Gastrointestinal Toxicity Rates Research Articles

Stereotactic body radiotherapy with a focal boost to the intraprostatic tumor for intermediate and high risk prostate cancer: 5-year efficacy and toxicity in the hypo-FLAME trial

BackgroundThe addition of an integrated focal boost to the intraprostatic lesion is associated with improved biochemical disease-free survival (bDFS) in patients with intermediate- and high-risk prostate cancer (PCa) in conventionally fractionated radiotherapy. Furthermore, whole gland stereotactic body radiotherapy (SBRT) demonstrated to be non-inferior to conventional radiotherapy for low- and intermediate-risk PCa. To investigate the combination of ultra-hypofractionated prostate SBRT with iso-toxic focal boosting for intermediate- and high-risk PCa, we performed the hypo-FLAME trial. MethodsPatients with intermediate- or high-risk PCa were enrolled in the phase II hypo-FLAME trial. All patients were treated with 35 Gy in 5 weekly fractions to the whole prostate gland with an iso-toxic integrated boost up to 50 Gy to the multiparametric MRI-defined tumor(s). If the dose constraints to the normal tissues would be exceeded, these were prioritised over the focal boost dose. The current analysis reports on the 5-year bDFS, late toxicity and health-related quality of life (HRQoL). ResultsBetween 2016 and 2018, 100 men were treated with a median follow-up of 61 months. The estimated 5-year bDFS (95 % CI) was 93 % (86 % to 97 %). At 5 years, the prevalence of grade 2 + genitourinary and gastrointestinal toxicity was 12 % and 4 %, respectively. ConclusionUltra-hypofractionated focal boost SBRT is associated with encouraging biochemical control rates up to 5-year follow-up in patients with intermediate- and high-risk PCa. Furthermore, prostate SBRT with iso-toxic focal boosting is associated with acceptable late genitourinary and gastrointestinal toxicity rates.

Melphalan Dose in Combination With Fludarabine Affects Gastrointestinal Toxicity and Graft-Versus-Host Disease After Allogeneic Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndromes

Fludarabine (Flu) and melphalan (Mel) reduced-intensity conditioning is frequently used for allogenic hematopoietic cell transplant (allo-HCT) in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). However, there is limited evidence on the impact of Mel dosing on toxicities and clinical outcomes of allo-HCT. We retrospectively compared 8/8 HLA-matched donor allo-HCT outcomes of 345 patients with AML or MDS receiving total Mel dose of 100 mg/m2 (Mel-100, n = 62) versus 140 mg/m2 (Mel-140, n = 283) in combination with Flu. Median age at allo-HCT was 66 years and median follow-up was 36.5 months. For Mel-100 versus Mel-140 groups, any grade gastrointestinal (GI) toxicity rates were 40.3% versus 67.8% (P < .001), day 100 grade II to IV acute graft-versus-host disease (GVHD) rates were 21.0% versus 43.1% (P = .001) and 2-year chronic GVHD rates were 17.4% versus 27.1% (P = .033). In multivariable analysis, Mel-140 resulted in higher risks of GI toxicity (HR = 1.83, P = .013), grade II to IV acute GVHD (HR=2.35, P = .003), and moderate/severe chronic GVHD (HR = 3.13, P = .007). Total Mel dose had no independent impact on oral mucositis, nonrelapse mortality, relapse, relapse-free survival, and overall survival. While independent validation of our observation is warranted, our findings support using Mel-100 in combination with Flu to minimize allo-HCT toxicities and morbidities related to GVHD.

Clinical Outcome Comparison between CT-Guided Versus all MRI-Guided Scenarios in Brachytherapy for Cervical Cancer: A Single-Institute Experience

ObjectivesImage-guided adaptive brachytherapy (IGABT) is the standard of care for patients with cervical cancer. The objective of this study was to compare the treatment outcomes and adverse effects of computed tomography (CT)-guided and magnetic resonance imaging (MRI)-guided scenarios. Materials and MethodsData of patients with cervical cancer treated using external beam radiotherapy followed by IGABT from 2012 to 2016 were retrospectively reviewed. CT-guided IGABT was compared with the three modes of MRI-guided IGABT: pre-brachytherapy (MRI Pre-BT) without applicator insertion for fusion, planning MRI with applicator in-place in at least 1 fraction (MRI ≥1Fx), and MRI in every fraction (MRI EveryFx). Patient characteristics, oncologic outcomes, and late radiation toxicity were analyzed using descriptive, survival, and correlation statistics. ResultsOverall, 354 patients were evaluated with a median follow-up of 60 months. The 5-year overall survival (OS) rates were 61.5%, 65.2%, 54.4%, and 63.7% with CT-guided, MRI PreBT, MRI ≥1Fx, and MRI EveryFx IGABT, respectively with no significant differences (p = 0.522). The 5-year local control (LC) rates were 92.1%, 87.8%, 80.7%, and 76.5% (p = 0.133), respectively, with a significant difference observed between the CT-guided and MRI ≥1Fx (p = 0.018). The grade 3–4 late gastrointestinal toxicity rates were 6% in the CT-guided, MRI ≥1Fx, and MRI EveryFx, and 8% in MRI PreBT. The grade 3–4 late genitourinary toxicity rates were 4% in the CT-guided, 2% in MRI PreBT, 1% in MRI ≥1Fx, and none in MRI EveryFx. No significant differences were observed in the oncologic and toxicity outcomes among MRI PreBT, MRI ≥1Fx, and MRI EveryFx. ConclusionsCT-guided IGABT yielded an acceptable 5-year OS, LC, and toxicity profile compared with all MRI scenarios and is a potentially feasible option in resource-limited settings.

Evaluating a hypofractionated radiotherapy schedule for prostate cancer at an institution in South Africa

Background: Hypofractionated radiotherapy (HFRT) in the treatment of prostate cancer (PCa) has logistical and cost advantages, especially in a resource constrained setting. Studies have demonstrated equivalent efficacy with HFRT schedules using Intensity Modulated Radiation Therapy (IMRT) as treatment modality. However, higher rates of acute and late gastrointestinal (GI) and genitourinary (GU) toxicity have been reported when compared to conventionally fractionated radiotherapy (CFRT). In this study, we evaluate the efficacy and toxicity rates of a HFRT schedule using 3D conformal radiotherapy (RT) as treatment modality.Aim: With this study, we aim to describe the safety and outcomes of a definitive HFRT schedule used for localised PCa. We hypothesise that there is no difference in the biochemical relapse rate and incidence rates of normal tissue toxicities between patients receiving CFRT and HFRT schedules.Setting: This RT schedule was used at Tygerberg Academic Hospital in South Africa for the treatment of localised prostate cancer.Methods: This is a retrospective study in which the records of patients diagnosed with localised PCa were reviewed. Patients were treated with either CFRT regimen to a total of 74Gy in 37 daily fractions for 5 days a week or a HFRT regimen to a total of 65Gy in 26 daily fractions for 4 days per week.Results: In all, 116 patients were included in the study with a median follow-up of 57.2 months from the start of RT. No statistically significant differences in overall survival (OS) and biochemical relapse-free survival were found between the two schedules. A significant difference in acute GI toxicity was observed, with a higher incidence noted in the HFRT schedule. No significant differences were observed in late GI toxicity or in early and late GU toxicities.Conclusion: This study observes a hypofractionated regimen using three-dimensional conformal radiation therapy (3DCRT) with similar efficacy and RT-related toxicities to CFRT.Contribution: The HFRT schedule used in this study could be useful in hospitals with limited access to resources.

Stereotactic Body Proton Therapy Versus Conventionally Fractionated Proton Therapy for Early Prostate Cancer: A Randomized, Controlled, Phase 3 Trial

PurposeWe aimed to determine if ultrahypofractionated proton therapy delivered via stereotactic body proton therapy (SBPT) is noninferior to conventionally fractionated proton therapy (CFPT) in patients with early prostate cancer. Methods and MaterialsThis study was a multicenter, randomized, controlled, noninferiority phase 3 trial that included patients with histologically confirmed low-risk prostate adenocarcinoma defined by Gleason score grouping 1, Prostate-specific antigen <10 ng/mL, and clinical stage T1-T2a N0 M0 according to 7th edition of the American Joint Committee on Cancer tumor-node-metastasis cancer staging system. Eligible participants were randomly assigned initially at a 1:1 ratio and later at a 2:1 ratio to SBPT (38 Gy in 5 fractions) or CFPT (79.2 Gy in 44 fractions). The primary endpoint was freedom from failure (FFF) at 2 years from the date of randomization. Noninferiority for FFF was determined based on 1-sided confidence intervals. Toxicities were compared at different time points using Fisher's exact test. Health-related quality-of-life (HRQoL) was analyzed at different time points using a mixed-effects linear model. This trial is registered with ClinicalTrials.gov, NCT01230866, and is closed to accrual. ResultsBetween December 10, 2010, and September 29, 2020, 144 patients were enrolled and 135 were randomly assigned (90 to the SBPT group and 45 to the CFPT group). The median follow-up was 5 years (IQR, 3.9-5.2). The 2-year FFF was 100% for both groups, with the 1-sided 5-year risk difference in FFF between groups reported as 2.63% (90% CI, −1.70% to 6.96%), favoring the SBRT arm, thus fulfilling the prespecified criteria for noninferiority of SBPT compared with CFPT. Rates of gastrointestinal and genitourinary G2 and G3 toxicities did not differ significantly between groups. Further, HRQoL metrics did not differ significantly between groups over the study's median follow-up. ConclusionsSBPT is noninferior to CFPT regarding FFF, with similar long-term genitourinary and gastrointestinal toxicity rates and minimal impact in patient-reported HRQoL over time.

A single arm phase 2 clinical trial of YIV-906 with neoadjuvant concurrent chemo-radiation therapy in patients with locally advanced rectal cancer.

Pre-operative chemoradiation for rectal cancer is often associated with severe gastrointestinal (GI) toxicity which can interrupt, delay, and/or lead to termination of treatment. In this study, we evaluated whether the addition of YIV-906, a novel herbal medicine proven to reduce GI toxicity associated with chemotherapy could also reduce GI side effects during standard pre-operative capecitabine and pelvic radiation therapy (RT) in the neoadjuvant setting for the treatment of locally advanced rectal cancer. This single arm clinical study enrolled 24 patients between Dec 23, 2014-Sep 17, 2018 at Smilow Cancer Hospital, a comprehensive cancer center at Yale New Haven Hospital. All patients were age ≥18 years, Eastern Cooperative Oncology Group 0-1 and with histologically confirmed T3-T4 and N0-N2, M0 adenocarcinoma of the rectum. Median follow-up was 61.9 months. All patients received concurrent pelvic external beam RT (50.4 Gy in 28 fractions), YIV-906 (taken orally 800 mg twice daily on days 1-4 of RT each week), and oral capecitabine delivered in a neo-adjuvant fashion, followed by definitive surgery. Toxicity was assessed weekly during radiation and until acute symptoms resolved and then at 28 days, 4 months, 7 months and 10 months. Toxicities were graded in accordance with Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. At the time of surgery, 4 patients (16.7%) had a complete or near-complete response. At a median follow-up of 61.9 months, the mean overall survival (OS) of our patient cohort was 74.9 months [95% confidence interval (CI): 67.3-82.5]. The estimated 5-year OS was 82.0%. We observed 0% acute grade 4 toxicities, and only two cases of acute grade 3 diarrhea (8.3%). The addition of YIV-906 to capecitabine based chemoradiation for locally advanced rectal cancer led to reduced rates of GI toxicity compared to historical controls, in particular grade 3 or greater diarrhea. These findings suggest YIV-906 should be evaluated in a randomized clinical trial to further assess potential reductions in the toxicity profile of chemoradiation for GI cancers.

Hypofractionated radiation therapy combined with androgen deprivation therapy for clinically node-positive prostate cancer.

This study aimed to analyze the treatment outcomes of combined definitive radiation therapy (RT) and androgen deprivation therapy (ADT) for clinically node-positive prostate cancer. Medical records of 60 patients with clinically suspected metastatic lymph nodes on radiological examination were retrospectively analyzed. Eight patients (13.3%) were suspected to have metastatic common iliac or para-aortic lymph nodes. All patients underwent definitive RT with a dose fractionation of 70 Gy in 28 fractions. ADT was initiated 2-3 months before RT and continued for at least 2 years. Biochemical failure rate (BFR), clinical failure rate (CFR), overall survival (OS), and prostate cancer-specific survival (PCSS) were calculated, and genitourinary and gastrointestinal adverse events were recorded. The median follow-up period was 5.47 years. The 5-year BFR, CFR, OS, and PCSS rates were 19.1%, 11.3%, 89.0%, and 98.2%, respectively. The median duration of ADT was 2.30 years. BFR and CFR increased after 3 years, and 11 out of 14 biochemical failures occurred after the cessation of ADT. Grade 2 and beyond late genitourinary and gastrointestinal toxicity rates were 5.0% and 13.3%, respectively. However, only two grade 3 adverse events were reported, and no grade 4-5 adverse events were reported. Patients with non-regional lymph node metastases did not have worse BFR, CFR, or adverse event rates. This study reported the efficacy and tolerable toxicity of hypofractionated definitive RT combined with ADT for clinically node-positive prostate cancer. Additionally, selected patients with adjacent non-regional lymph node metastases might be able to undergo definitive RT combined with ADT.

Clinical Outcomes of 3 Versus 4 Fractions of Magnetic Resonance Image-Guided Brachytherapy in Cervical Cancer

PURPOSEMRI-guided brachytherapy (MRgBT) is essential in the management of locally advanced cervical cancer. This study compares disease and toxicity outcomes in cervical cancer patients treated with 24 Gy/3 fractions (Fr) versus the conventional 28 Gy/4 Fr. METHODS AND MATERIALSThis retrospective study included 241 consecutive patients with FIGO 2018 stage IB-IVA cervical cancer treated with definitive chemoradiation between April 2014 - March 2021. Disease-free survival (DFS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Cumulative incidence of local failure (LF), distant failure (DF) and G2+ gastrointestinal (GI), urinary (GU) and vaginal toxicity were estimated using the cumulative incidence function with death as a competing risk and compared using the Gray's test. RESULTSOf the 241 patients, 42% received 24 Gy/3 Fr and 58% received 28 Gy/4 Fr. With a median follow up of 3.2 (range 0.2-9.2) years, there were 14 local, 41 regional nodal and 51 distant failures in 63 (26%) patients. No significant differences were found between the 24 Gy/3 Fr vs 28 Gy/4 Fr group in 3-year DFS (77% vs 68%, P = 0.21), 3-year cumulative incidence of LF (5% vs 7%, P = 0.57), DF (22% vs 25%, P = 0.86), G2+ GI toxicity (11% vs 20%, P = 0.13), or G2+ vaginal toxicity (14% vs 17%, P = 0.48), respectively. The 3-year cumulative G2+ urinary toxicity rate was lower in the 24 Gy/3 Fr group (9% vs 23%, P = 0.03). CONCLUSIONCervical cancer patients treated with 24 Gy/3 Fr had similar DFS, LF, DF, GI and vaginal toxicity rates, and a trend towards lower G2+ urinary toxicity rate compared to those treated with 28 Gy/4 Fr. A less resource-intensive brachytherapy fractionation schedule of 24 Gy/3 Fr is a safe alternative to 28 Gy/4 Fr for definitive treatment of cervical cancer.

Retrospective study on the toxicity induced by stereotactic body radiotherapy: overview of the reunion experience on prostate cancer in elderly patients.

Prostate cancer is the fourth most commonly diagnosed cancer among men worldwide. Various tools are used to manage disease such as conventional radiotherapy. However, it has been demonstrated that large prostate volumes were often associated with higher rates of genitourinary and gastrointestinal toxicities. Currently, the improvements in radiotherapy technology have led to the development of stereotactic body radiotherapy, which delivers higher and much more accurate radiation doses. In order to complete literature data about short-term outcome and short-term toxic effects of stereotactic body radiotherapy, we aimed to share our experience about gastrointestinal and genitourinary toxicities associated with stereotactic body radiotherapy in prostate cancer in patients over 70 years old. We retrospectively reviewed the medical records of elderly patients with prostate cancer treated between 2021 and 2022. The elderly patients were treated with a non-coplanar robotic stereotactic body radiotherapy platform using real-time tracking of implanted fiducials. The prostate, with or without part of the seminal vesicles, was treated with a total dose of 36.25 Gy delivered in five fractions, each fraction being administered every other day. We analyzed a total of 80 elderly patients, comprising 38 low-, 37 intermediate- and 5 high-risk patients. The median follow-up duration was 12 months. We did not observe biochemical/clinical recurrence, distant metastasis, or death. Grade 2 acute genitourinary toxicity was observed in 9 patients (11.25%) and Grade 2 acute gastrointestinal toxicity in 4 patients (5.0%). We did not observe any grade 3 or more acute or late toxicities. Over the follow-up period, we noted a low frequency of gastrointestinal and genitourinary toxicities induced by stereotactic body radiotherapy in the context of prostate cancer in elderly patients. Therefore, stereotactic body radiotherapy seems to represent a promising treatment option for elderly patients, with acceptable acute toxicity.

A pooled patient-reported outcomes analysis of moderately hypofractionated proton beam therapy and photon-based intensity modulated radiation therapy for low- or intermediate-risk prostate cancer.

We sought to characterize and compare late patient-reported outcomes (PROs) after moderately hypofractionated intensity modulated radiation therapy (IMRT) and proton beam therapy (PBT) for localized prostate cancer (PC). This multi-institutional analysis included low- or intermediate-risk group PC patients treated with moderately hypofractionated radiation to an intact prostate stratified by treatment modality: IMRT or PBT. The primary outcomes were prospectively collected patient-reported late gastrointestinal (GI) and genitourinary (GU) toxicity assessed by International Prostate Symptom Score (IPSS) and Expanded PC Index Composite (EPIC). Multivariable regression analysis (MVA) controlling for age, race, and risk group tested the effect of time, treatment, and their interaction. 287 IMRT and 485 PBT patients were included. Intermediate risk group (81.2 vs. 68.2%; p < 0.001) and median age at diagnosis (70 vs. 67 years; p < 0.001) were higher in the IMRT group. On MVA, there was no significant difference between modalities. PBT IPSS did not differ from IMRT IPSS at 12 months (odds ratio [OR], 1.19; p = 0.08) or 24 months (OR, 0.99; p = 0.94). PBT EPIC overall GI function at 12 months (OR, 3.68; p = 0.085) and 24 months (OR 2.78; p = 0.26) did not differ from IMRT EPIC overall GI function. At 24 months, urinary frequency was no different between PBT and IMRT groups (OR 0.35; p = 0.096). This multi-institutional analysis of low- or intermediate-risk PC treated with moderately hypofractionated PBT and IMRT demonstrated low rates of late patient-reported GI and GU toxicities. After covariate adjustment, late GI and GU PROs were not significantly different between PBT or IMRT cohorts.

Unraveling the safety of adjuvant radiotherapy in prostate cancer: impact of older age and hypofractionated regimens on acute and late toxicity - a multicenter comprehensive analysis.

The objective of this study was to assess the impact of age and other patient and treatment characteristics on toxicity in prostate cancer patients receiving adjuvant radiotherapy (RT). This observational study (ICAROS-1) evaluated both acute (RTOG) and late (RTOG/EORTC) toxicity. Patient- (age; Charlson's comorbidity index) and treatment-related characteristics (nodal irradiation; previous TURP; use, type, and duration of ADT, RT fractionation and technique, image-guidance systems, EQD2 delivered to the prostate bed and pelvic nodes) were recorded and analyzed. A total of 381 patients were enrolled. The median EQD2 to the prostate bed (α/β=1.5) was 71.4 Gy. The majority of patients (75.4%) were treated with intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT). Acute G3 gastrointestinal (GI) and genitourinary (GU) toxicity rates were 0.5% and 1.3%, respectively. No patients experienced >G3 acute toxicity. The multivariable analysis of acute toxicity (binomial logistic regression) showed a statistically significant association between older age (> 65) and decreased odds of G≥2 GI acute toxicity (OR: 0.569; 95%CI: 0.329-0.973; p: 0.040) and decreased odds of G≥2 GU acute toxicity (OR: 0.956; 95%CI: 0.918-0.996; p: 0.031). The 5-year late toxicity-free survival rates for G≥3 GI and GU toxicity were 98.1% and 94.5%, respectively. The only significant correlation found (Cox's regression model) was a reduced risk of late GI toxicity in patients undergoing hypofractionation (HR: 0.38; 95% CI: 0.18-0.78; p: 0.008). The unexpected results of this analysis could be explained by a "response shift bias" concerning the protective effect of older age and by treatment in later periods (using IMRT/VMAT) concerning the favorable effect of hypofractionation. However, overall, the study suggests that age should not be a reason to avoid adjuvant RT and that the latter is well-tolerated even with moderately hypofractionated regimens.

Preoperative Intensified Chemoradiation with Intensity-Modulated Radiotherapy and Simultaneous Integrated Boost Combined with Capecitabine in Locally Advanced Rectal Cancer: Long-Term Outcomes of a Real-Life Multicenter Study

Background: Despite the feasibility and promising activity data on intensity-modulated RT and simultaneous integrated boost (IMRT-SIB) dose escalation in preoperative chemoradiation (CRT) for locally advanced rectal cancer (LARC), few data are currently available on long-term outcomes. Patients and Methods: A cohort of 288 LARC patients with cT3-T4, cN0-2, cM0 treated with IMRT-SIB and capecitabine from March 2013 to December 2019, followed by a total mesorectal excision (TME) or an organ-preserving strategy, was collected from a prospective database of 10 Italian institutions. A dose of 45 Gy in 25 fractions was prescribed to the tumor and elective nodes, while the SIB dose was prescribed according to the clinical practice of each institution on the gross tumor volume (GTV). Concurrent capecitabine was administered at a dose of 825 mg/m2 twice daily, 7 days a week. The primary objective of the study was to evaluate long-term outcomes in terms of local control (LC), progression-free survival (PFS) and overall survival (OS). The secondary objective was to confirm the previously reported feasibility, safety and efficacy (pCR, TRG1-2 and downstaging rates) of the treatment in a larger patient population. Results: All patients received a dose of 45 Gy to the tumor and elective nodes, while the SIB dose ranged from 52.5 Gy to 57.5 Gy (median 55 Gy). Acute gastrointestinal and hematologic toxicity rates of grade 3–4 were 5.7% and 1.8%, respectively. At preoperative restaging, 36 patients (12.5%) with complete or major clinical responses (cCR or mCR) were offered an organ-preserving approach with local excision (29 patients) or a watch and wait strategy (7 patients). The complete pathologic response rate (pCR) in radically operated patients was 25.8%. In addition, 4 TME patients had pT0N1 and 19 LE patients had pT0Nx, corresponding to an overall pT0 rate of 31.3%. Of the 36 patients selected for organ preservation, 7 (19.5%) required the completion of TME due to unfavorable pathologic features after LE or tumor regrowth during W-W resulting in long-term rectal preservation in 29 of 288 (10.1%) of the total patient population. Major postoperative complications occurred in 14.2% of all operated patients. At a median follow-up of 50 months, the 5-year PFS and OS rates were 72.3% (95% CI: 66.3–77.4) and 85.9% (95% CI: 80.2–90.1), respectively. The 5-year local recurrence (LR) rate was 9.2% (95% CI: 6.0–13.2), while the distant metastasis (DM) rate was 21.3% (95% CI: 16.5–26.5). The DM rate was 24.5% in the high-risk subset compared to 16.2% in the low-intermediate risk group (p = 0.062) with similar LR rates (10% and 8%, respectively). On multivariable analysis, cT4 and TRG3–5 were significantly associated with worse PFS, OS and metastasis-free survival. Conclusions: Preoperative IMRT-SIB with the moderate dose intensification of 52.5–57.5 Gy (median 55 Gy) and the full dose of concurrent capecitabine confirmed to be feasible and effective in our real-life clinical practice. Organ preservation was shown to be feasible in carefully selected, responsive patients. The favorable long-term survival rates highlight the efficacy of this intensified treatment program. The incorporation of IMRT-SIB with a more effective systemic therapy component in high-risk patients could represent a new area of investigational interest.

Safety of Ultrahypofractionated Pelvic Nodal Irradiation in the Definitive Management of Prostate Cancer: Systematic Review and Meta-analysis

Aim: This systematic review and meta-analysis aimed to evaluate the evidence for ultra-hypofractionated pelvic nodal irradiation in prostate cancer patients, with a focus on reported acute and late toxicities. Methods: A comprehensive search was conducted in five electronic databases (PubMed, Scopus, Web of Science, Cochrane Library, Clinicaltrials.gov) from inception until 23 March 2023. Eligible publications included patients with intermediate- and high-risk and node positive prostate cancer who underwent elective or therapeutic ultra-hypofractionated pelvic nodal irradiation. Primary outcomes included the presence of grade ≥2 rates of acute and late gastrointestinal and genitourinary toxicity based on the Common Terminology Criteria for Adverse Events (CTCAE) scale or Radiation Therapy Oncology Group (RTOG) scales. Quality assessment was performed using NIH tools for non-controlled before and after clinical trials, as well as single-arm observational studies. Since all outcomes were categorical variables, proportion was calculated to estimate the effect size and compare the outcomes after the intervention. Results: We identified 16 publications that reported the use of ultra-hypofractionated radiotherapy to treat the pelvis in prostate cancer. Seven publications met our criteria and were included in the meta-analysis, including 417 patients. The median total dose to the pelvic lymph nodes was 25 Gy (range: 25 - 28.5 Gy), with a median of 5 fractions. The prostate received a median dose of 40 Gy (range: 35 to 47.5 Gy). All studies utilized androgen deprivation therapy for a median duration of 18 months. The median follow-up period was 3 years (range: 0.5-5.6 years). The rates of acute grade ≥2 gastrointestinal and genitourinary toxicity were 8% (CI 95%: 1% to 15%) and 29% (CI 95%: 18% to 41%), respectively. For late grade ≥2 gastrointestinal and genitourinary toxicity, the rates were 13% (CI 95%: 5% to 21%) and 29% (CI 95%: 17% to 42%), respectively. Conclusion: Ultra-hypofractionated pelvic nodal irradiation appears to be a safe approach in terms of acute and late genitourinary and gastrointestinal toxicity.

Comparison of Low Dose Rate and High Dose Rate Brachytherapy Boost Techniques in Prostate Cancer: Evaluation of Toxicity.

The ASCENDE-RT trial has been criticized for higher rates of chronic severe toxicity (18% genitourinary (GU)) than expected with a low dose rate (LDR) boost technique. We compared clinical outcomes of LDR and high dose rate (HDR) boost in the acute and chronic setting from a large single institution experience over a continuous 20-year period, with a focus on GU and gastrointestinal (GI) toxicity during treatment of prostate cancer. We retrospectively reviewed patients treated with LDR boost (2003 - 2013) and HDR boost (2014 - 2018). Clinical and treatment-related prognostic factors including age, stage, androgen deprivation therapy (ADT), dosimetry details, and toxicity data were recorded. Toxicity was scored according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Multi-variable analysis (MVA) was performed to evaluate variables associated with toxicity. A total of 184 men were evaluated (87 LDR and 97 HDR) with a median follow-up of 7.1 years and 4.0 years, respectively. Most patients (92% LDR and 57% HDR) received ADT in addition to BT. The median EBRT dose was 46 Gy for LDR and 45 Gy for HDR (range 25 - 50 Gy). Prostate D90% was similar at 104% and 105% in the LDR and HDR groups, respectively. Urethra D10% and Rectum V100% were both higher with LDR compared to HDR with 155% vs 119% and 0.436% vs 0.073%, respectively. Severe (grade 3+) toxicity was rare (Table 1), with 3.4% of LDR patients experiencing grade 3 chronic GU toxicity. With HDR, 3.1% and 1% of patients experienced acute and chronic grade 3 GU toxicity, respectively. Although non-severe GU toxicity (grade 1-2) was similar between groups (95% LDR vs 89% HDR, p = 0.16), LDR patients experienced more grade 2 GU events (80.5% acute; 82.8% chronic) compared to HDR patients (45.4% acute; 57.7% chronic). There were no severe GI toxicities in the acute or chronic period. Non-severe acute GI toxicity was more common with HDR, while non-severe chronic GI toxicity was more common with LDR. On MVA, acute GU toxicity (any grade) was associated with short term ADT (p = 0.01) and Urethra D10% (p < 0.05); Chronic GU toxicity (any grade) was associated with age (p = 0.09) and Prostate V150cc (p = 0.07) but not BT boost technique. This comparative retrospective analysis of BT boost techniques reveals the overall rate of severe GU and GI toxicity to be low with both LDR and HDR. HDR boost appears to have a slightly more favorable ratio of Grade 1 to Grade 2 GU toxicity and improved urethra/rectum dosimetry. Our analysis suggests that the dosimetric advantages of HDR may deliver small reductions in GU toxicity.

A Prospective Phase II Dose Escalation Study Using IMRT for High Risk N0M0 Prostate Cancer.

Published data supports the use of very high dose intensity modulated radiotherapy (IMRT) in achieving high efficacy and low toxicity for high-risk prostate cancer (HRPCa). This phase II multi-institutional non-randomized prospective dose escalation study using intensity modulated radiotherapy (IMRT) for high risk N0M0 prostate cancer was designed to investigate dose escalation using 1.8 Gy increments from baseline 75.6 Gy up to maximum 81 Gy, once dose volume constraints were adhered to. Inclusion criteria were patients undergoing a radical course of RT for high and very high-risk disease, defined as one or more of the criteria ≥ T3*, ≥ Gleason 8, Prostate specific antigen (PSA) > 20ng/ml. All patients received Androgen Deprivation Therapy (ADT) and none had radiological evidence of distant metastatic disease. The primary objective was to determine if dose escalated IMRT for high risk localized prostate cancer could provide freedom from biochemical relapse (BR; PSA rising > nadir +2ng/mL or initiation of salvage hormone therapy) similar to that reported in the literature. The Kaplan-Meier method was used to estimate survival times. Secondary objectives included OS, Disease Free Survival (DFS), and the incidence and severity of Genito-urinary (GU), Gastro-intestinal (GI) and erectile dysfunction (ED) toxicities (CTCAE v.3). Toxicities and performance status were collected and graded weekly during RT, 2 months after completing RT, 8 months' post RT, and 6 monthly thereafter to year five and annually thereafter to year nine. A total of 230 evaluable patients were enrolled between April 2009 and June 2016. The median follow-up was 7.3 years. The cumulative proportion of patients surviving without BR at 5 years was 91% (95% Confidence Interval (CI): 86% to 94%). Overall survival at 5 and 7 years was 92% (88% to 95%) and 89% (83% to 92%) respectively, while the cumulative proportion of patients free from disease was 89% (84% to 93%) at 5 years and 81% (75% to 86%) at 7 years. The incidence of acute G2 and G3 toxicities were; GU; 57.8% G2, 12.6% G3, GI; 15.2% G2, 0.4% G3, ED; 30.0% G2 and 61.7% G3. The incidence of late G2, G3 and G4 toxicities were; GU; 40.9% G2, 8.7% G3, GI; 36.5% G2, 2.2% G3, 0.4% G4, ED; 11.7% G2 and 86.1% G3. The percentage of patients receiving each dose level was; 3.5% received 75.6Gy in 42 fractions, 2.2% received 77.4Gy in 43 fractions, 93% received 81Gy in 45 fractions. The findings indicate that high-dose IMRT is well tolerated and is associated with excellent long-term tumor-control outcomes in patients with localized high and very high-risk prostate cancer, with 91% of patients surviving at 5 years without biochemical relapse. The rates of long term G3 GU and GI toxicity were low at 8.7% and 0.4% respectively.

Toxicity and Patient Reported Quality of Life after PSMA-PET and mpMRT-Based Focal Dose Escalated Definitive Radiotherapy in Prostate Cancer Patients: 2-Year Follow-Up of the HypoFocal Phase II Trial

The prospective, 2-armed non-randomized HypoFocal phase II trial investigates the safety and feasibility of focal dose escalated external beam radiotherapy (EBRT) and high-dose-rate brachytherapy (HDR-BT) for prostate cancer (PCa) patients based on PSMA-PET and multiparametric MRI. This approach improves tumor coverage and thus putatively treatment effectiveness but leads to larger boost volumes. Here we present toxicity and patient reported quality of life (QoL) results after 2 years follow-up (FU) MATERIALS/METHODS: Patients with intermediate- or high-risk PCa and cN0/cM0 stage were included. Patients in arm A received 60 Gy in 20 fractions to the prostate with an integrated boost of up to 75 Gy. Patients in arm B received one session HDR-BT with 15 Gy to the prostate and a boost of up to 19 Gy, followed by EBRT of 44 Gy in 20 fractions. Boost volumes were defined by PSMA-PET and mpMRI based on validated approaches. Genitourinary (GU) and gastrointestinal (GI) toxicity (CTCAE v5.0) and QoL with IPSS and EORTC questionnaires (QLQ30 and PR25) were assessed. Fifty patients were treated in both arms in two centers (Freiburg and Berlin). Table 1 shows patients characteristics. In arm, A grade 2 GU and GI toxicity rates after 2 years were 8% and 4%. There were no grade 3 GU toxicities. Two patients experienced grade 3 GI toxicities due to multifactorial causes. In Arm B grade 2 GU and GI toxicity rates after 2 years were 17% and 0%. No grade 3 toxicities were observed in arm B. Toxicities were not statistically significantly different between baseline and 2y FU (p>0.055). QoL analysis was performed with patients with available questionnaires at baseline and 2y FU (12-15 in Arm A and 13-15 in Arm B). Only bowel function (p = 0.0005, median 4 vs 25 points) in Arm A and sexual- (p = 0.016, median 25 vs 50 points) and bowel function (p = 0.004, median 0 vs 8 points) and dyspnea (p = 0.031, median 0 vs 0 points) in Arm B decreased significantly after 2 year FU. Other QoL items were not significantly different. Bowel symptoms were significantly worse in Arm A compared to Arm B (p = 0.003). Median PSA values after 2 years were 0.23 ng/ml in Arm A and 0.33 ng/ml in Arm B. Despite large boost volumes, the 2 years FU of the HypoFocal-Phase II trials shows no significantly increased GU and GU toxicities compared to baseline symptoms. Patients reported about a good QoL but increased bowel symptoms after 2 years, particularly if treated with EBRT only. Implementation of PSMA-PET into focal dose escalated radiotherapy approaches appears safe and feasible. However, radioproctitis demands careful management. The current PSA values suggest a highly effective therapy, but longer FU is needed to evaluate oncological outcomes. The HypoFocal-SBRT phase III trial will evaluate the PSMA-PET and mpMRI-based focal dose escalated SBRT.

Focal Brachytherapy for Localized Prostate Cancer: Systematic Review and Meta-Analysis

Advances in image-guided brachytherapy have increased the interest in focal brachytherapy (F-BT) approaches to optimize disease control, while reducing the toxicities associated whole gland treatments for prostate cancer (PCa). In this study we performed a systematic review to report biochemical control (BC), and genitourinary (GU) and gastrointestinal (GI) toxicity rates in patients with localized prostate cancer treated with F-BT as a definitive or salvage modality. This project was registered in the PROSPERO database (ID CRD42022320921). A comprehensive literature search was conducted in Cochrane Central databases, Cochrane Database of Systematic Reviews, Embase Classic +Embase, and Medline ALL, all from the OvidSP platform and Web of Science from Clarivate, from each database's inception to July 2022. Search was restricted to English and included terms: focal brachytherapy/prostate cancer, partial brachytherapy/prostate cancer. In total, 14862 articles were identified. Manuscripts that not related to focal or partial prostate brachytherapy, review papers and studies not reporting BC were excluded. After eliminating duplicates, and studies deemed irrelevant by consensus among three independent reviewers, 44 articles remained for in-depth review and data extraction. Thirty studies that included BC outcomes were included for this analysis, comprising 1556 patients treated with F-BT for PCa. Of these, 1094 (70%) and 462 (30%) underwent F-BT as definitive monotherapy or salvage, respectively; while 585 (38%) and 971 (62%) received HDR or LDR, respectively. For F-BT as monotherapy, the most commonly prescribed dose for HDR was 19 Gy in 1 fraction (range 19-24 Gy), and for LDR, 145 Gy (90-160Gy). Whereas for salvage F-BT, most common dose schedule of HDR was 19Gy in 1 fraction (19-27GY) and LDR 145Gy (144-145Gy). BC random effects estimate for F-BT monotherapy at 1-, 2-, 3-, and 5-years were 100% (P = 1.0), 96% (P = 0.45), 91% (P = 0.45) and 87% (P< 0.01), respectively. Whereas BC random effects estimate for salvage at 1-, 2-, 3-, and 5-years were 91% (P = 0.86), 68% (0.17), and 57% (P = 0.20), respectively. GI and GU grade 3-4 crude toxicity rates for monotherapy and salvage ranged from 0-3.33% and 0-17%, respectively. Over the last decade, there has been increasing interest in F-BT approaches, both as monotherapy and in the salvage setting. BC and toxicity profiles of F-BT appear favorable, and future studies directly comparing with whole-gland treatments are warranted.

Assessing the toxicity after moderately hypofractionated prostate and whole pelvis radiotherapy compared to conventional fractionation.

To evaluate acute and late gastrointestinal (GI) and genitourinary (GU) toxicities after moderately hypofractionated (HF) or conventionally fractionated (CF) primary whole-pelvis radiotherapy (WPRT). Primary prostate-cancer patients treated between 2009 and 2021 with either 60 Gy at 3 Gy/fraction to the prostate and 46 Gy at 2.3 Gy/fraction to the whole pelvis (HF), or 78 Gy at 2 Gy/fraction to the prostate and 50/50.4 Gy at 1.8-2 Gy/fraction to the whole pelvis (CF). Acute and late GI and GU toxicities were retrospectively assessed. 106patients received HF and 157 received CF, with amedian follow-up of 12and 57months. Acute GI toxicity rates in the HF and CF groups were, respectively, grade2: 46.7% vs. 37.6%, and grade3: 0% vs. 1.3%, with no significant difference (p = 0.71). Acute GU toxicity rates were, respectively, grade2: 20.0% vs. 31.8%, and grade3: 2.9% vs. 0%, (p = 0.04). We compared prevalence of late GI and GU toxicities between groups after 3,12, and 24months and did not find any significant differences (respectively, p = 0.59, 0.22, and 0.71 for GI toxicity; p = 0.39, 0.58, and 0.90 for GU toxicity). Moderate HF WPRT was well tolerated during the first 2years. Randomized trials are needed to confirm these findings.

Impact of planning organ at risk volume margins and matching method on late gastrointestinal toxicity in moderately hypofractionated IMRT for locally advanced pancreatic ductal adenocarcinoma

BackgroundThis study examined the differences in late gastrointestinal (GI) toxicities in moderately hypofractionated intensity-modulated radiation therapy (IMRT) for locally advanced pancreatic ductal adenocarcinoma (LA-PDAC) by changing the planning organs at risk volume (PRV) margin and the target matching method and assessed the causes of adverse events.MethodsWe examined 37 patients with LA-PDAC who underwent moderately hypofractionated IMRT between 2016 and 2020 at our institution; 23 patients were treated with wide PRV margins and soft tissue matching (Protocol A) and 14 with narrow PRV margins and fiducial marker matching (Protocol B). The GI toxicities, local control (LC) rate, and overall survival (OS) were assessed for each protocol. The initially planned and daily doses to the gross tumor volume (GTV), stomach, and duodenum, reproduced from cone-beam computed tomography, were evaluated.ResultsThe late GI toxicity rate of grades 3–4 was higher in Protocol B (42.9%) than in Protocol A (4.3%). Although the 2-year LC rates were significantly higher in Protocol B (90.0%) than in Protocol A (33.3%), no significant difference was observed in OS rates. In the initial plan, no deviations were found for the stomach and duodenum from the dose constraints in either protocol. In contrast, daily dose evaluation for the stomach to duodenal bulb revealed that the frequency of deviation of V3 Gy per session was 44.8% in Protocol B, which was significantly higher than the 24.3% in Protocol A.ConclusionsReducing PRV margins with fiducial marker matching increased GI toxicities in exchange for improved LC. Daily dose analysis indicated the trade-off between the GTV dose coverage and the irradiated doses to the GI. This study showed that even with strict matching methods, the PRV margin could not be reduced safely because of GI inter-fractional error, which is expected to be resolved with online adaptive radiotherapy.

From once-weekly to semi-weekly whole prostate gland stereotactic radiotherapy with focal boosting: Primary endpoint analysis of the multicenter phase II hypo-FLAME 2.0 trial

Background and purposeThe hypo-FLAME trial showed that once-weekly (QW) focal boosted prostate stereotactic body radiotherapy (SBRT) is associated with acceptable acute genitourinary (GU) and gastrointestinal (GI) toxicity. Currently, we investigated the safety of reducing the overall treatment time (OTT) of focal boosted prostate SBRT from 29 to 15 days. Material and methodsPatients with intermediate- and high-risk prostate cancer were treated with SBRT delivering 35 Gy in 5 fractions to the whole prostate gland with an iso-toxic boost up to 50 Gy to the intraprostatic lesion(s) in a semi-weekly (BIW) schedule. The primary endpoint was radiation-induced acute toxicity (CTCAE v5.0). Changes in quality of life (QoL) were examined in terms of proportions achieving a minimal clinically important change (MCIC). Finally, acute toxicity and QoL scores of the BIW schedule were compared with the results of the prior QW hypo-FLAME schedule (n = 100). ResultsBetween August 2020 and February 2022, 124 patients were enrolled and treated BIW. No grade ≥3 GU or GI toxicity was observed. The 90-days cumulative incidence of grade 2 GU and GI toxicity rates were 47.5% and 7.4%, respectively. Patients treated QW scored significant less grade 2 GU toxicity (34.0%, p = 0.01). No significant differences in acute GI toxicity were observed. Furthermore, patients treated QW had a superior acute bowel and urinary QoL. ConclusionSemi-weekly prostate SBRT with iso-toxic focal boosting is associated with acceptable acute GU and GI toxicity. Based on the comparison between the QW and BIW schedule, patients should be counselled regarding the short-term advantages of a more protracted schedule.Registration number ClinicalTrials.gov: NCT04045717.