Late Gastrointestinal Research Articles

Comparative effectiveness of moderate hypofractionation with volumetric modulated arc therapy versus conventional 3D-radiotherapy after radical prostatectomy

PurposeHypofractionated radiotherapy for prostate cancer is well established for definitive treatment, but not well defined in the postoperative setting. The purpose of this analysis was to assess oncologic outcomes and toxicity in a large cohort of patients treated with conventionally fractionated three-dimensional (3D) conformal radiotherapy (CF) and hypofractionated volumetric modulated arc therapy (HF) after radical prostatectomy.MethodsBetween 1994 and 2019, a total of 855 patients with prostate carcinoma were treated by postoperative radiotherapy using CF (total dose 65–72 Gy, single fraction 1.8–2 Gy) in 572 patients and HF (total dose 62.5–63.75 Gy, single fraction 2.5–2.55 Gy) in 283 patients. The association of treatment modality with biochemical control, overall survival (OS), and gastrointestinal (GI) and genitourinary (GU) toxicity was assessed using logistic and Cox regression analysis.ResultsThere was no difference between the two modalities regarding biochemical control rates (77% versus 81%, respectively, for HF and CF at 24 months and 58% and 64% at 60 months; p = 0.20). OS estimates after 5 years: 95% versus 93% (p = 0.72). Patients undergoing HF had less frequent grade 2 or higher acute GI or GU side effects (p = 0.03 and p = 0.005, respectively). There were no differences in late GI side effects between modalities (hazard ratio 0.99). Median follow-up was 23 months for HF and 72 months for CF (p < 0.001).ConclusionFor radiation therapy of resected prostate cancer, our analysis of this largest single-centre cohort (n = 283) treated with hypofractionation with advanced treatment techniques compared with conventional fractionation did not yield different outcomes in terms of biochemical control and toxicities. Prospective investigating of HF is merited.

Rectal Radiation Dose and Clinical Outcomes in Prostate Cancer Patients Treated With Stereotactic Body Radiation Therapy With and Without Hydrogel.

BackgroundPatients with prostate cancer treated with stereotactic body radiation therapy (SBRT) may experience gastrointestinal (GI) toxicity. The hydrogel may mitigate this toxicity by reducing the rectal radiation dose. The purpose of this study is to compare rectal radiation dose and GI toxicity in patients receiving prostate SBRT with and without hydrogel.MethodsConsecutive patients treated with SBRT between February 2017 and January 2020 with and without hydrogel were retrospectively identified. Baseline characteristics including prostate volume, rectal diameter, body mass index (BMI), age, pretreatment prostate-specific antigen (PSA), Gleason score, T-stage, and androgen deprivation therapy (ADT) usage were compared. Dosimetric outcomes (V40Gy, V36Gy, V32Gy, V38Gy, and V20Gy), rates of acute (≤90 days) and late (>90 days) GI toxicity, and PSA outcomes were evaluated for patients with and without hydrogel.ResultsA total of 92 patients were identified (51 hydrogel and 41 non-hydrogel). There were no significant differences in baseline characteristics. Rectal V38(cc) was significantly less in the hydrogel group (mean 0.44 vs. mean 1.41 cc, p = 0.0002), and the proportion of patients with V38(cc) < 2 cc was greater in the hydrogel group (92% vs. 72%, p = 0.01). Rectal dose was significantly lower for all institutional dose constraints in the hydrogel group (p < 0.001). The hydrogel group experienced significantly less acute overall GI toxicity (16% hydrogel vs. 28% non-hydrogel, p = 0.006), while the difference in late GI toxicity trended lower with hydrogel but was not statistically significant (4% hydrogel vs. 10% non-hydrogel, p = 0.219). At a median follow-up of 14.8 months, there were no biochemical recurrences in either group.ConclusionHydrogel reduces rectal radiation dose in patients receiving prostate SBRT and is associated with a decreased rate of acute GI toxicity.

Radiotherapy-related toxicity for localized prostate cancer: meta-analysis comparing conventional or moderately hypofractionated vs. ultrahypofractionated protocols.

To compare toxicities in relation to standard radiation treatments [conventional fractionation RT (CRT) and moderate hypofractionated RT (MRT)] with ultrahypofractionated RT (URT) in the treatment of patients with localized PCa. A searched was performed in Medline, Embase, Cochrane CENTRAL, and LILACS to January 2020 for studies comparing URT to CRT and/or MRT in relation to genitourinary (GU) and gastrointestinal (GI) toxicity in the treatment of patients with localized PCa. URT, MRT and CRT were defined as protocols delivering a daily dose of ≥5Gy, 2.4-4.9Gy, and <2.4Gy per fractions regardless total dose, respectively. Eight studies with 2929 patients with localized PCa were included in the analysis. These eight studies did not find any difference between URT and MRT/CRT groups in relation to acute GU toxicity (21.0% × 23.8%, RD -0.04; 95% CI -0.13, 0.06; p = 0.46; I2 = 89%) and acute GI toxicity (4.9% × 6.9%, RD -0.03; 95% CI -0.07, 0.01; p = 0.21; I2 = 79%). Six studies did not find any difference between URT and MRT/CRT groups in relation to late GU toxicity (3.9% × 4.7%, RD -0.01; 95% CI -0.03, 0.00; p = 0.16; I2 = 19%) and late GI toxicity (2.1% × 3.5%, RD -0.01; 95% CI -0.03, 0.00; p = 0.05; I2 = 22%). The present study suggests that acute GU/GI and late GU/GI toxicity are similar between URT and standard protocols. More studies with longer follow-ups directed to oncology outcomes are warranted before any recommendation on this topic.

Impact of rectal spacer on toxicity reduction in men treated with proton versus photon therapy.

247 Background: Dose escalation in prostate cancer (PCa) radiotherapy (RT) is limited by toxicity to surrounding tissue, including the rectum. Rectal spacers improve bowel toxicity in men treated with photons (i.e. IMRT). However, the relative benefit of rectal spacers in men treated with protons remains unknown. Further, proton therapy may result in high-dose exposure to the anterior rectal wall due to lateral penumbra with conventional opposed lateral beam arrangement. We hypothesize that rectal spacers will confer greater toxicity benefit in the setting of proton therapy compared with photon therapy. Methods: We conducted an IRB approved, single institution, retrospective review of patients receiving definitive conventional or moderate hypofractionated photon IMRT or pencil-beam scanning proton RT for localized PCa from 2018-2021. Four cohorts were compared: Photon with (Ph+RS) or without (Ph-RS) rectal spacer, and proton with (Pr+RS) or without (Pr-RS) rectal spacer. Rates of pelvic nodal treatment were equivalent between protons and photons within the +/- rectal spacer cohorts. Acute (&lt;3 months) and late (≥ 3 month) toxicity was compared amongst the four cohorts. Cumulative incidence of physician-reported grade 1-2 gastrointestinal (GI) toxicity (CTCAE V5.0) was compared using Chi-square or Fisher’s exact test. Patient-reported bowel toxicity was evaluated using International Prostate Expanded Prostate Composite Index- Clinical Practice (EPIC-CP) and compared using linear mixed modeling. Results: 164 patients were eligible for analysis: 38 Ph-RS, 50 Ph+RS, 26 Pr-RS, &amp; 50 Pr+RS. Median follow-up was 17.6 months. In men treated with protons, physician-reported acute G1-2 GI toxicity was significantly lower in men with versus without rectal spacer (6.12 vs 30.77%, Pr+RS vs Pr-RS, respectively; p=0.009) and there was a trend towards lower late G1-2 GI toxicity (8.51 vs 26.09%, Pr+RS vs Pr-RS, respectively; p=0.08). In men treated with photons, there were no significant differences in physician-reported acute or later GI toxicity with versus without rectal spacer. No significant differences in patient-reported outcomes were observed with versus without spacer in the proton or photon cohorts. Conclusions: Rectal spacer use was associated with a lower CTCAE grade 1-2 acute GI toxicity in men treated with protons, and this difference was not observed in men treated with photons. While this study is limited by low sample size, a relatively greater benefit of rectal spacer with proton vs. photon therapy was observed. Further prospective analyses in larger cohorts are ongoing to validate these hypothesis-generating findings.

Two-Year Toxicity and Efficacy of Carbon Ion Radiotherapy in the Treatment of Localized Prostate Cancer: A Single-Centered Study.

BackgroundWe aimed at determining the safety and feasibility of spot-scanning carbon ion radiotherapy (CIRT) for patients with localized prostate cancer.MethodsWe enrolled 118 patients with localized prostate cancer who underwent treatment with spot-scanning CIRT at the Shanghai Proton and Heavy Ion Center (SPHIC) from January 2016 to December 2020. The dose was gradually increased from relative biological effectiveness (RBE)-weighted dose (DRBE) = 59.2–65.6 Gy in 16 fractions. The primary endpoint was the occurrence of acute and late toxicities, while the secondary endpoints were biochemical relapse-free survival (bRFS), distant metastasis-free survival (DMFS), prostate cancer-specific survival (PCSS), and overall survival (OS).ResultsThe median follow-up time was 30.2 months (4.8–62.7 months). Acute grade 1 and 2 genitourinary (GU) toxicities were 15.3% and 18.6%, while acute grade 1 and 2 gastrointestinal (GI) toxicities were 2.5% and 0%, respectively. Late grade 1 and 2 GU toxicities were 4.2% and 1.7%, respectively. No late GI toxicity was observed. Moreover, there were no cases of severe acute or late toxicity (≥ grade 3). No significant association were observed between the factors and the acute GU toxicities, except for clinical target volume (CTV) (p = 0.031) on multivariate analysis. The 2-year bRFS, DMFS, PCSS, and OS were 100%, 100%, 100%, and 98.8%, respectively.ConclusionThe 2-year outcomes were encouraging, providing additional and useful information on the feasibility and safety of spot-scanning CIRT for treating prostate cancer. Thus, we recommend long-term follow-up and prospective multicentered studies to reinforce the role of CIRT in the management of localized prostate cancer.

Association of Incidence of Acid-related Upper Gastrointestinal Disorders With Glycated Hemoglobin Level.

Previous cross-sectional studies show diabetes and higher levels of plasma hemoglobin A1c (HbA1c) are associated with a higher prevalence of gastrointestinal (GI) complications. However, whether the glycemic status is associated with incident acid-related upper GI disorders remains unclear. We aimed to determine the effect of hyperglycemia per se, in terms of HbA1c, on the incidence of acid-related disorders. We analyzed consecutive subjects who had undergone repeated upper endoscopies as part of the health examinations at the National Taiwan University Hospital from 2005 to 2011. Acid-related endoscopic abnormalities were defined as erosive esophagitis (EE), Barrett's esophagus (BE), and peptic ulcer disease (PUD), which included gastric ulcers (GUs) and duodenal ulcers (DUs). All subjects were categorized by 3 tertiles of HbA1c levels. We analyzed the occurrence of respective acid-related disorders during the follow-up period. A total of 11 391 participants (mean HbA1c level 5.6 ± 0.7%) were enrolled in this longitudinal study. During the 38 426.3 person-years of follow-up (mean duration 3.37 ± 1.59 years), the incidence of EE, BE, GU, DU, PUD, and any acid-related disorders were 22.1%, 0.5%, 4.5%, 8.6%, 12.3%, and 30.3%, respectively. The higher HbA1c level was associated with higher risk of disease incidents, except BE, during the follow-up (all log-rank P < .001). In the Cox regression analyses with confounding factors fully adjusted, the hazard ratios for EE, GU, DU, PUD, and acid-related disorders were 1.174, 1.339, 1.24, 1.24, and 1.186, respectively, for the third tertile of HbA1c (all P < .05). Higher HbA1c level was associated with a higher risk of acid-related upper GI endoscopic abnormalities. Efforts toward better glycemic control may help to prevent the development of late GI complications.

Acute and Late Rectal Toxicity Following Hypofractionated Radiotherapy in Patients With Prostate Cancer: Results of a Prospective Study.

Previous randomized clinical trials have shown that moderate hypofractionation has a non-inferior or even superior efficacy to conventionally fractionated external beam radiation therapy (EBRT) in low and intermediate-risk prostate cancer. We herein aimed to evaluate the acute and late gastrointestinal (GI) toxicity of hypofractionated radiotherapy (HRT) in a real-world setting. Patients with intermediate-risk prostate adenocarcinoma eligible to receive HRT were prospectively enrolled. All patients were submitted to rectoscopy after completion of HRT, every three months after radiotherapy for the first year and every six months for the second year. Toxicity events were classified as acute, when presenting during radiotherapy or within the first three months following its completion, and as late when appearing three months to three years post-HRT. Twenty prostate cancer patients participated in this study and received 22 sessions of HRT (5 sessions a week; 2.75 Gy per session) and an overall dose of 60.5 Gy. None of our patients developed acute GI toxicity; late GI toxicity (RTOG/EORTC grade 3 rectal bleeding) was observed in 1 patient only (1/20, 5%), at 6- and 12-months post-HRT. No rectal mucosa damage was observed on follow-up rectoscopy in the acute phase in any of our patients; five patients (5/20, 25%) developed late telangiectasias. Vienna retroscopy score (VRS) was 1 in 4/5 patients (80%) and 2 in 1/5 (20%). Minimal radiation-induced rectal mucosal damage was observed in our patient population, and only as a late event, further attesting to the safety of HRT in this setting.

Two-Weekly High-Dose-Rate Brachytherapy Boost After External Beam Radiotherapy for Localized Prostate Cancer: Long-Term Outcome and Toxicity Analysis.

PurposeEvaluation of clinical outcome of two-weekly high-dose-rate brachytherapy boost after external beam radiotherapy (EBRT) for localized prostate cancer.Methods338 patients with localized prostate cancer receiving definitive EBRT followed by a two-weekly high-dose-rate brachytherapy boost (HDR-BT boost) in the period of 2002 to 2019 were analyzed. EBRT, delivered in 46 Gy (DMean) in conventional fractionation, was followed by two fractions HDR-BT boost with 9 Gy (D90%) two and four weeks after EBRT. Androgen deprivation therapy (ADT) was added in 176 (52.1%) patients. Genitourinary (GU)/gastrointestinal (GI) toxicity was evaluated utilizing the Common Toxicity Criteria for Adverse Events (version 5.0) and biochemical failure was defined according to the Phoenix definition.ResultsMedian follow-up was 101.8 months. 15 (4.4%)/115 (34.0%)/208 (61.5%) patients had low-/intermediate-/high-risk cancer according to the D`Amico risk classification. Estimated 5-year and 10-year biochemical relapse-free survival (bRFS) was 84.7% and 75.9% for all patients. The estimated 5-year bRFS was 93.3%, 93.4% and 79.5% for low-, intermediate- and high-risk disease, respectively. The estimated 10-year freedom from distant metastasis (FFM) and overall survival (OS) rates were 86.5% and 70.0%. Cumulative 5-year late GU toxicity and late GI toxicity grade ≥ 2 was observed in 19.3% and 5.0% of the patients, respectively. Cumulative 5-year late grade 3 GU/GI toxicity occurred in 3.6%/0.3%.ConclusionsTwo-weekly HDR-BT boost after EBRT for localized prostate cancer showed an excellent toxicity profile with low GU/GI toxicity rates and effective long-term biochemical control.

Dosimetric Predictors of Toxicity in Patients With Early-Stage Prostate Cancer Treated With Moderately Hypofractionated IMRT or PBT: A Multi-Institutional Analysis

<h3>Purpose/Objective(s)</h3> Limited published data address modifiable risk factors for significant toxicity complicating moderately hypofractionated schedules of intensity-modulated radiation therapy (IMRT) and proton-beam therapy (PBT) in patients with early-stage prostate cancer (PC). This study explored dosimetric predictors of Grade 3+ gastrointestinal (GI) and genitourinary (GU) toxicity following IMRT or PBT in this patient population. <h3>Materials/Methods</h3> The study population included patients from five tertiary referral centers treated from 2002-2018 for low- or intermediate-risk biopsy-proven prostate adenocarcinoma. All patients were treated with moderately hypofractionated radiation defined as 250–300 cGY per daily fraction given over 4-6 weeks. Primary outcomes were late GI and GU toxicity as defined by CTCAE v4.0. Dosimetric variables included PTV max dose, PTV volume, bladder V31 Gy, bladder V50 Gy, bladder V70 Gy, bladder max dose, rectum V31 Gy, rectum V50 Gy, rectum V70 Gy, rectum max dose, penile bulb V10 Gy, penile bulb V15 Gy, and the left and right femoral head V40 Gy. The association of dosimetric variables with treatment toxicity was assessed with the Wilcoxon signed-rank test. <h3>Results</h3> Dosimetric data were obtained for 1139 patients, including 667 treated with IMRT and 472 treated with PBT. Median follow-up for the two groups was 46.0 and 48.5 months, respectively. Late toxicity rates for the total population were 4.7% for Grade 3+ GU toxicity and 1.5% for Grade 3+ GI toxicity. Grade 3+ GU toxicity was associated with prostate volume, bladder V31 Gy and bladder V50 Gy (<i>P</i> = 0.016, <i>P</i> = 0.018, <i>P</i> = 0.028), but not with bladder V70 Gy or maximum dose to the bladder. Grade 3+ GI toxicity was not associated with any of the dosimetric variables. When analyzed by treatment group, Grade 3+ GU toxicity was observed in 3% of the IMRT cohort and 1.7% of the PBT cohort. Grade 3+ GI toxicity was seen only in PBT and was observed in 1.5% of patients. Proton plans were associated with less radiation exposure of rectum and bladder at lower doses (rectum V31 Gy: 13% vs 16%, <i>P</i> < 0.001; bladder V31 Gy: 18% vs 26%, <i>P</i> < 0.001), while IMRT was associated with less radiation exposure of rectum and bladder at higher doses (rectum V70 Gy: 0.4% vs 2%, <i>P</i> < 0.001; bladder V70 Gy: 1% vs 3%, <i>P</i> < 0.001). Photon plans yielded superior V40 Gy to the femoral heads, and superior V10 Gy and V15 Gy to the penile bulb (<i>P</i> < 0.001, <i>P</i> < 0.003, <i>P</i> < 0.002). <h3>Conclusion</h3> In this multi-institutional analysis of 1139 early-stage PC patients treated with moderately hypofractionated IMRT or PBT, risk of serious late GU and GI complications was low for both treatment groups. Analysis of the dosimetric variables identified an association of Grade 3+ GU toxicity with low-dose radiation exposure of the bladder. Grade 3+ GI toxicity was unrelated to dosimetric variables. PBT plans yielded less exposure of non-target organs to lower-dose radiation while IMRT plans yielded less exposure of non-target organs to higher-dose radiation.

Patient Reported Outcomes (PRO) in Those Receiving a High Dose Rate (HDR) Brachytherapy Prostate Boost Compared to Intensity Modulated Radiotherapy (IMRT) Alone

Prospective data show improved biochemical control-at a cost of worse urinary and overall physical function scores-in patients receiving a low dose rate (LDR) prostate brachytherapy boost when compared to IMRT alone. An HDR prostate boost may cause less toxicity than LDR brachytherapy. We, therefore, compared patient status post an HDR prostate boost or IMRT alone to see if there were any differences in PRO data between groups.American Urologic Association (AUA) symptom score and Sexual Health Inventory for Men (SHIM) score were prospectively collected for men with intermediate/high risk prostate cancer at a single institution. Genitourinary (GU) and gastrointestinal (GI) toxicity were also obtained and graded using the Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Patients had undergone either IMRT plus an HDR prostate boost (n = 53) or IMRT alone (n = 346). Patients were excluded if they had prior TURP, a history of irritable bowel disease (IBD), or a prostate size greater than 75 cc. PRO were compared at baseline and at 1-2 years. AUA and SHIM scores were compared using a two-sample Wilcoxon rank-sum test.We identified 346 patients treated between 2001 and 2018 with IMRT alone (80 Gy median EBRT dose) and 53 patients treated with HDR boost (46 Gy median EBRT dose). Patient characteristics and unadjusted PRO scores are reported below in the table. There was no grade 4 or 5 acute or late GU or GI events.Zero grade 3 late GI events occurred in the IMRT plus HDR group, while 1.7% of patients (n = 6) in the IMRT alone group experienced late grade 3 GI toxicity; this difference was not statistically significant. Patients receiving an HDR boost have greater change in AUA score at 1-2 years compared to the IMRT alone patients; this change does not appear clinically significant. SHIM scores are higher in the HDR group before and after treatment, suggesting patients selected for a prostate boost may have better erectile function at baseline. Lastly, clinicians seem more comfortable withholding ADT in patients receiving an HDR prostate boost, possibly due to the higher ablative dose provided by HDR brachytherapy.

Patient and Dosimetric Predictors of Genitourinary and Gastrointestinal Toxicity After Prostate SBRT: A Secondary Analysis of a Prospective, Multi-Institutional Phase II Trial

Stereotactic body radiation therapy (SBRT) is an emerging treatment option for localized prostate cancer. However, optimal patient selection & normal tissue tolerances for prostate SBRT are not well defined. We therefore analyzed patient factors & dosimetric correlates for genitourinary (GU) and gastrointestinal (GI) toxicity on a multi-institutional prospective trial.Patients (pts) with low- and intermediate-risk prostate cancer were enrolled on a phase II trial from 2011-2020. A dose of 36.25 Gy in 5 fractions to the PTV and 40 Gy to the prostate gland was administered on non-consecutive days. No androgen deprivation therapy or rectal spacer were used. Pts received a CT simulation with Foley catheter for urethral delineation. The clinical target volume was prostate (low-risk) or prostate plus 2cm of proximal seminal vesicles (intermediate-risk). Multiple dosimetric measures for bladder, urethra, & rectum were prospectively recorded. The maximum acute & late GU and GI toxicities using CTCAE v.3.0 were assessed at protocol-specific time points. Linear logistic regression was used to assess factors associated with Grade 1+ GI & GU toxicities. A multivariate (MV) model was constructed using all covariates with P-values < 0.2 on univariate (UV) analysis.A total of 160 evaluable men were enrolled. Median age was 67.9 years (IQR 62.6-73.2), 60 men (37.5%) were low risk, and 100 (62.5%) were intermediate risk. Median follow-up was 2.2 years. No patient factor or dosimetric correlate predicted acute Grade 1+ GU toxicity (all tested covariates P > 0.2). Treatment isodose line (P = 0.065) & age (P = 0.098) reached borderline significance for acute Grade 1+ GI toxicity on UV analysis, though neither were significant on MV analysis (P = 0.057 and P = 0.103, respectively). For late Grade 1+ GU toxicity, prior TURP, bladder V37(cc), bladder D10%, baseline AUA, & treatment isodose line reached borderline significance on UV analysis. On MV analysis, treatment isodose line trended towards significance at P = 0.055. For late Grade 1+ GI toxicity, rectum D20%, rectum D10%, rectum D5%, & history of coronary artery disease reached borderline significance on UV analysis, & a history of coronary artery disease predicted Grade 1+ GI toxicity on MV analysis (odds ratio 4.7, 95% CI 1.37-15.9, P = 0.009).No patient factor or dosimetric correlate predicted acute GI or GU toxicity after prostate SBRT. Late GU toxicity is possibly attributable to dose inhomogeneity. A history of coronary artery disease predicts for late GI toxicity, possibly due to anticoagulation.

Quality Metric to Assess Adequacy of Hydrogel Rectal Spacer Placement for Prostate Radiotherapy and Association of Metric Score With Dosimetric and Gastrointestinal Toxicity Outcomes

<h3>Purpose/Objective(s)</h3> Hydrogel rectal spacer placement (HSP) has been shown to minimize rectal dose during prostate cancer radiotherapy, yet its potential benefit for modulating rectal toxicity could in large part depend upon the quality of prostate-rectal separation achieved from HSP. We therefore developed a practical quality metric to evaluate HSP, validating its association with rectal dose reduction, as well as physician- and patient-reported rectal toxicity using a prospective dataset of men treated with prostate stereotactic body radiotherapy (SBRT). <h3>Materials/Methods</h3> Using the axial T2-weighted MRI images from a small pilot cohort of men with HSP who had been treated at our institution with prostate SBRT, a hydrogel spacer quality metric was devised from prostate-rectal space thickness (PRST) measurements. A score of 0, 1, or 2 was assigned to a PRST of < 0.3 cm, 0.3-0.9 cm, or ≥1 cm, respectively; an overall spacer quality score (SQS) was computed from individual scores (total of 9) at rectal midline and 1 cm to the right and left, located at the level of the prostate base, midgland, and apex. This quality metric was then applied to MRI simulation scans of 43 men with low/intermediate risk prostate cancer who had been enrolled on a multi-institutional phase II study to assess safety and efficacy of HSP during prostate SBRT. Associations between SQS and rectal dosimetry, late gastrointestinal (GI) toxicity, and EPIC bowel quality of life were quantified in these men treated with 45 Gy in 5 fractions. <h3>Results</h3> Among this cohort, the majority had a SQS of 1 (n = 18; 42%) or 2 (n = 18; 42%). SQS was associated with maximum rectal point dose (rectal Dmax; <i>P</i> = 0.001), maximum dose to 1 cc of rectum (D1cc; <i>P</i> = 0.003), and volume of rectum receiving ≥100% of prescription dose (V45; <i>P</i> = 0.03). For those with SQSs of 0, 1 and 2, the median rectal Dmax (cGy) was 4683, 4600, and 3921, respectively. SQS was associated with incidence of late GI toxicity (<i>P</i> = 0.03) and highest late GI toxicity score (<i>P</i> = 0.02). Among the 20 men who developed late GI toxicity, 57%, 67% and 22% with Grade ≥1 had a SQS of 0, 1, and 2, respectively. Men with SQSs of 2 compared to 0-1 had 1.36 times lower odds of an increased rectal Dmax (95% CI: 1.14-1.63); and 1.20 times lower odds of an increased rectal D1cc (95% CI: 1.07-1.34). Men with SQSs of 2 versus 0-1 had 3.30 times lower odds of a higher late GI toxicity score (95% CI: 1.18-9.28). While evidence of a significant difference in baseline EPIC bowel summary score between SQSs was not observed (<i>P</i> = 0.07) as expected, men with SQSs of 2 compared to 0-1 had 3.52 times higher odds (95% CI: 0.91-13.64) of a superior bowel summary score 12 months from prostate SBRT. <h3>Conclusion</h3> We developed a reliable, easy to use, and informative metric for assessing HSP, which appears to be associated with rectal dosimetry and late GI toxicity in men treated with prostate SBRT.

A Prospective, Single-Arm, Phase II, Multi-Center Study of Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer

To measure the biochemical disease-free survival (bDFS) & the rates of acute & late gastrointestinal (GI) or genitourinary toxicity (GU) following stereotactic body radiation therapy (SBRT) for clinically localized prostate adenocarcinoma.Eligible men aged 18 years & older with NCCN low- & intermediate-risk prostate cancer & ECOG performance status 0-1 were enrolled at two institutions. Participants were simulated with a Foley catheter to visualize the prostatic urethra. All patients received MRI. Participants received 36.25 Gy in 5 fractions on non-consecutive days to the planning target volume (PTV) with a simultaneous boost of 40 Gy to the entire prostate. Treatment was performed on a linear accelerator or frameless robotic radiosurgery system. Androgen deprivation therapy & hydrogel spacer placement were not permitted. The coprimary endpoints were grade 3 or higher GI or GU toxicity as measured by CTCAE v3.0 & bDFS using the Phoenix criteria. This study was designed to test the null hypothesis that the cumulative incidence of Grade 3 or higher GI/GU toxicity rate at 2 years was less than 10%. With n = 200 eligible patients, there was 99% power of identifying an unacceptable toxicity rate if the true toxicity rate was 20% with a one-sided significance level of 0.05. Assuming a 2-year bDFS rate of 97% for SBRT, a sample size of 200 patients also provided 92% power to determine if SBRT was superior to a historical bDFS control rate of 92%. Secondary endpoints were quality of life (QoL), prostate cancer-specific mortality, & overall survival.From January 2011 to July 2020, we enrolled 163 men. The trial was stopped early due to slow accrual. Two men were deemed ineligible & one man withdrew consent leaving 160 evaluable men. Median age was 67.9 years (IQR 62.6-73.2), 60 men (37.5%) were low risk, and 100 (62.5%) were intermediate risk. Median prostate volume was 41.5 cm3 (IQR 35.0-59.2), median baseline IPSS was 7 (IQR 3-12), and median baseline SHIM was 15 (IQR 3-23). Median PTV coverage was 96.9%. With a median follow-up of 2.2 years, the worst acute GU toxicity proportions were grade 2 in 51 (31.9%) & grade 1 in 66 (41.2%) patients, and the worst acute GI toxicity proportions were grade 2 in 7 (4.3%) and grade 1 in 30 (18.8%) patients. The cumulative incidence of late GI and GU grade 2 adverse events were 3.1% and 20.6%, respectively. No acute or late grade 3 or higher GI or GU toxicities were reported, meeting the co-primary safety endpoint (P < 0.001). 2-year bDFS was 98%, significantly higher than historical control (P < 0.01). Dosimetric correlates for toxicities and QoL will be reported separately.In one of the largest prospective series to date, prostate SBRT for low- and intermediate-risk prostate cancer is efficacious and well tolerated, with high rates of early biochemical control and low rates of clinically significant toxicity. Long-term outcomes will be reported with longer follow-up.

Primary Endpoint Analysis of a Randomized Phase III Trial of Hypofractionated vs. Conventional Post-Prostatectomy Radiotherapy: NRG Oncology GU003

<h3>Purpose/Objective(s)</h3> To determine if hypofractionated post-operative prostate bed radiotherapy (HYPORT) does not increase patient-reported genitourinary (GU) or gastrointestinal (GI) toxicity over conventionally fractionated post-operative radiotherapy (COPORT). <h3>Materials/Methods</h3> Eligibility criteria were: 1) an undetectable PSA (< 0.1 ng/mL) with either margin negative pT3pN0/X or margin positive pT2pN0/X adenocarcinoma of the prostate or 2) a detectable PSA (≥ 0.1 ng/mL) and pT2/3pN0/X disease. HYPORT was 62.5 Gy to the prostate bed in 25 fractions of 2.5 Gy. COPORT was 66.6 Gy in 37 fractions of 1.8 Gy. Lymph node RT was not allowed. Androgen deprivation therapy (ADT) ≤ 6 months was allowed. Patients were stratified according to baseline Expanded Prostate cancer Index Composite (EPIC) score (four tiers based on GU and GI scores) and ADT use (yes vs. no) then randomized 1:1. The co-primary endpoints were based on change scores (24-month score minus baseline score) from the GU and GI domains of the EPIC. The hypothesis is that the mean change scores at 24 months are no worse for HYPORT than it is for COPORT. The non-inferiority margins were based on 0.5*standard error from NRG Oncology/RTOG 0415: -5 for GU and -6 for GI. Two hundred eighty-two patients provide ≥ 90% power with a one-sided alpha = 0.025 for each domain while inflating for non-compliance/loss to follow-up. <h3>Results</h3> Between July 2017 and July 2018, 298 patients were screened and 296 were randomized: 144 to HYPORT and 152 to COPORT. Compliance with the EPIC was 100% at baseline, 83% at the end of RT, 77% at 6 months, 78% at 12 months, and 73% at 24 months. At the end of RT, the HYPORT and COPORT mean GU change scores were neither clinically significant nor significantly different and remained so at 6 and 12 months. The mean GI change scores for HYPORT and COPORT were both clinically significant and significantly different at the end of RT (HYPORT mean GI = -15.0 vs COPORT mean GI = -6.8 <i>P</i> ≤ 0.01). However, both the HYPORT and COPORT mean GI change scores clinically and statistically significant differences were resolved at 6 and 12 months. The 24-month mean GU and GI change scores for HYPORT and COPORT remained neither clinically nor statistically significant (HYPORT mean GU = -5.2 vs COPORT mean GU = -3.0, <i>P</i> = 0.81; HYPORT mean GI = -2.2 vs COPORT mean GI = -1.5, <i>P</i> = 0.12). With a median follow-up for censored patients of 2.1 years, there was no difference between HYPORT versus COPORT for biochemical failure defined as a PSA ≥ 0.4 ng/mL followed by a value higher than the first by any amount (2-yr actuarial, 12% vs 8%, <i>P</i> = 0.29) or local failure (2-yr actuarial, 0.7% vs 0.8%, <i>P</i> = 0.35). <h3>Conclusion</h3> HYPORT is non-inferior to COPORT in terms of late patient-reported GU or GI toxicity. More follow-up is needed to appropriately assess disease control endpoints. In some clinic scenarios, HYPORT may be considered an acceptable practice standard.

Updated Toxicity and Quality-of-Life Outcomes From a Randomized Phase III Trial of Extreme Hypofractionated vs. Standard Fractionated Proton Therapy for Low-Risk Prostate Cancer

<h3>Purpose/Objective(s)</h3> We present an interim analysis of toxicity and quality-of-life (QOL) from a randomized phase III trial of extreme hypofractionated versus standard hypofractionated proton therapy for low-risk prostate cancer. <h3>Materials/Methods</h3> From 2011-2020, low-risk prostate cancer patients were randomized in a 1:2 fashion to standard fractionation (79.2 Gy [RBE] in 44 fractions, Arm A) versus extreme hypofractionation (38 Gy [RBE] in 5 fractions, Arm B) proton therapy. Patients were excluded if they had an American Urological Association Symptom Index (AUASI) > 17. Toxicity was defined according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and adjusted for pre-treatment toxicities. Patients completed Expanded Prostate Cancer Index Composite + (EPIC), Short Form 12 (SF) and AUASI surveys at baseline and 3, 6, 12, 18, 24 and 36 months. <h3>Results</h3> Forty-six patients were included in Arm A and 84 patients in Arm B. Median follow-up was 50 months. The majority of patients were clinical T1c (89% Arm A, 84.5% Arm B, <i>P</i> = 0.86) and a PSA > 4-10 (80.4% Arm A, 78.6% Arm B, <i>P</i> = 1.00). For both groups, median AUASI was 5 (range 0-14). Four patients (1 Arm A, 3 Arm B) had died at the time of last follow-up, none related to their prostate cancer or treatment. Between the two arms, no significant differences were noted in acute treatment-related genitourinary (GU) or gastrointestinal (GI) toxicities: acute GU grade ≥ 2 (0% Arm A, 5% Arm B), GU grade ≥ 3 (0% each arm), GI grade ≥ 2 (0% Arm A, 2% Arm B), grade ≥ 3 (0% each arm). Similarly, no significant differences were noted in late treatment-related GU or GI toxicities: late GU grade ≥ 2 (26% Arm A, 33% Arm B), GU grade ≥ 3 (2% Arm A, 1% Arm B), GI grade ≥ 2 (13% Arm A, 19% Arm B), GI grade ≥ 3 (0% each arm). When analyzing QOL by arm and timepoints, only EPIC Overall scores at 36 months were clinically significantly different (> MID) between the two arms with Arm B having improved scores (+29.62 points, <i>P</i> = 0.02). Other QOL domains (EPIC Urinary, EPIC Bowel, AUASI) were not clinically significantly different between the two arms across timepoints. <h3>Conclusion</h3> In a phase III randomized controlled trial comparing extreme hypofractionation to standard fractionation for the treatment of prostate cancer, no significant differences for treatment-related acute or late, grade ≥ 2 or ≥ 3, toxicity were found for GU or GI toxicities. Additionally, improved EPIC Overall scores at 36 months were found in patients treated with extreme hypofractionation. This trial was registered with Western IRB 20101536, and NCT01230866.

Impact of Hydrogel and Hyaluronic Acid Rectal Spacer on Rectal Dosimetry and Toxicity in Low-Dose-Rate Prostate Brachytherapy: A Multi-Institutional Analysis of Patient Outcomes

To report on rectal dosimetry and toxicity outcomes in men with prostate cancer (PCa) treated with I125 low-dose rate brachytherapy (LDR-BT) with or without hydrogel (HS) or hyaluronic acid (HA) rectal spacer (RS) insertion. The working hypothesis is the increased retroprostatic distance achieved from RS insertion results in reduced rectal dosimetry and subsequent reduction in rectal toxicity outcomes.Seventy consecutive men treated with LDR-BT between December 2017 and July 2019 were included in this study, twenty-eight (40%) men had RS insertion according to the preference of the referring urologist, compared to a group of forty-two men (60%) without RS. Descriptive statistics were used to compare the RS safety, dosimetric effects on organs at risk (rectum and urethra), as well as gastrointestinal (GI) and genitourinary (GU) toxicities (assessed using the CTCAEv4) between the two groups.The mean prostate-rectal separation with RS at mid prostate was 9.9mm (SD 2.8mm). There were no post-operative complications for RS insertion. There was significantly reduced rectal dosimetry in RS group vs non-RS group, the median RV100 was 0cc (IQR = 0-0.0cc) vs 0.4cc (IQR = 0.1-1.1cc) (P < 0.001) respectively. Mean rectal D1cc and D2cc were 52.4% vs 84.2% (P < 0.001) and 45.7% vs. 70.0% (P < 0.001) for RS and non-RS group respectively. There were no discernible differences in the mean urethral D20, D5, and D1. There were significantly less ≥ grade 1 acute and late GI toxicities in the RS group when compared to the non-RS group (0% vs 24% P = 0.004 for acute GI toxicity: 4% vs 33%, P = 0.003 for late GI toxicity). Strong association remained for RS with late GI toxicity (odds ratios < 0.2) even after accounting for the confounding effects of post-implant RV100, D1cc and D2cc.Insertion of RS in men treated with LDR-BT is safe and results in significantly lower values in rectal dosimetry. The reduction in rectal dosimetry with RS insertion translates into significantly reduced rates of acute and late GI toxicities.

Prostate Stereotactic Body Radiation Therapy With a Focal Simultaneous Integrated Boost: Late Toxicity and Biochemical Recurrence Results From a Prospective Trial

<h3>Purpose/Objective(s)</h3> Stereotactic Body Radiation Therapy (SBRT) is increasingly utilized as a definitive treatment option for patients with prostate adenocarcinoma, especially in the low or intermediate risk setting. The aim of this study is to assess the late toxicity and biochemical recurrence rates of a single institution prospective clinical trial evaluating prostate SBRT with simultaneous integrated boost (SIB) targeting focal lesions as defined by magnetic resonance imaging (MRI). <h3>Materials/Methods</h3> Patients were eligible if they had biopsy-proven low or intermediate risk prostate adenocarcinoma with initial prostate specific antigen (PSA) values ≤20 ng/mL, clinical stage from T1c to T2c, and Gleason score ≤7. Patients also had to have one or more focal lesions on MRI and an MRI-defined total prostate volume of < 120 cm³. All patients received SBRT delivered to the entire prostate to a dose of 36.25 Gy in 5 fractions with an SIB to the lesions seen on MRI to 40 Gy in 5 fractions. Late toxicity was defined as any possible treatment-related adverse event occurring after three months from the completion of SBRT and graded according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). Biochemical recurrence was defined by the Phoenix definition of PSA increase of 2 ng/mL above the nadir. <h3>Results</h3> A total of 26 patients were enrolled, and all enrolled patients underwent planned SBRT. Six patients (23.1%) had low risk disease and twenty patients had intermediate risk disease (76.9%). Eight patients (30.8%) received androgen deprivation therapy. Median follow up was 40.5 months (range 12-64 months). No biochemical failures have yet been observed. Three patients (11.5%) experienced late grade 2 genitourinary (GU) toxicity requiring cystoscopy; two of these three patients experienced hematuria requiring cystoscopy and one patient experienced dysuria requiring cystoscopy. Six patients (23.1%) had late grade 2 GU toxicity requiring medications such as tamsulosin or oxybutynin. Two patients (7.7%) had late grade 2 gastrointestinal (GI) toxicity; both patients experienced hematochezia requiring colonoscopy and were found to have proctitis requiring steroids per rectum. There was no grade 3 or higher toxicity events observed. <h3>Conclusion</h3> The results of this study support that SBRT to the entire prostate to a dose of 36.25 Gy in 5 fractions with focal SIB to 40 Gy in 5 fractions is not associated with undue late GI or GU toxicity. Thus far, this regimen has excellent biochemical control. Focal dose escalation with an SIB planning approach may be an opportunity to improve biochemical control while limiting dose to nearby organs at risk.

Association of Gut Microbiome Characteristics With the Late Gastrointestinal Toxicities After Pelvic Receiving Radiation Treatment for Cervical, Vaginal, and Anal Cancers

Radiation therapy is curative for treating cervical, vaginal, and anal cancers, but can lead to gut toxicities that reduce quality of life in recovering patients. Previously, higher gut microbiome diversity was shown to be positively correlated with less severe acute gastrointestinal (GI) toxicities per patient-reported assessments of bowel function. The goal of this study was to explore effects of gut microbiome diversity and composition on late GI toxicities. We hypothesized that the occurrence of late GI toxicities in patients that receive abdominal radiation therapy correlates with gut microbiome diversity.We collected and analyzed rectal swabs from 66 patients with cervical, anal, and vaginal cancer receiving standard of care treatment. Samples from baseline and week 5 of treatment were sequenced using 16Sv4 ribosomal RNA (rRNA) gene sequencing. We also retrospectively evaluated the late (occurring after 3 months) radiation induced GI toxicities of patients who had completed their treatment 2 years prior using the RTOG/EORTC Late Radiation Morbidity Scoring Schema and the Common Terminology Criteria for Adverse Events (CTCAE) v.5. The gut microbial diversity of the patients was then characterized by indexes of richness, evenness and diversity. 59 patients were included in the analysis; exclusion criteria were lack of either follow-up or microbiome data and receiving additional radiation therapy or chemotherapy. Independent students t-tests were used to compare the alpha diversity metrics between patients who experienced late toxicities and those who did not. Beta diversity was evaluated using linear discriminant analysis effect size (LEfSe) to identify bacteria taxa that were differentially enriched in groups of patients with no toxicity against those with toxicity, and independent t-tests were used to compare the relative abundances of these taxa between patients with and without late toxicities.37.3% of patients per RTOG/EORTC criteria and 42.4% per CTCAE criteria experienced late GI toxicities (RTOG > = 1, CTCAE > = 1). Overall, neither the alpha diversity at baseline nor at week 5 was significantly different in patients who experienced late toxicities compared with those who didn't. Of the 22 taxa identified in the LEFse analysis, Sutterella species were higher at baseline in patients who did not experience late GI toxicities (0.21% vs. 0.72%, respectively, P = 0.01 for RTOG/EORTC criteria; 0.19% vs. 0.79%, respectively, P = 0.004 per CTCAE criteria).The presence of Sutterella was significantly associated with late toxicity, consistent with prior observations of acute toxicity. Overall, is no strong association between gut microbiome diversity and the presence of late GI toxicities in patients who have received radiation therapy for cervical, vaginal, and anal cancers. The observation has implications in the ongoing search for gut microbiome-targeted treatments for mitigating side effects of radiation.E.J. Lynn: None. M.B. El Alam: None. T. Karpinets: None. D. Lin: None. R. Kouzy: None. K. Court: None. X. Wu: None. M.P. Mezzari: None. N. Ajami: None. T. Solley: None. L.L. Lin: Employee; VA Hospital. Research Grant; AstraZeneca. Travel Expenses; AstraZeneca. L. Ramondetta: None. A. Jhingran: American Board of Radiology. P.J. Eifel: Travel Expenses; National Cancer Center Network. Stock; Apple Computer. K. Schmeler: None. B.D. Minsky: None. E.J. Koay: Research Grant; PANCAN-AACR, MD Anderson Cancer Center, Philips, National Institutes of Health, General Electric, Elekta, Stand Up 2 Cancer, Project Purple. Royalty; Taylor and Francis LLC. Patent/License Fees/Copyright; Pending Patent. I help coordinate scientific and advocacy activities for this Foundation, focused on radiation oncology. P. Das: Honoraria; MD Anderson Cancer Center Madrid, National Cancer Institute/Leidos, ASTRO. Consultant; Adlai Nortye. C.M. Taniguchi: Research Grant; NIH, Reaumond Foundation, Mark Foundation. Consultant; Phebra Pty, Ltd, Xerient Pharmaceuticals. Advise on various radiation products; Accuray. A.H. Klopp: Research Grant; MD Anderson Cancer Center SPORE Grant. L. Colbert: None.

A phase I/II study of acute and late physician assessed and patient-reported morbidity following whole pelvic radiation in high-risk prostate cancer patients

Background The aim of this study was to assess acute and late morbidity measured by the physician and patient-reported outcomes (PROs) in high-risk prostate cancer (PC) patients receiving whole pelvic intensity-modulated radiotherapy (IMRT) in the setting of a national clinical trial. Material and methods A total of 88 patients with adenocarcinoma of the prostate and high-risk parameters were enrolled from 2011 to 2013. All patients received 78 Gy in 39 fractions of IMRT delivering simultaneous 78 Gy to the prostate and 56 Gy to the seminal vesicles and lymph nodes. Physician-reported morbidity was assessed by CTCAE v.4.0. PROs were registered for gastro-intestinal (GI) by the RT-ARD score, genito-urinary (GU) by DAN-PSS, sexual and hormonal by EPIC-26, and quality of life (QoL) by EORTC QLQ-C30. Results Median follow-up (FU) time was 4.6 years. No persistent late CTCAE grade 3+ morbidity was observed. Prevalence of CTCAE grade 2+ GI morbidities varied from 0 to 6% at baseline throughout FU time, except for diarrhea, which was reported in 19% of the patients post-RT. PROs revealed increased GI morbidity (≥1 monthly episode) for "rectal urgency", "use of pads", "incomplete evacuation", "mucus in stool" and "bowel function impact on QoL" all remained significantly different (p < .05) at 60 months compared to baseline. CTCAE grade 2+ GU and sexual morbidity were unchanged. GU PROs on obstructive and irritative GU items (≥daily episode) increased during RT and normalized at 24 months. No clinically significant differences were found in sexual, hormonal, and QoL scores compared to baseline. Conclusions Whole pelvic RT resulted in a mild to the moderate burden of late GI morbidities demonstrated by a relatively high prevalence of PROs. Whereas, physician-assessed morbidity revealed a low prevalence of late GI morbidity scores. This emphasizes the importance of using both PROs and physician-reported scoring scales when reporting late morbidity in clinical trials.

Correlation Between the Transient Elevation of Peripheral Eosinophil Count During Radiotherapy and Acute Diarrhea.

This study aimed to evaluate the association between the change in peripheral eosinophil count during postoperative pelvic radiotherapy and gastrointestinal (GI) toxicities in patients with cervical cancer. The medical records of 163 patients with cervical cancer who underwent postoperative concurrent chemoradiotherapy between 2000 and 2016 were analyzed. Among the peripheral blood cell counts, transient elevation of the eosinophil count was observed during radiotherapy. Of the 163 patients, 117 developed grade ≥2 diarrhea during radiotherapy, and 25 patients developed grade ≥2 late GI toxicities. In multivariate analysis, the maximum eosinophil count and age emerged as independent predictors of grade ≥2 acute diarrhea during radiotherapy, while bowel bag V 40 Gy and age were predictive of grade ≥2 late GI toxicities. Early detection of transient elevation of eosinophil may facilitate early treatment of acute diarrhea during radiotherapy.