Acute GU Research Articles

Radiation technique and outcomes following moderately hypofractionated treatment of low risk prostate cancer: A secondary analysis of the NRG oncology RTOG 0415 randomized clinical trial.

243 Background: While intensity-modulated radiotherapy (IMRT) is commonly used to deliver moderately hypofractionated radiotherapy (MHRT) for prostate cancer (PC), IMRT has not been prospectively compared to three-dimensional conformal radiotherapy (3D-CRT) in the context of MHRT. This secondary analysis of the phase III RTOG 0415 trial compares survival outcomes and toxicity across RT technique between IMRT and 3D-CRT for low-risk PC. Methods: The phase III, non-inferiority trial RTOG 0415 randomized patients with low risk PC to either MHRT (70Gy at 2.5Gy/fraction) or conventionally fractionated radiation (CFRT; 73.8Gy at 1.8Gy/fraction) with stratification by RT technique. A secondary analysis for differences in overall (OS), biochemical recurrence free survival (BRFS), or toxicity by EPIC scores and Common Terminology Criteria for Adverse Events (CTCAE) was performed. For patient and tumor characteristics, continuous data were compared with Wilcoxon rank sum test and categorical data with Chi-squared test, as appropriate. Rates of BRFS and overall survival (OS) were calculated using the Kaplan-Meier method. Results: 1079 patients received the allocated intervention with a median follow up of 5.8 years. RT technique was balanced between treatment arms, with 79.1% of patients receiving IMRT. RT protocol compliance was > 95% for both IMRT and 3D-CRT. There were no significant differences in BRFS between patients treated with 3D-CRT versus IMRT for all patients (p = 0.33), those randomized to CFRT (p = 0.78), or those randomized to MHRT (p = 0.24). Overall survival did not differ by RT technique as well. For all patients, there was no difference in acute and late GI and GU toxicity rates across RT technique. For patients treated with MHRT, late grade 2 GU toxicity was more common with IMRT than 3D-CRT (31.3% vs 23.4%; p = 0.004). On logistic regression analysis, only poor baseline urinary function, defined as an EPIC score of 90 or below, correlated with acute (p < 0.001) or late (p < 0.001) GU toxicity. Baseline bowel function did not correlate to GI toxicity. Conclusions: RT technique did not impact survival outcomes or toxicity rates following MHRT for low risk PC. Higher rates of late CTCAE grade 2+ GU and GI toxicity observed within the RTOG 0415 MHRT arm were not disproportionally observed following 3D-CRT than IMRT. These data highlight the need for careful consideration of target delineation and normal tissue constraints in the selection and delivery of appropriate RT technique.

Cost and Toxicity Comparisons of Two IMRT Techniques for Prostate Cancer: A Micro-Costing Study and Weighted Propensity Score Analysis Based on a Prospective Study.

BackgroundIntensity modulated radiation therapy (IMRT) combined with androgen deprivation therapy (ADT) has become the standard treatment for patients with high-risk prostate cancer. Two techniques of rotational IMRT are commonly used in this indication: Volumetric Modulated Arc Therapy (VMAT) and helical tomotherapy (HT). To the best of our knowledge, no study has compared their related costs and clinical effectiveness and/or toxicity in prostate cancer. We aimed to assess differences in costs and toxicity between VMAT and HT in patients with high-risk prostate cancer with pelvic irradiation.Material and MethodsWe used data from the “RCMI pelvis” prospective multicenter study (NCT01325961) including 155 patients. We used a micro-costing methodology to identify cost differences between VMAT and HT. To assess the effects of the two techniques on total actual costs per patient and on toxicity we used stabilized inverse probability of treatment weighting.ResultsThe mean total cost for HT, €2019 3,069 (95% CI, 2,885–3,285) was significantly higher than the mean cost for VMAT €2019 2,544 (95% CI, 2,443–2,651) (p <.0001). The mean ± SD labor and accelerator cost for HT was €2880 (± 583) and €1978 (± 475) for VMAT, with 81 and 76% for accelerator, respectively. Acute GI and GU toxicity were more frequent in VMAT than in HT (p = .021 and p = .042, respectively). Late toxicity no longer differed between the two groups up to 24 months after completion of treatment.ConclusionUse of VMAT was associated with lower costs for IMRT planning and treatment than HT. Similar stabilized long-term toxicity was reported in both groups after higher acute GI and GU toxicity in VMAT. The estimates provided can benefit future modeling work like cost-effectiveness analysis.

One Fraction Size Does Not Fit All: Patient Preferences for Hypofractionated Radiation Therapy From a Discrete Choice Experiment

PurposeHypofractionated external beam radiation therapy (EBRT) is a standard of care option for localized prostate cancer. To inform clinical practice we quantified patients’ preferences for convenience, efficacy, and toxicity risks, of conventional, moderate hypofractionation, and stereotactic radiation therapy regimens. Methods and MaterialsWe used a discrete choice experiment with a voluntary sample consisting of patients treated with EBRT for localized prostate cancer at our academic cancer center. In 2019, 58 participants, mean (SD) age of 72.9 (7.1) years, agreed to complete an in-person 1:1 discrete choice experiment. Each participant made 12 choices between 2 unique EBRT scenarios, each described by 5 attributes: (1) treatment time; (2) fiducial markers; and risk of (3) prostate specific antigen recurrence; (4) acute and (5) late GI or GU toxicity. Patient preferences were estimated using mixed multinomial logistic regression, and prespecified subgroups with conditional logistic regression. ResultsAll attributes were statistically significant, thus influenced participants’ choices. Risks of prostate specific antigen recurrence (β = −2.581), late (β = −1.854), and acute (β = −1.005) toxicity were most important to participants (P < .001 for each), followed by EBRT length (β = −0.728; P = .017) and fiducial marker implantation (β = −0.563; P = .004). Older (β = −0.063; 95% confidence interval, −0.12, −0.01) and rural (β = −0.083; 95% CI -0.14, −0.02) participants significantly preferred shorter EBRT and were less willing-to-extend treatment to reduce toxicity risk. ConclusionsPatients with prostate cancer place importance on EBRT attributes, and some are willing to trade-off increased risk of toxicity for improved convenience. Our findings promote shared clinical decision-making because patients are interested in learning about the trade-offs involved.

A Phase I Trial of Highly Conformal, Hypofractionated Post Prostatectomy Radiotherapy

Increasingly hypofractionated dose schedules for post prostatectomy radiotherapy to the prostate bed were investigated on a phase I trial. The final toxicity results for patients treated on Arm 2 (no visible recurrence on pelvic MRI) are reported here. The primary objective of this trial was to determine the maximal tolerated hypofractionated dose (MTHD) regimen.Patients were treated on 1 of 3 dose levels (DL): 56.4 Gy in 20 fractions (DL1), 51.2 Gy in 15 fractions (DL2), and 44.2 Gy in 10 fractions (DL3). Patients underwent treatment to the prostate bed (RTOG Consensus); pelvic nodal irradiation was not allowed. Concurrent androgen deprivation therapy (ADT) was used at the discretion of the treating physician. Dose escalation followed a standard 3+3 design with an expansion for 6 additional patients at the maximal tolerated dose (MTHD). Dose limiting toxicity (DLT) was defined as grade 3 (G3) toxicity lasting > 4 days that occurred during or up to 21 days following RT. Toxicity was scored during RT and for 2 years following completion using the CTCAE v4.0. Toxicity was considered acute within 90 days of RT and late after 90 days.Between 01/2018 and 08/2019, 15 patients with a median age of 70 (47-76) underwent RT. Nine patients (60%) underwent concurrent ADT. Patients were classified as NCCN favorable-intermediate (n = 3), unfavorable-intermediate (n = 2), high-risk (n = 9), and very-high risk (n = 1). Three patients were treated at DL1, 3 at DL2, and 9 at DL3. Median follow up was 24 months (9.7-24.0). One patient was removed from study at 9.7 months for PSA progression. There were no DLTs, and no patients required a treatment break. Nine patients (60%) experienced a maximum acute G2 GI toxicity. Within these 9 patients there were 11 total acute G2 GI events consisting of diarrhea in 1 patient (duration: 37 days), proctitis in 5 patients (median duration: 25 days), and worsening hemorrhoids in 5 patients (median duration: 17 days, all occurred in patients with baseline G1 hemorrhoids). One patient developed acute G3 GI toxicity (proctitis) on DL3 which resolved to G2 with medical management in < 4 days. No acute G2 or G3 GU toxicities were observed, however acute G1 dysuria was common (n = 6). Late G2 GI and GU toxicity each occurred in 3 patients respectively. Late G3 GU toxicity occurred in 2 patients (self-limited hemorrhagic cystitis in a patient on DL2, worsening of baseline incontinence in a patient on DL3). There were no ≥ G4 acute or late toxicities.The MTHD for hypofractionated post-operative radiotherapy to the prostate bed was 44.2 Gy in 10 daily fractions. Consistent with recent reports on hypofractionation in the intact prostate setting, acute ≥G2 GI toxicity was observed frequently. Late toxicity rates were similar to rates reported in these prior studies.

Dosimetric Predictors of Toxicity and Quality of Life Following Single Fraction High Dose-Rate Prostate Brachytherapy

<h3>Purpose/Objective(s)</h3> Little is known about optimal dose constraints when high dose rate (HDR) brachytherapy is used as monotherapy for prostate cancer. Most dose constraints for HDR monotherapy were extrapolated from predictors of toxicity when HDR brachytherapy was combined with external beam radiotherapy as a boost. We sought to determine clinical and dosimetric predictors of toxicity and health related quality of life (HRQOL) in men treated with HDR brachytherapy as monotherapy. <h3>Materials/Methods</h3> Eligible patients were treated with single fraction HDR brachytherapy as monotherapy on two prospective clinical trials at a single institution. Patients in the first trial (HDR-mono) received a single fraction of 19 Gy without a dominant intraprostatic lesion (DIL) boost, and patients from the second trial (MARS) received 19 Gy in a single fraction with an MRI-guided DIL boost to ≥ 23 Gy. ADT was not used. Univariable and multivariable logistic regression was used to evaluate clinical (age, IPSS score, prostate volume, alpha blocker use at baseline, and receipt of a DIL boost) and dosimetric (prostate V100, V150, V200, D90, Urethral Dmax and D10, and Rectal Dmax and V80) predictors of CTCAE v4 acute/late toxicity and HRQOL changes measured with expanded prostate index composite (EPIC). Three classifications of late minimally clinically important changes (MCICs) were evaluated: small (> 0.5 standard deviation [SD]), moderate (> 1.0 SD) and severe (> 2.0 SD) declines compared to baseline. <h3>Results</h3> 147 patients were included (87 from HDR-mono, 60 from MARS). Median follow-up was 62.8 months. Only increasing prostate size predicted acute GU toxicity ≥ grade 2 (OR 1.05, 95% CI 1.01–1.09, <i>P</i> = 0.021). On multivariable regression, predictors of late GU toxicity ≥ grade 2 were not receiving a DIL boost (OR 3.78, 95% CI 1.88–7.83, <i>P</i> < 0.001) and higher baseline IPSS score (OR 1.89, 95% CI 1.89–3.18, <i>P</i> = 0.015). Rectal and urethral dose constraints were not associated with late GU/GI toxicity ≥ grade 2. Contrary to our hypothesis, small (OR 0.91, 95% CI 0.81–0.98, <i>P</i> = 0.032) and moderate (OR 0.91, 95% CI 0.80–0.98, <i>P</i> = 0.037) urinary MCICs were less frequent in those with higher urethral Dmax. No impact of urethra D10 on urinary MCICs was seen. Rectal Dmax and V80 did not predict bowel MCIC changes at any threshold. <h3>Conclusion</h3> We were unable to identify dose constraints that were predictive of late toxicity or relevant HRQOL changes in single fraction HDR brachytherapy. This suggests dose parameters used in these trials were safe, and that minor variability in plan dosimetry likely has little clinical significance. While increasing urethral Dmax paradoxically predicted for less frequent urinary MCICs, we do not believe this finding is clinically relevant. Further research exploring optimal dose constraints to be used in HDR brachytherapy as monotherapy for prostate cancer is warranted.

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.

Metastasis-Directed Therapy for Oligoprogressive Castration-Resistant Prostate Cancer ― Preliminary Results of the Prospective, Single-Arm MEDCARE Trial

In metastatic castration-refractory prostate cancer (mCRPC), clinical progression usually implies the start of a new systemic treatment-line. When clinical progression is limited to a few new and/or progressive lesions, while all other lesions are still responsive to ongoing treatment, the term 'oligoprogression' is used. Retrospective data demonstrated that metastasis-directed therapy (MDT) to the oligoprogressive lesions substantially postponed the start of next-line systemic treatment (NEST). Based on these results, the prospective, single-arm MEDCARE trial was initiated.MEDCARE is a prospective, single-arm, monocentric pilot-study, investigating the use of MDT in oligoprogressive mCRPC. Oligoprogression was defined as ≤3 new and/or progressive metastatic lesions or local progression (counting as 1 new lesion) diagnosed on CT or bone scan. Additional MRI was allowed for confirmation. All patients also underwent an 18F PSMA PET-CT as investigational imaging, to assess its predictive value and impact on treatment policy. Ongoing systemic treatment at the time of oligoprogression was continued. MDT consisted of stereotactic body radiation therapy (SBRT) or metastasectomy. The primary endpoint of the trial was NEST-free survival, calculated from the last day of MDT until the start of NEST. Clinical progression-free survival (cPFS) and toxicity scoring with CTCAE v4 scoring were secondary endpoints.Between January 2020 and January 2021, 20 patients were included in the trial. Median age at time of inclusion was 74 years (IQR 67-78). Median PSA and PSA doubling time were 4 ng/ml (IQR 2-11) and 4 months (IQR 3-5), respectively. Eleven patients had 1 progressive lesion on conventional imaging, 7 patients had 2 progressive lesions and 2 patients had 3 progressive lesions. The most frequent location of progressive lesions was the bone (16/20). One patient was treated for a progressive liver metastasis, and one patient presented with progression in the prostatic fossa. Two more patients had a combination of progression in pelvic and retroperitoneal lymph nodes (N1/M1a disease). All patients with progressive metastatic lesions were treated with SBRT (30 Gy in 3 fractions (BED 130 Gy for a/b = 3). The patient with local progression was treated with conventional radiotherapy (77 Gy in 35 fractions (BED 133 Gy for a/b = 3)). At a median follow-up of 6 months (IQR 2-9), 8 patients experienced clinical progression, and five patients were started on NEST. Median NEST-FS was 12 months. Three patients died, 2 deaths were prostate cancer related and 1 patient died of small cell lung cancer. MDT was well tolerated, with 3 patients experiencing grade 1 toxicity, and two patients grade 2 toxicity (acute GU toxicity). There were no patients with grade 3 or higher toxicity.The first results of the MEDCARE trial (NCT04222634) investigating MDT in oligoprogressive CRPC are promising, with negligible toxicity.

Hypofractionated External Beam Irradiation with Single HDR Iridium 192 Boost in the Treatment of intermediate and High Risk Prostate Cancer Patients Initial acute and late side effects

Purpose: Dose escalation has been shown to improve biochemical outcome in the treatment of prostate cancer. The use of precision radiotherapy whether using IMRT, proton’s or other appropriate means have been utilized in an effort to reduce side effects while engaging in dose escalation. However, it is well known that best way to ensure precision delivery of radiation is with the use of brachytherapy. In prostate cancer the use of HDR brachytherapy exploits the low α/β ratios. We sought to evaluate our combination of moderate hypofractionated external beam irradiation with a single HDR boost in terms of acute/late toxicity in patients with intermediate and high risk prostate cancer. Method: 69 patients whose age range from 49 to 83 (med = 69 y.o.) years old were offered treatment utilizing the combination of moderate hypofractionated external beam irradiation and single HDR boost. The external beam irradiation consists of 17 fractions of 250 cGy per fraction, which using BED evaluation most closely approximated our previous more conventionally delivered external beam (23 fractions/200 cGy per fraction) irradiation in this setting. All patients were treated with either 3D conformal or IMRT; within 2 weeks of completion of external beam irradiation a single 1500 cGy iridium 192 implant was delivered. Our dose constraints have been previously published but our stated goal was to delivered 98% of the dose to the prostate treatment volume identified by ultrasound. 29 patients received ADT at the discretion of the treating Urology team. Follow up has been maintained on all patients and has ranged from 11 to 53 months (median 37 months). Results: Assessment of acute / late toxicity was assessed using the RTOG/EORTC criteria. Overall 36/69 (52%) developed ACUTE GI toxicity. 49% developed Gr I/II while two patients developed Gr III. 14.5% reported late GI toxicity, all were GR I / II. Without surprise 98% reported acute GU toxicity. Of these 67/69 had Gr I/II with a single patient reporting GR III. However, after 6 months only 8 (11.5%) had persistent GR I/II issues. An additional patient went on to develop GR III toxicity. Conclusion: While further follow up will be required before definitive statements can be made regarding the oncologic effectiveness of this treatment combination, the early toxicity profiles are very encouraging. We continue to offer this treatment regimen for select intermediate/high risk prostate cancer patients.

Evaluating Clinical Outcomes in 3D vs. 2D Vaginal Brachytherapy

Vaginal brachytherapy (VB) for early stage endometrial cancer (EC) has technologically evolved with the incorporation of 3D imaging into treatment planning. When our institution transitioned from phantom-based 2D template planning to 3D CT-based planning, we implemented selective optimization of standard dwell times for cases with bowel adhered to the vaginal apex. Our hypothesis was that optimizing 3D plans with unfavorable bowel dosimetry would result in no detriment to local control and potentially improve treatment tolerability. We reviewed records of patients with stage I-II EC treated with VB at our institution from 1/2017-6/2019 (3D group). We compared patient, tumor, and treatment characteristics to a historic cohort treated at our institution between 2011-2015 (2D group). Patients had minimum 6 months follow-up. Patients with stage III-IV disease, prior or concurrent pelvic radiation, or synchronous pelvic primary were excluded. Recurrence-free survival (RFS), local control, and treatment tolerability (any acute toxicity recorded prospectively on treatment) were analyzed. Statistical analyses were performed in Stata and included Chi-square and Wilcoxon Rank Sum tests to compare between-group characteristics and Cox proportional hazards analysis to assess RFS. A total of 403 patients were included (n = 99/3D and n = 304/2D). The 3D vs. 2D groups were similar in age, weight, gravidity, cylinder sizes, histology, and chemotherapy, though differed in race (p = 0.004) and % stage IA/IB/II (p = 0.022). VB dose was similar, with majority receiving either 18Gy/3 fractions (46% vs. 46%) or 21Gy/3 fractions (40% vs. 38%) to 5mm depth. In the 3D cohort, however, the proportion of vagina treated was less (3D median 50%, IQ range 43-56% vs. 2D median 60%, IQ range 50-67%; p<0.001). and standard dwell times were decreased to improve bowel dosimetry in 21%. Median follow-up times were 524 and 903 days in the 3D and 2D groups, respectively. There was no significant difference in RFS (HR 0.48, 95% CI 0.19-1.22, p = 0.122). Vaginal recurrence occurred in 1 and 2 patients, respectively, with recurrence distal to treated mucosa in all cases. There were no significant differences between groups in rates of acute GI (14.1% vs. 10.9%, p = 0.376), GU (8.1% vs. 11.2%, p = 0.380), or vaginal (20.2% vs. 19.4%, p = 0.827) toxicities. All toxicities were mild (grade 1-2). In the 3D patients, there were no significant differences (p>0.05) in bowel, rectal, or bladder Dmax or D2cc values between those with vs. without symptoms on treatment. 3D vs. 2D planning maintained excellent local control despite selectively reducing the volume of prescription isodose overlapping with bowel. Treatment tolerability was favorable in both groups with no benefit observed in the short term, however, longer follow-up is needed to compare late outcomes.

Phase I Trial Of MRI-Linac Based Stereotactic Body Radiation Therapy With Simultaneous Integrated Boost For Localized Prostate Cancer (NCT03664193)

The treatment paradigm for localized prostate cancer (PCa) can potentially be improved by utilizing recent advances in MRI-based radiation approaches (MRI-Linac) to deliver precise, individualized therapy to areas at greatest risk of disease recurrence while avoiding adjacent normal organs. A phase I feasibility and safety study was designed to deliver MRI-Linac based SBRT with a simultaneous integrated boost (SIB) for PCa patients with dominant intraprostatic nodule (DIN)s on PSMA PET or MRI imaging. The study has completed accrual and we now report our outcomes. From 11/2018- 10/2019, 30 patients with localized PCa and DIN(s) were enrolled. SBRT dose of 36.25 Gy was prescribed. The DIN was defined on PSMA PET and/or MRI and boosted to 37.5 -45 Gy while meeting normal tissue constraints. Use of rectal spacer and PSMA PET was optional. All patients were treated on an MRI-Linac (MRIdian Viewray) with live MRI guidance. Adaptive planning was allowed. Acute toxicity was assessed using CTCAE 5.0. Baseline and follow up sexual, GI and GU patient reported outcomes were assessed. A total of 30 patients (median age 73) were treated on this study, categorized as low, intermediate, and high risk PCa (27%, 63%, and 10% respectively). A mean dose of 40 Gy was delivered to the DIN (range, 37.5 – 45 Gy), demonstrating feasibility of our approach. A total of 23/30 patients had a rectal spacer placed, which did not reduce the maximum rectal dose, but decreased rectal D1cc. Six patients had PSMA PET/MR imaging available. Alterations in prostate volume were recorded on MR. The median prostate volume by the end of treatment increased by 6.1 cm3 corresponding to a significant volumetric change of 20.8% compared to baseline (Range -3.9% to 30.5%). As a result of these volumetric changes, the D95 decreased by median of 9.6%. There were no G3 or higher acute treatment related toxicities. Acute G2 GU and GI toxicity was noted in 27% (n = 8) and 7% (n = 2) of patients, respectively. Evaluable patients (22 out of 30) demonstrate that 91% have IPSS scores back or below baseline (+/- 1 pt) by 3 months follow up, with no significant change in the EPIC urinary or bowel domain. MRI-Linac based SBRT with SIB is a feasible and safe approach to treat localized PCa, maximizing dose to regions at greatest risk while minimizing toxicity to adjacent organs. MRI imaging during treatment demonstrates that the prostate undergoes enlargement and subsequent contracture during SBRT, suggesting size fluctuations must be accounted for. The addition of PSMA PET/MR improves both staging and delineation of the DIN, and may be an elegant partner to MRI-Linac based prostate SBRT with SIB. A Phase II study to test the efficacy of PSMA PET/MR based, MRI-Linac SBRT with SIB with option of adaptive replanning, has received funding to open in the near future as a subsequent protocol.

Clinical Results Of Proton Boost Combined With Pelvic IMRT For Node-Positive Prostate Cancer: Dosimetric Analysis And Patient-Reported Outcomes

Previous studies demonstrated the efficacy of radiation therapy for clinically node-positive prostate cancer. However, there are few reports on treatment strategies incorporating proton therapy. The purpose of this study was to evaluate the clinical outcome of pelvic IMRT combined with proton boost for node-positive prostate cancer, including toxicity and patient reported outcomes (PROs) of health-related quality of life (QOL), and to perform dosimetric comparison of boost plans between proton therapy and IMRT. From March 2013 to May 2016, 12 patients with node-positive prostate adenocarcinoma were treated by pelvic IMRT with 45 Gy/25 fr followed by proton boost with 34 GyE/17 fr to the prostate and seminal vesicles and 26 GyE/13 fr to positive lymph nodes. Biochemical failure was defined according to the Phoenix definition. Adverse effects were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Dosimetric comparisons were carried out between proton therapy and IMRT regarding boost plans. The same CTVs, dose fractionation and target volume coverage, and OAR dose constraints were used. All 12 patients completed the Expanded Prostate Cancer Index Composite (EPIC) health-related QOL questionnaire before and at 1-36 months after treatment. The median follow-up period was 59 months (range, 42-80 months). The Gleason score was 7 in 1 patient, 8 in 3 patients, and 9 in 8 patients. The median PSA level before treatment was 38.8 ng/ml (range, 11-230). All patients underwent androgen deprivation therapy for a median duration of 48.5 months. Three patients had biochemical failure. Two of them experienced extrapelvic recurrence. There was no grade 3 or higher acute or late GI and GU toxicity. Planning target volume coverage by the prescription dose was similar between the proton and IMRT plans. In the proton plan, mean rectum V40Gy was significantly lower than in the IMRT plan (44.4% vs 59.3%). The dose to the small intestine for 1 cc and to the colon for 1 cc was 45.1 and 52.3 Gy, respectively, in the proton plans, and 47.0 and 55.7 Gy, respectively, in the IMRT plans, but there were no significant differences. Mean bowel bother score and bowel function score at 6-36 months were similar to or greater than the scores before treatment. Mean urinary summary QOL score was 86.2 before treatment and 82.0, 92.0, 86.7, and 89.8 at 1, 6, 12, and 36 months, respectively. Proton boost combined with pelvic IMRT was feasible and offered reductions in radiation doses to gastrointestinal organs at risk in patients with node-positive prostate cancer. No grade 3 AEs were observed after IMRT plus proton boost and no change was noted in PROS scores. Further studies are warranted for a larger population.

Feasibility of Stereotactic MR-Guided Adaptive Radiotherapy in Localized Prostate Cancer

Extreme hypofractionation by use of SBRT is being frequently used in localized prostate cancer (Pca), after the early studies have resulted in favorable outcome and acceptable toxicity. Stereotactic MR-guided Adaptive Radiotherapy (SMART) has the advantages for markerless, MR guidance with daily adaptation and smaller PTV margins. We aimed to report our initial experience with SMART in localized Pca. Between 09/18-10/19, 35 consecutive patients with T1c-T3aN0M0 Pca were treated with MRidian MRLINAC (ViewRay, OH). Risk groups were low in 20%, intermediate in 57% and high in 23%. MR and CT simulation was done after 3 hours of fasting, fleet enema and 40 mins after 250 cc water. Isotropic PTV margin was 3 mm over CTV (prostate+/-seminal vesicles). Static IMRT plans to give 3625 cGy/5 fractions were studied. 26% received androgen ablation. All patients were treated every other day. Median follow up time was 7 (Range: 1-14) months. Plan adaptation was done in 74% of 175 fractions. The reasons for plan adaptation were target volume coverage in 38%, OAR violation in 26% and both in 32%. Overall treatment time was median 45 min (29-95 min, range). Acute GU toxicity was seen in 34% as Gr1 and in 11% as Gr2. GI toxicity was seen as Gr 1 in 6%. Alpha blocker was needed during treatment for urinary symptoms in 23% of patients. No grade 3 or higher acute or late toxicity was observed. Early PSA kinetics after treatment were positive as expected from SBRT. Only 1 high risk patient developed systemic metastasis and another patient developed biochemical failure. SMART is a tolerable and convenient markerless treatment method for localized Pca patients. Our early results support low toxicity with high rate of local control.

Haematotoxicity in IMRT/VMAT curatively treated anal cancer.

Curative chemoradiotherapy of squamous cell carcinoma achieves long-term complete remissions in most patients and minimizing treatment toxicity becomes crucial issue. The aim of the retrospective analysis was to determine an acceptable dose to the bone marrow for radiotherapy planning not leading to increased haematological toxicity. In the period 2013-2019, 40 patients with squamous cell carcinoma were curatively treated at the Department of Oncology of the University Hospital Motol using intensity modulated radiotherapy (IMRT) /volumetric modulated arc radiotherapy (VMAT) technique. Women make up 90% of the group, the average age at the time of dia-gnosis was 65 years (47-81). Chemotherapy mitomycin C and 5-fluorouracil was given to 68% of patients. The bone marrow was contoured in the Varian Eclipse planning system, version 15.6. Acute hematotoxicity (G3, 4, 5 according to Common Terminology Criteria for Adverse Events - CTCAE) was significantly associated with the concomitant chemoradiotherapy (P = 0.002) and the average dose to the bone marrow 27 Gy (P = 0.011). Late haematological toxicity was mild (maximum grade 1), asymptomatic, and no dependence of late haematotoxicity on any risk factor (age, gender, WHO performance status, bone marrow dose, CHT, BMI, smoking, stage) was proved. The overall survival at 5 years was 100% in stage I, 83% in stage II, 61% in stage III and 0% in stage IV. Local control at 5 years is 100% in stage I, 92% in stage II, 87% in stage III and 0% in stage IV. Local recurrence developed in 5% of radically treated patients. Distant metastases occurred in 8% of radically treated patients. Local recurrences or metastases occurred only during the first 2 years after the treatment. Radical chemoradiotherapy in the treatment of squamous cell anal carcinoma is highly effective. IMRT/VMAT enabled to apply a sufficiently effective dose to the tumor and elective areas and reduced not only acute skin, GI and GU toxicity, but also acute haematological toxicity in cases with the dose Dmean to bone marrow lower than 27 Gy. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical, papers.

Lymph node–directed simultaneous integrated boost in patients with clinically lymph node–positive cervical cancer treated with definitive chemoradiotherapy: clinical outcomes and toxicity

Lymph node (LN)–positive cervical cancer is associated with a poor prognosis. We report outcomes for women with LN-positive cervical cancer treated with intensity-modulated radiation therapy (IMRT) with dose-escalated simultaneous integrated boost (SIB) to involved LNs. Between 2005 and 2017, 59 women with LN-positive, non-metastatic, cervical cancer underwent definitive chemoradiotherapy (CRT) with an image-guided LN boost to a median dose of 56.25 Gy in 25 fractions. Acute and late adverse events (AEs) were recorded per common terminology criteria for adverse events. The Kaplan-Meier method was used to estimate the overall survival (OS), progression-free survival (PFS), and locoregional control (LRC). Median age was 49 years (IQR 37–56). Women had involved LNs in the pelvis (56%) or pelvis and para-aortic (PA) LNs (44%), with a median of 3 (IQR 2–6) grossly involved LNs per patient. Median follow-up was 30 months (IQR 11–45). Estimated 3-year OS, PFS, and LRC were 67% (95% CI, 51%–84%), 60% (95% CI, 45%–76%), and 89% (95% CI, 76%–99%), respectively. PA LN involvement (HR 2.51; 95% CI, 1.05–5.99; p = 0.04) and the presence of ≥ 4 grossly involved LNs (HR 2.79; 95% CI, 1.16–6.71; p = 0.02) were associated with a higher risk of disease progression on univariate analysis. The incidence of treatment-related acute grade 3+ acute GI or GU AEs was 3%, while late GI or GU treatment-related AEs occurred in 12%. Chemoradiation with a LN-directed SIB for women with LN-positive cervical cancer is well tolerated and is associated with excellent oncologic outcomes. In this report, we evaluated the oncologic efficacy and adverse events associated with definitive chemoradiotherapy with a simultaneous integrated boost to grossly involved lymph nodes for women with lymph node–positive cervical cancer. We have identified acceptable rates of adverse events and excellent oncologic outcomes, even in a very high risk cohort of women with cervical cancer.

Abstract A084: Personalized prediction of radiation sensitivity

Abstract Purpose/Objective: Patients of different races with similar cancers are often treated with radiation according to safety criteria largely collected from patients of European origin. However, even among those patients, toxicities are not predictable. Patients of African origin appear to have more severe skin radiation reactions, particularly Black women with breast cancer, than other populations. We have developed a technique using circulating cell-free DNA (cfDNA) that appears to predict toxicity in patients with otherwise similar radiation dosimetry, allowing for early intervention to prevent side effects (marketed as RadToxTM, DiaCarta, Inc.). Methods: Pre-clinical studies were performed in mice with white (BALB/c), brown (C3H/HeJ), or black (C57BL/6) fur. Radiation was delivered to the hind limb, and the skin reaction was evaluated. Blood was collected to evaluate changes in cfDNA as compared to severity of cutaneous toxicity. A phase I/II clinical study (n=54) was also performed to determine if plasma cfDNA measured early in a radiotherapy course can predict the subset of patients who experience grade 2 or higher radiotoxicity. Results: The most severe toxicity was seen in the C57BL/6 mice, and at similar doses the increase in cfDNA was higher than in the other two strains. Fifty-four patients were evaluable for the clinical study. Radiation significantly increased cfDNA on all days following the first radiation session. Acute maximum GI toxicity score, but not acute GU toxicity, was significantly correlated with cfDNA levels obtained on days 1, 2, 3, 4, and 5 of radiotherapy (p&amp;lt;0.005). Conclusions: Plasma cfDNA levels predicted the mouse strain that experienced more severe toxicity, and in a small study detected acute bowel toxicity. A larger study is needed to confirm the results and the value of the test for identifying patients who need special interventions to reduce toxicity. Further testing of this hypothesis is under evaluation in an NCI-funded multi-institutional study. Citation Format: Natalie Lockney, Steven G Swarts, Jennifer Li, Christopher Morris, Randal Henderson, Steven B Zhang, Zhenhuan Zhang, Sadasivan Vidyasagar, Reshu Gupta, Katherine Casey-Sawicki, Robert Zlotecki, Paul Okunieff. Personalized prediction of radiation sensitivity [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr A084.

MicroRNA-based biomarkers of the radiation response in prostate cancer.

163 Background: Intermediate and high-risk prostate cancer can be cured with radiation (RT) to the prostate and pelvic lymph nodes with androgen deprivation therapy (ADT), but both acute and late toxicity of the GU and GI systems are common. There are no biomarkers predicting radiation outcomes, limiting the opportunity to best personalize prostate radiation therapy. Methods: A prospectively enrolled single arm trial for locally advanced prostate cancer patients (T1-T4N0-N1M0) treated with definitive RT (74Gy IMRT) plus ADT was studied. Biologic samples were available in 108 of 138 patients. Toxicity was recorded using the RTOG morbidity grading system. We applied a panel of microRNA-based germline mutations shown to predict cancer therapy endpoints. Machine learning techniques were used to simultaneously identify prognostic features and perform classification of the biomarkers. Upsampling nested LOO-CV was used to assess performance and generality. Independent Fisher’s exact tests were performed to identify statistically significant marginal associations. Three classifiers were studied: logistic regression with elastic net regularization (EN-LR), classification trees (CT), and random forests (RF), with corresponding hyper-parameters of regularization weights (EN-LR), minimum split and bucket level sample size (CT), number of trees and mtry (RF). Normalized on the simplex, feature importance was defined as absolute value of regression weights for EN-LR, and cumulative decrease in Gini impurity for primary and surrogate splits at each node/splits for CT and RF. Results: Grade 2 or higher toxicity included acute GI (11%), acute GU (34%), late GI (3%) and late GU (16%). GI and GU toxicity and acute and late toxicity had unique predictive biomarkers. The top three marginal genetic associations for late GU toxicity were microRNA site variants in CD6 and CD274 (PDL1)(p.val &lt; 0.01) and BRCA2 (p.val = 0.014). Using RF, CT and EN_LR we could predict late GU toxicity with up to 70% sensitivity, 96% specificity, and 90% accuracy. Conclusions: We have identified microRNA-based biomarkers that can predict late GU toxicity. Work incorporating patient reported outcomes and to identify biomarkers for additional endpoints is ongoing.

Stereotactic body radiotherapy boost toxicity for high and intermediate-risk prostate cancer: Report of a multi-institutional study.

365 Background: External beam radiation therapy (EBRT) with androgen suppression (AS) and low dose rate (LDR)brachytherapy boost has been shown to improve biochemical progression free survival in unfavorable intermediate risk and high-risk prostate cancer (PC) compared to EBRT and AS. Excellent rates of local control in locally advanced prostate cancer with EBRT with high dose rate brachytherapy (HDR) boost. Prostate Stereotactic Radiosurgery (SBRT) may be an alternative to brachytherapy in patients with unfavorable intermediate and high-risk PC. Here we report the toxicity of pelvic lymph node/prostate EBRT and SBRT as the radiation boost in a large retrospective cohort. Methods: 473 patients with intermediate or high-risk PC, from the Radiosurgery Society Registry, Beth Israel Deaconess Medical Center, Georgetown University, and 5 Australian centers, were included. Patients received treatment from 3/2004- 9/2018 were the basis of this IRB approved retrospective study. The prostate and pelvis nodes were treated with between 36-50.4 Gy in 1.8/2.0 Gy fractions of radiation therapy EBRT. Patients received a SBRT boost to the prostate. Boost dose was 19-19.5 Gy (range 19-36.25 Gy). 274 and 199 patients presented with unfavorable or high-risk disease. The median follow-up was 33 months (IQR:18-63). Results: 33 deaths of 473 patients occurred in this cohort, 8 of which were caused by PC. There were 13.9% (n=66) acute Grade 1 or 2 GI toxicities (11.8% grade 1, 2.1% grade 2). There were 27.7% (n=131) acute Grade 1 or 2 GU toxicities (19.2% grade 1, 8.5% grade 2). No severe acute GU or GI toxicities were reported. There were 32 (6.8%) Grade 1 and 3 (0.6%) Grade 2 late GI toxicities. There were 9 (1.9%) Grade 3 and 1 (0.2%) Grade 4 late GI toxicities. There were 60 (12.7%) Grade 1 and 23 (4.9%) Grade 2 late GU toxicities. 15 (3.2%) Grade 3, but no Grade 4 late GU toxicity were reported. Conclusions: In this large multi-institutional retrospective cohort SBRT boost to pelvic/prostate EBRT had acceptable acute and late toxicities. The high dose per fraction of SBRT is similar to the dose delivered with HDR. This data raises the hypothesis that SBRT boost should be evaluated in additional clinical trials.

Post-HIFU locally relapsed prostate cancer: high-dose salvage radiotherapy guided by molecular imaging

To evaluate tolerance and biochemical control rates of salvage external beam radiotherapy (EBRT) in patients with local relapse from prostate cancer (PC) after high-intensity focused ultrasound (HIFU) as primary treatment. Twenty-four patients presented biochemical failure of PC. Salvage EBRT to the residual prostate was performed with moderate hypofractionation schedule (MHRT) in 28 fractions (n = 16) or with extreme hypofractionation schedule (SBRT) in 5 fractions (n = 8) by means of image-guided volumetric modulation arc therapy. In case of MHRT, the median dose was 71.4Gy, whereas in case of SBRT it was 32.5Gy. The median follow-up was 28months. The median PSA nadir was 0.26ng/mL. In case of MHRT, the median PSA nadir was 0.15ng/mL and occurred within a median time of 19months. In case of SBRT, the median PSA nadir was 0.64ng/mL and occurred within a median time of 8months. No G3 higher acute or late toxicity after EBRT was observed. Only three patients presented with G2 acute GI toxicity (actinic proctitis). Twelve patients experienced acute G1 GU toxicity: 8/16 of men treated with MHRT and 4/8 of men treated with SBRT. Complete local control of disease was achieved in 23/24 patients (96%). Our data confirm the feasibility and the low toxicity of salvage EBRT with both schedules of treatment after HIFU failure. The findings of low acute toxicity and good biochemical control rates are encouraging, but a larger number of patients and a longer follow-up are needed to confirm these results.

Exploring the Impact of External Urethral Length on Acute Urinary Toxicity in Patients Undergoing High Dose Rate Brachytherapy for Prostate Cancer

The pre-operative and post-operative length of the external urethra sphincter (EUS) in patients undergoing radical prostatectomy has previously been reported to correlate with urinary incontinence. We aimed to determine if external urethral length impacts rates of urinary incontinence in patients undergoing high dose rate (HDR) brachytherapy. We performed a retrospective cohort study of patients with localized prostate cancer treated with MRI-based HDR brachytherapy monotherapy on a prospectively maintained database of prostate HDR patients treated from 2017-2018. Patients were treated with 13.5 Gy in 2 fractions delivered 1-2 weeks apart. CT images were used for catheter identification, and a T2 weighted MRI was obtained after the implant for target and normal structure delineation. The planning target volume (PTV) consisted of the prostate with an asymmetric expansion of 0-5 mm, with inclusion of the proximal seminal vesicles. Expanded Prostate Cancer Composite - 26 (EPIC-26) was evaluated at baseline, 1 month, 3 months, 6 months, then every 6 months thereafter. Linear mixed effects models were used to estimate mean EPIC-26 scores, International Prostate Symptom Score (IPSS) scores, and CTCAE v.5.0 genitourinary and gastrointestinal toxicity over time based on EUS length which was dichotomized as ≤ (short) or > (long) than the median. During analysis, changes were also classified as minimal clinically important difference (MCID). 46 patients were treated with definitive HDR using MRI-based planning, including 1 NCCN high risk , 32 intermediate risk, and 13 low risk patients. Median follow up was 4.18 months. The median EUS length was 1.7 cm (range 0.5-2.35 cm). There was no difference in baseline mean EPIC-26 scores in any domains. For the Urinary Incontinence domain, baseline mean scores were similar for short and long EUS (87.79 vs. 91.42; p=0.96). Patients with a short EUS had a greater decline in Urinary Incontinence mean scores at 1 month (72.51 vs. 83.59), 3 months (73.16 vs. 92.59), and 6 months (76.47 vs. 93.01), meeting MCID at all time points after treatment, although this was only marginally significantly associated with EPIC-26 urinary incontinence scores (p=0.05). EUS length was not associated with other EPIC-26 scores, changes in IPSS scores, or acute GU or GI toxicity. In concordance with surgical literature, shorter EUS length may be associated with acute urinary incontinence outcomes as assessed by EPIC-26 scores, however our series is limited by short follow-up and small sample size. Further research is required to validate our findings and, if so, may guide discussion with patients in the future regarding risks and benefits of brachytherapy.

Acute Adverse Events and Patient Reported Outcomes from Para-aortic Nodal Radiotherapy in Gynecologic Malignancies

To report prospectively collected physician-reported adverse events (AEs) and patient reported outcomes (PRO) for patients with gynecologic malignancies receiving para-aortic nodal radiotherapy. We included patients with gynecologic malignancies treated with curative-intent RT at our institution between 2013 and 2018. Physician-reported AEs were prospectively assessed before, at completion of RT, and three months following RT completion, using CTCAE Version 4.0. AEs were categorized and reported with the highest grade per patient. Patients were enrolled on a prospective PRO registry to assess treatment impact on quality of life with a gynecologic malignancy-specific PRO CTCAE. For inclusion in this analysis, receipt of curative-intent external beam radiotherapy inclusive of para-aortic lymph nodes and completion of baseline and post-treatment questionnaires were required. Radiation treatment volumes extending cranially beyond the superior aspect of the L4 vertebral body were categorized as para-aortic fields. 51 patients met inclusion criteria. Primary diagnosis was cervical (26, 51%), endometrial (23, 45%), vaginal (1, 2%), and vulvar (1, 2%). All patients were treated with IMRT. Twenty-six patients received definitive radiotherapy, while 25 patients received adjuvant radiotherapy. Median external beam radiotherapy dose was 45 Gy (range 45- 64 Gy). Forty-four (86%) patients received brachytherapy with a median dose of 28 Gy (range10- 30 Gy). Twenty-three (45.1%) patients received chemotherapy prior to RT and 28 (54.9%) received concurrent chemotherapy with RT. There were no grade 4 or 5 AEs. There were 6 grade 3 AEs in 4 patients: anemia (2), proctitis, fatigue, radiation dermatitis, and nausea. Grade 1 or 2 AEs included GI in 39 (76%), urinary in 9 (17%), gynecologic in 16 (31%), and dermatologic in 4 patients (8%). Twenty-one patients completed consecutive PRO-CTCAE. PRO-CTCAE questionnaires were assessed on a 5-point scale with significant symptoms considered level 3, 4, or 5: occasionally, frequently or almost constantly; somewhat, quite a bit or very much; moderate, severe or very severe. Significant rates of GI and GU symptoms at baseline and following treatment are listed in the table below. Para-aortic RT for gynecologic malignancies is associated with expected increases in acute GU and GI physician-reported AEs and patient-reported symptoms with patients reporting more severe symptoms than physicians. Significant recovery 3 months post-RT was observed in PRO-CTCAE surveys.Abstract 2794; Table 1SymptomBaseline (%)End of RT(%)3 Months Post-RT (%)Diarrhea306625Flatulence607053Bowel incontinence303815Bowel incontinence interference3525Urinary frequency276230Urinary frequency interference131915Urinary urgency1760Urinary urgency interference7295Urinary incontinence interference231915 Open table in a new tab