapy, and the development of metastasis were 95.1%, 0%, and 0%, respectively. CONCLUSIONS: Hypofractionated RT to the prostate bed in 15 treatments was safe, with an acceptable GU and GI toxicity profile. Further study in large, randomized trials is warranted.

Radiation Dose-Volume Effects for Liver SBRT.

Stereotactic body radiation therapy (SBRT) has emerged as an effective, noninvasive treatment option for primary liver cancer and metastatic disease occurring in the liver. Although SBRT can be highly effective for establishing local control in hepatic malignancies, a tradeoff exists between tumor control and normal tissue complications. The objective of the present study was to review the normal tissue dose-volume effects for SBRT-induced liver and gastrointestinal toxicities and derive normal tissue complication probability models.

Impact of High-Dose-Rate and Low-Dose-Rate Brachytherapy Boost on Toxicity, Functional and Cancer Outcomes in Patients Receiving External Beam Radiation Therapy for Prostate Cancer: A National Population-Based Study.

PURPOSE: External beam radiation therapy (EBRT) with brachytherapy boost reduces cancer recurrence in patients with prostate cancer compared with EBRT monotherapy. However, randomized controlled trials or large-scale observational studies have not compared brachytherapy boost types directly. METHODS AND MATERIALS: This observational cohort study used linked national cancer registry data, radiation therapy data, administrative hospital data, and mortality records of 54,642 patients with intermediate-risk, high-risk, and locally advanced prostate cancer in England. The records of 11,676 patients were also linked to results from a national patient survey collected at least 18 months after diagnosis. Competing risk regression analyses were used to compare gastrointestinal (GI) toxicity, genitourinary (GU) toxicity, skeletal-related events (SRE), and prostate cancer-specific mortality (PCSM) at 5 years with adjustment for patient and tumor characteristics. Linear regression was used to compare Expanded Prostate Cancer Index Composite 26-item version domain scores (scale, 0-100, with higher scores indicating better function). RESULTS: Five-year GI toxicity was significantly increased after low-dose-rate brachytherapy boost (LDR-BB) (32.3%) compared with high-dose-rate brachytherapy boost (HDR-BB) (16.7%) or EBRT monotherapy (18.7%). Five-year GU toxicity was significantly increased after both LDR-BB (15.8%) and HDR-BB (16.6%), compared with EBRT monotherapy (10.4%). These toxicity patterns were matched by the mean patient-reported bowel function scores (LDR-BB, 77.3; HDR-BB, 85.8; EBRT monotherapy, 84.4) and the mean patient-reported urinary obstruction/irritation function scores (LDR-BB, 72.2; HDR-BB, 78.9; EBRT monotherapy, 83.8). Five-year incidences of SREs and PCSM were significantly lower after HDR-BB (2.4% and 2.7%, respectively) compared with EBRT monotherapy (2.8% and 3.5%, respectively). CONCLUSIONS: Compared with EBRT monotherapy, LDR-BB has worse GI and GU toxicity and HDR-BB has worse GU toxicity. HDR-BB has a lower incidence of SREs and PCSM than EBRT monotherapy.

Hypofractionated Postprostatectomy Radiation Therapy for Prostate Cancer to Reduce Toxicity and Improve Patient Convenience: A Phase 1/2 Trial.

PURPOSE: The phase 1 portion of this multicenter, phase 1/2 study of hypofractionated (HypoFx) prostate bed radiation therapy (RT) as salvage or adjuvant therapy aimed to identify the shortest dose-fractionation schedule with acceptable toxicity. The phase 2 portion aimed to assess the health-related quality of life (QoL) of using this HypoFx regimen. METHODS AND MATERIALS: Eligibility included standard adjuvant or salvage prostate bed RT indications. Patients were assigned to receive 1 of 3 daily RT schedules: 56.6 Gy in 20 Fx, 50.4 Gy in 15 Fx, or 42.6 Gy in 10 Fx. Regional nodal irradiation and androgen deprivation therapy were not allowed. Participants were followed for 2 years after treatment with outcome measures based on prostate-specific antigen levels, toxicity assessments (Common Terminology Criteria for Adverse Events, v4.0), QoL measures (the Expanded Prostate Cancer Index Composite [EPIC] and EuroQol EQ-5D instruments), and out-of-pocket costs. RESULTS: There were 32 evaluable participants, and median follow-up was 3.53 years. The shortest dose-fractionation schedule with acceptable toxicity was determined to be 42.6 Gy in 10 Fx, with most patients (23) treated with this schedule. Grade 3 genitourinary (GU) and gastrointestinal (GI) toxicities occurred in 3 patients and 1 patient, respectively. There was 1 grade 4 sepsis event. Higher dose to the hottest 25% of the rectum was associated with increased risk of grade 2+ GI toxicity; no dosimetric factors were found to predict for GU toxicity. There was a significant decrease in the mean bowel, but not bladder, QoL score at 1 year compared with baseline. Prostate-specific antigen failure occurred in 34.3% of participants, using a definition of nadir plus 2 ng/mL. Metastases were more likely to occur in regional lymph nodes (5 of 7) than in bones (2 of 7). The mean out-of-pocket cost for patients during treatment was $223.90. CONCLUSIONS: We identified 42.6 Gy in 10 fractions as the shortest dose-fractionation schedule with acceptable toxicity in this phase 1/2 study. There was a higher than expected rate of grade 2 to 3 GU and GI toxicity and a decreased EPIC bowel QoL domain with this regimen. Future studies are needed to explore alternative adjuvant/salvage HypoFx RT schedules after radical prostatectomy.

Dietary Methionine Supplementation Exacerbates Gastrointestinal Toxicity in a Mouse Model of Abdominal Irradiation.

BACKGROUND AND PURPOSE: Identification of appropriate dietary strategies for prevention of weight and muscle loss in cancer patients is crucial for successful treatment and prolonged patient survival. High-protein oral nutritional supplements decrease mortality and improve indices of nutritional status in cancer patients; however, high-protein diets are often rich in methionine, and experimental evidence indicates that a methionine-supplemented diet (MSD) exacerbates gastrointestinal toxicity after total body irradiation. Here, we sought to investigate whether MSD can exacerbate gastrointestinal toxicity after local abdominal irradiation, an exposure regimen more relevant to clinical settings. MATERIALS AND METHODS: Male CBA/CaJ mice fed either a methionine-adequate diet or MSD (6.5 mg methionine/kg diet vs 19.5 mg/kg) received localized abdominal X-irradiation (220 kV, 13 mA) using the Small Animal Radiation Research Platform, and tissues were harvested 4, 7, and 10 days after irradiation. RESULTS: MSD exacerbated gastrointestinal toxicity after local abdominal irradiation with 12.5 Gy. This was evident as impaired nutrient absorption was paralleled by reduced body weight recovery. Mechanistically, significant shifts in the gut ecology, evident as decreased microbiome diversity, and substantially increased bacterial species that belong to the genus Bacteroides triggered proinflammatory responses. The latter were evident as increases in circulating neutrophils with corresponding decreases in lymphocytes and associated molecular alterations, exhibited as increases in mRNA levels of proinflammatory genes Icam1, Casp1, Cd14, and Myd88. Altered expression of the tight junction-related proteins Cldn2, Cldn5, and Cldn6 indicated a possible increase in intestinal permeability and bacterial translocation to the liver. CONCLUSIONS: We report that dietary supplementation with methionine exacerbates gastrointestinal syndrome in locally irradiated mice. This study demonstrates the important roles registered dieticians should play in clinical oncology and further underlines the necessity of preclinical and clinical investigations in the role of diet in the success of cancer therapy.