A Randomized Feasibility Trial of Stereotactic Prostate Radiation Therapy With or Without Elective Nodal Irradiation in High-Risk Localized Prostate Cancer (SPORT Trial).

PURPOSE: The aim of this study was to establish the feasibility of a randomized clinical trial comparing SABR with prostate-only (P-SABR) or with prostate plus pelvic lymph nodes (PPN-SABR) in patients with unfavorable intermediate- or high-risk localized prostate cancer and to explore potential toxicity biomarkers. METHODS AND MATERIALS: Thirty adult men with at least 1 of the following features were randomized 1:1 to P-SABR or PPN-SABR: clinical magnetic resonance imaging stage T3a N0 M0, Gleason score ≥7 (4+3), and prostate-specific antigen >20 ng/mL. P-SABR patients received 36.25 Gy/5 fractions/29 days, and PPN-SABR patients received 25 Gy/5 fractions to pelvic nodes, with the final cohort receiving a boost to the dominant intraprostatic lesion of 45 to 50 Gy. Phosphorylated gamma-H2AX (γH2AX) foci numbers, citrulline levels, and circulating lymphocyte counts were quantified. Acute toxicity information (Common Terminology Criteria for Adverse Events, version 4.03) was collected weekly at each treatment and at 6 weeks and 3 months. Physician-reported late Radiation Therapy Oncology Group (RTOG) toxicity was recorded from 90 days to 36 months postcompletion of SABR. Patient-reported quality of life (Expanded Prostate Cancer Index Composite and International Prostate Symptom Score) scores were recorded with each toxicity time point. RESULTS: The target recruitment was achieved, and treatment was successfully delivered in all patients. A total of 0% and 6.7% (P-SABR) and 6.7% and 20.0% (PPN-SABR) experienced acute grade ≥2 gastrointestinal (GI) and genitourinary (GU) toxicity, respectively. At 3 years, 6.7% and 6.7% (P-SABR) and 13.3% and 33.3% (PPN-SABR) had experienced late grade ≥2 GI and GU toxicity, respectively. One patient (PPN-SABR) had late grade 3 GU toxicity (cystitis and hematuria). No other grade ≥3 toxicity was observed. In addition, 33.3% and 60% (P-SABR) and 64.3% and 92.9% (PPN-SABR) experienced a minimally clinically important change in late Expanded Prostate Cancer Index Composite bowel and urinary summary scores, respectively. γH2AX foci numbers at 1 hour after the first fraction were significantly higher in the PPN-SABR arm compared with the P-SABR arm (P = .04). Patients with late grade ≥1 GI toxicity had significantly greater falls in circulating lymphocytes (12 weeks post-radiation therapy, P = .01) and a trend toward higher γH2AX foci numbers (P = .09) than patients with no late toxicity. Patients with late grade ≥1 bowel toxicity and late diarrhea experienced greater falls in citrulline levels (P = .05). CONCLUSIONS: A randomized trial comparing P-SABR with PPN-SABR is feasible with acceptable toxicity. Correlations of γH2AX foci, lymphocyte counts, and citrulline levels with irradiated volume and toxicity suggest potential as predictive biomarkers. This study has informed a multicenter, randomized, phase 3 clinical trial in the United Kingdom.

Computed Tomography-based Radiomics for Risk Stratification in Prostate Cancer.

PURPOSE: To explore the role of Computed tomography (CT)-based radiomics features in prostate cancer risk stratification. METHODS AND MATERIALS: The study population consisted of 506 patients with prostate cancer collected from a clinically annotated database. After applying exclusion criteria, 342 patients were included in the final analysis. CT-based radiomics features were extracted from planning CT scans for prostate gland-only structure, and machine learning was used to train models for Gleason score (GS) and risk group (RG) classifications. Repeated cross-validation was used. The discriminatory performance of the developed models was assessed using receiver operating characteristic area under the curve (AUC) analysis. RESULTS: Classifiers using CT-based radiomics features distinguished between GS ≤ 6 versus GS ≥ 7 with AUC = 0.90 and GS 7(3 + 4) versus GS 7(4 + 3) with AUC = 0.98. Developed classifiers also showed excellent performance in distinguishing low versus high RG (AUC = 0.96) and low versus intermediate RG (AUC = 1.00), but poorer performance was observed for GS 7 versus GS > 7 (AUC = 0.69). An overall modest performance was observed for validation on holdout data sets with the highest AUC of 0.75 for classifiers of low versus high RG and an AUC of 0.70 for GS 7 versus GS > 7. CONCLUSIONS: Our results show that radiomics features from routinely acquired planning CT scans could provide insights into prostate cancer aggressiveness in a noninvasive manner. Assessing models on training data sets, the classifiers were especially accurate in discerning high-risk from low-risk patients and in classifying GS 7 versus GS > 7 and GS 7(3 + 4) versus G7(4 + 3); however, classifiers were less adept at distinguishing high RG versus intermediate RG. External validation and prospective studies are warranted to verify the presented findings. These findings could potentially guide targeted radiation therapy strategies in radical intent radiation therapy for prostate cancer.

Efficacy of a rectal spacer with prostate SABR-first UK experience.

OBJECTIVE: This study assessed the use of implanted hydrogel rectal spacers for stereotactic ablative radiotherapy-volumetric modulated arc therapy (SABR-VMAT) patients, investigating practicality, dosimetric impact, normal tissue complication probability (NTCP) and early toxicity. METHODS: Data from the first 6 patients treated within a prostate SABR and rectal spacer trial were examined to determine spacer insertion tolerability, resultant changes in treatment planning and dosimetry and early toxicity effects. CT scans acquired prior to spacer insertion were used to generate SABR plans which were compared to post-insertion plans. Plans were evaluated for target coverage, conformity, and organs at risk doses with NTCPs also determined from resultant dose fluences. Early toxicity data were also collected. RESULTS: All patients had successful spacer insertion under local anaesthetic with maximal Grade 1 toxicity. All plans were highly conformal, with no significant differences in clinical target volume dose coverage between pre- and post-spacer plans. Substantial improvements in rectal dose metrics were observed in post-spacer plans, e.g. rectal volume receiving 36 Gy reduced by ≥42% for all patients. Median NTCP for Grade 2 + rectal bleeding significantly decreased from 4.9 to 0.8% with the use of a rectal spacer (p = 0.031). To date, two episodes of acute Grade 1 proctitis have been reported following treatment. CONCLUSION: The spacer resulted in clinically and statistically significant reduction in rectal doses for all patients. Advances in knowledge: This is one of the first studies to investigate the efficacy of a hydrogel spacer in prostate SABR treatments. Observed dose sparing of the rectum is predicted to result in meaningful clinical benefit.

A novel CBCT-based method for derivation of CTV-PTV margins for prostate and pelvic lymph nodes treated with stereotactic ablative radiotherapy.

BACKGROUND: Traditional CTV-PTV margin recipes are not generally applicable in the situation of stereotactic ablative radiotherapy (SABR) treatments of multiple target volumes with a single isocentre. In this work, we present a novel geometric method of margin derivation based on CBCT-derived anatomical data. METHODS: Twenty patients with high-risk localized prostate cancer were selected for retrospective review. Individual volumes of interest (prostate, prostate and seminal vesicles and pelvic lymph nodes) were delineated on five representative CBCTs and registered to the planning CT using two registration protocols: bone match or prostate-based soft tissue match. Margins were incrementally expanded around composite CTV structures until 95% overlap was achieved. RESULTS: CTV-PTV margins of 5.2, 6.5 and 7.6 mm were required for prostate, prostate and seminal vesicles and pelvic lymph nodes respectively using a prostate matching protocol. For the prostate and seminal vesicle structures, margins calculated using our method displayed good agreement with a conventional margin recipe (within ±1.0 mm). CONCLUSIONS: We have presented an alternative method of CTV-PTV margin derivation that is applicable to SABR treatments with more than one isocentric target. These results have informed an institutional trial of prostate and pelvic nodal SABR in men with high-risk localized prostate cancer.

Prostate cancer treated with brachytherapy; an exploratory study of dose-dependent biomarkers and quality of life.

BACKGROUND: Low-dose-rate permanent prostate brachytherapy (PPB) is an attractive treatment option for patients with localised prostate cancer with excellent outcomes. As standard CT-based post-implant dosimetry often correlates poorly with late treatment-related toxicity, this exploratory (proof of concept) study was conducted to investigate correlations between radiation - induced DNA damage biomarker levels, and acute and late bowel, urinary, and sexual toxicity. METHODS: Twelve patients treated with 125I PPB monotherapy (145Gy) for prostate cancer were included in this prospective study. Post-implant CT based dosimetry assessed the minimum dose encompassing 90% (D90%) of the whole prostate volume (global), sub-regions of the prostate (12 sectors) and the near maximum doses (D0.1cc, D2cc) for the rectum and bladder. Six blood samples were collected from each patient; pre-treatment, 1 h (h), 4 h, 24 h post-implant, at 4 weeks (w) and at 3 months (m). DNA double strand breaks were investigated by staining the blood samples with immunofluorescence antibodies to γH2AX and 53BP1 proteins (γH2AX/53BP1). Patient self-scored quality of life from the Expanded Prostate Cancer Index Composite (EPIC) were obtained at baseline, 1 m, 3 m, 6 m, 9 m, 1 year (y), 2y and 3y post-treatment. Spearman's correlation coefficients were used to evaluate correlations between temporal changes in γH2AX/53BP1, dose and toxicity. RESULTS: The minimum follow up was 2 years. Population mean prostate D90% was 144.6 ± 12.1 Gy and rectal near maximum dose D0.1cc = 153.0 ± 30.8 Gy and D2cc = 62.7 ± 12.1 Gy and for the bladder D0.1cc = 123.1 ± 27.0 Gy and D2cc = 70.9 ± 11.9 Gy. Changes in EPIC scores from baseline showed high positive correlation between acute toxicity and late toxicity for both urinary and bowel symptoms. Increased production of γH2AX/53BP1 at 24 h relative to baseline positively correlated with late bowel symptoms. Overall, no correlations were observed between dose metrics (prostate global or sector doses) and γH2AX/53BP1 foci counts. CONCLUSIONS: Our results show that a prompt increase in γH2AX/53BP1foci at 24 h post-implant relative to baseline may be a useful measure to assess elevated risk of late RT - related toxicities for PPB patients. A subsequent investigation recruiting a larger cohort of patients is warranted to verify our findings.

Class solutions for SABR-VMAT for high-risk prostate cancer with and without elective nodal irradiation.

BACKGROUND: The purpose of this study is to find the optimal planning settings for prostate SABR-VMAT for high-risk prostate cancer patients irradiated to prostate only (PO) or prostate and pelvic lymph nodes (PPLN). METHODS: For 10 patients, plans using 6MV flattened, flattening-filter-free (FFF) 6MV (6 F) and FFF 10MV (10 F) photon beams with full and partial arc arrangements were generated and compared. The prescribed dose was 40Gy to the prostate with 25Gy to the PLN in 5 fractions. Plans were then evaluated for PTV coverage, dose fall-off, and OAR doses. The number of monitor units and the treatment delivery times were also compared. Statistical differences were evaluated using a paired sample Wilcoxon signed rank test with a significance level of 0.05%. RESULTS: A total of 150 plans were generated for this study. Acceptable PO plans were obtained using single arcs, while two arcs were necessary for PPLN. All plans were highly conformal (CI ≥1.3 and CN ≥0.90) with no significant differences in the PTV dose coverage. 6MV plans required significantly longer treatment time and had higher dose spillage compared to FFF plans. Superior plans were obtained using 10 F 300° partial arcs for PO with the lowest rectal dose, dose spillage and the shortest treatment times. For PPLN, 6 F and 10 F plans were equivalent. CONCLUSIONS: SABR-VMAT with FFF photon beams offers a clear benefit with respect to shorter treatment delivery times and reduced dose spillage. Class solutions using a single 10 F 300° arc for PO and two 10 F or 6 F partial 300° arcs for PPLN are proposed.

Temporal patterns of late bowel and bladder radiotherapy toxicity in a randomised controlled trial assessing duration of neo-adjuvant hormones in prostate cancer.

BACKGROUND: To assess the temporal patterns of late gastrointestinal (GI) and genitourinary (GU) radiotherapy toxicity and resolution rates in a randomised controlled trial (All-Ireland Cooperative Oncology Research Group 97-01) assessing duration of neo-adjuvant (NA) hormone therapy for localised prostate cancer. MATERIAL AND METHODS: Node negative patients with > 1 of: PSA > 20 ng/mL, Gleason score ≥ 7, and stage T3 or more, were included. Follow-up, including toxicity assessment, was three-monthly in the early stages and yearly thereafter. RESULTS: Median follow-up from the end of RT was 6.8 years. In the interval between 90 days following the end of RT and the last toxicity assessment, GI and GU toxicity (any grade) was found in 50% and 51% of 240 and 241 patients, respectively. For those who did develop toxicity, the median time from end of RT until the first development of any grade GI or GU toxicity was 1.2 years and 1.6 years, respectively, whilst median time to final resolution was 1.6 years and 2.2 years, respectively. Grade 2 (G2) or greater GI and GU toxicity occurred in 29 (12.1%) and 40 (16.6%) patients, respectively. The proportion with unresolved G2 + GI and GU toxicity was 89% and 79%, respectively, in year 1, 69% and 65% in year 2, 59% and 52% in year 3 and 27% and 32% in year 5. CONCLUSION: Long-term toxicities continue to occur many years after NA hormone therapy and RT. The rate of occurrence does not appear to reduce within the time frame during which our patients were followed. The percentage of patients suffering from G2 + toxicity at any time is however low. Resolution of these toxicities continues for the duration of the follow-up.