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Acute Toxicity and Early Patient Reported Outcomes in a Randomized Phase II Trial of High Dose-Rate Brachytherapy as Monotherapy in Low and Intermediate Risk Prostate Cancer
PROFFERED PAPER #7: OUTCOMES & TOXICITIES
Investigation into Delivered Doses for Hepatocellular Carcinoma Patients Treated with Concurrent Sorafenib and Stereotactic-Body Radiotherapy (SBRT) Jasmine Chena, Jean-Pierre Bissonnetteab, Tim Craigab, Pablo Munoza, Laura Dawsonab and Michael Veleca a - Princess Margaret Cancer Centre b - Dept. of Radiation Oncology, University of Toronto Purpose/Aim: A previous Phase I study for advanced hepatocellular carcinoma combining SBRT with the targeted therapy Sorafenib resulted in dose-limiting normal tissue toxicities. Some of these patients also exhibited large shrinkages in the liver volume after only one week of treatment. Toxicity can arise from multiple contributing factors such as the underlying patient biology, synergistic effects of combined therapies, or radiation technique. Studies have shown delivered SBRT doses to normal tissues can vary substantially compared to planned doses, which can confound interpretation of clinical outcomes. Therefore, delivered doses for this patient cohort were assessed to potentially improve the correlation of dose to toxicity outcomes. Method/Process: Fourteen patients treated on the Phase I trial described above were investigated. Prescribed doses were individualized based on liver dosimetry (range 30-54 Gy in 6 fractions) with maximal planned doses to the luminal gastrointestinal organs ranging from 31-34 Gy to 0.5 cc. Delivered doses were retrospectively recalculated on daily cone-beam CT acquired originally for image-guidance. Each cone-beam CT and associated doses were mapped back to the planning CT using deformable image registration, followed by dose summation to estimate the total delivered dose. Planned and delivered doses were compared for the normal liver volume (mean dose, and dose to 800 cc) and gastrointestinal organs (maximum dose to 0.5 cc). Results for patients with toxicities were evaluated in more detail to investigate whether higher doses than were anticipated were delivered to critical normal tissues. Results/Benefits/Challenges: The average deviation between delivered and planned doses to normal liver was 0.3 Gy or 2% (range -0.2 to 1.0 Gy [-1% to 6%]). Five patients with liver function decline at 3 months had on average higher planned and delivered doses to normal liver versus those with stable liver function (planned mean doses of 15.8 vs. 14.0 Gy , planned dose to 800cc of 16.5 vs. 7.3 Gy [p>0.05]). Five of the 14 patients (36%) had delivered dose deviations to all gastrointestinal organs within 1 Gy of the planned values and two (14%) had lower delivered doses to all organs versus planning (range -0.4 to -4.8 Gy [-3% to -16%]). The remaining seven patients (50%) had increased delivered doses to one or more organs versus planning (range 1.3 Gy to 4.4 Gy [6% to 14%]). Of the eight patients with gastrointestinal organs identified as dose-limiting at planning (planned maximum doses of 26-34 Gy), three of them received increased delivered doses as follows: small bowel increase from 34 to 36 Gy, large bowel increase from 32 to 33 Gy, and large bowel increase from 31 to 34 Gy. The first two patients also experienced serious dose-limiting gastrointestinal toxicities. Conclusion/Impact/Outcomes: Reconstruction of delivered doses was performed to increase accuracy of dosimetry estimates in an effort to interpret SBRT-related toxicities. Because delivered normal tissue doses can vary substantially, conservative approaches may be required at planning, such as the use of planning risk volumes, or during treatment delivery, such as monitoring delivered doses online. This may be particularly important when novel targeted biologic agents are used that may lead to unexpected anatomical and functional changes in critical normal tissues.
Acute Toxicity and Early Patient Reported Outcomes in a Randomized Phase II Trial of High Dose-Rate Brachytherapy as Monotherapy in Low and Intermediate Risk Prostate Cancer Gerard Mortonab, Hans Chungab, Merrylee McGuffinc, Laura D’Alimontebc, Liying Zhangd, Ananth Ravibe, Joelle Helouab and Andrew Loblawab a - Department of Radiation Oncology, Sunnybrook Health Sciences Centre
S14
b - Department of Radiation Oncology, University of Toronto c - Department of Radiation Therapy, Sunnybrook Health Sciences Centre d - Biostatistics, Sunnybrook Health Sciences Centre e - Department of Medical Physics, Sunnybrook Health Sciences Centre Purpose/Aim: High dose-rate (HDR) brachytherapy is most commonly combined with external beam radiotherapy (EBRT) to treat intermediate and high risk prostate cancer. HDR monotherapy (without EBRT) is emerging as a safe and effective alternative to low dose-rate brachytherapy for selected patients with organ-confined disease. However, there is currently no standard fractionation schedule for HDR monotherapy. Our purpose is to compare the acute effects of one vs two fractions of HDR monotherapy in the setting of a prospective randomized clinical trial. Method/Process: All participants were accrued from a single metropolitan cancer centre in Ontario. Eligible participants had stage T1c/T2a adenocaricoma of the prostate, Gleason 6/7, PSA <20 ng/ml and prostate volume <60cc. Consenting participants were randomly assigned to receive either one 19Gy fraction (Arm1) or two 13.5Gy fractions (Arm2) of HDR delivered using an outpatient ultrasound-based technique. Assessments were completed using CTCAE v4 and the International Prostate Symptom Score (IPSS) at baseline, 6 and 12 weeks post-treatment. Results/Benefits/Challenges: 170 participants were accrued, 87 randomized to Arm1 and 83 to Arm2. Median age of participants was 65, median prostate volume was 35cc and the majority of patients were classified as intermediate risk (77%). The highest acute GI toxicity was Grade2 with only 4 patients (2.4%) experiencing any Grade2 GI toxicity. The highest acute GU toxicity was Grade3 with a single patient experiencing hematuria requiring bladder irrigation. The most common Grade2 GU toxicities were retention (50%) and frequency (21%). There was no significant difference between treatment arms for any acute GI or GU toxicities. A significant association was found between prostate volume and Grade2 urinary retention (p¼0.0036). Mean IPSS scores were significantly different from baseline at week 6 (5.5vs10.4,p<0.001) and week 12 (5.5vs7.4,p<0.001). When compared between treatment arms, IPSS scores were significantly higher in Arm2 (p¼0.036). Conclusion/Impact/Outcomes: Overall, both fractionation schedules were well tolerated with minimal acute GI and GU toxicities experienced by participants. Patients in Arm2 reported more acute urinary symptoms with significantly higher IPSS scores. These patients continue on long-term follow-up to determine late effects and outcomes of one and two fraction HDR monotherapy.
Patient-reported Adverse Events Following Trans-rectal Ultrasound-guided Intra-prostatic Marker Insertion Tara Rosewallab, Andrew Bayleyab, Peter Chungab and Charles Cattonab a - Princess Margaret Cancer Centre b - Department of Radiation Oncology, University of Toronto Purpose/Aim: Significant improvements in the precision of radiotherapy delivery have been made using radio-opaque intra-prostatic markers (IPM). Despite widespread clinical implementation, there is little information available on the frequency and severity of adverse events associated with IPM insertion. The purpose of this study was to quantify patient-reported adverse events following ultrasound-guided, trans-rectal implantation of IPM and to determine the factors that may influence the frequency and severity of those adverse events. Method/Process: A cohort of 100 prostate cancer patients was prospectively accrued. Procedural parameters that may be associated with the risk of adverse events were documented in a data collection form by the interventional radiologist immediately after the IPM insertion. All patients completed an adverse events questionnaire immediately after IPM insertion and approximately 3 to 5 days later. Results/Benefits/Challenges: All patients were successfully implanted with 3 IPM following a course of prophylactic antibiotics. Local anaesthetic was used in only 2% of patients, and the radiologist reported that only 4% of patients complained of pain. Conversely, 49% of patients reported that the procedure
Conference Proceedings from RTi3 2017/Journal of Medical Imaging and Radiation Sciences 48 (2017) S1-S22
Investigation into Delivered Doses for Hepatocellular Carcinoma Patients Treated with Concurrent Sorafenib and Stereotactic-Body Radiotherapy (SBRT) Jasmine Chena, Jean-Pierre Bissonnetteab, Tim Craigab, Pablo Munoza, Laura Dawsonab and Michael Veleca a - Princess Margaret Cancer Centre b - Dept. of Radiation Oncology, University of Toronto Purpose/Aim: A previous Phase I study for advanced hepatocellular carcinoma combining SBRT with the targeted therapy Sorafenib resulted in dose-limiting normal tissue toxicities. Some of these patients also exhibited large shrinkages in the liver volume after only one week of treatment. Toxicity can arise from multiple contributing factors such as the underlying patient biology, synergistic effects of combined therapies, or radiation technique. Studies have shown delivered SBRT doses to normal tissues can vary substantially compared to planned doses, which can confound interpretation of clinical outcomes. Therefore, delivered doses for this patient cohort were assessed to potentially improve the correlation of dose to toxicity outcomes. Method/Process: Fourteen patients treated on the Phase I trial described above were investigated. Prescribed doses were individualized based on liver dosimetry (range 30-54 Gy in 6 fractions) with maximal planned doses to the luminal gastrointestinal organs ranging from 31-34 Gy to 0.5 cc. Delivered doses were retrospectively recalculated on daily cone-beam CT acquired originally for image-guidance. Each cone-beam CT and associated doses were mapped back to the planning CT using deformable image registration, followed by dose summation to estimate the total delivered dose. Planned and delivered doses were compared for the normal liver volume (mean dose, and dose to 800 cc) and gastrointestinal organs (maximum dose to 0.5 cc). Results for patients with toxicities were evaluated in more detail to investigate whether higher doses than were anticipated were delivered to critical normal tissues. Results/Benefits/Challenges: The average deviation between delivered and planned doses to normal liver was 0.3 Gy or 2% (range -0.2 to 1.0 Gy [-1% to 6%]). Five patients with liver function decline at 3 months had on average higher planned and delivered doses to normal liver versus those with stable liver function (planned mean doses of 15.8 vs. 14.0 Gy , planned dose to 800cc of 16.5 vs. 7.3 Gy [p>0.05]). Five of the 14 patients (36%) had delivered dose deviations to all gastrointestinal organs within 1 Gy of the planned values and two (14%) had lower delivered doses to all organs versus planning (range -0.4 to -4.8 Gy [-3% to -16%]). The remaining seven patients (50%) had increased delivered doses to one or more organs versus planning (range 1.3 Gy to 4.4 Gy [6% to 14%]). Of the eight patients with gastrointestinal organs identified as dose-limiting at planning (planned maximum doses of 26-34 Gy), three of them received increased delivered doses as follows: small bowel increase from 34 to 36 Gy, large bowel increase from 32 to 33 Gy, and large bowel increase from 31 to 34 Gy. The first two patients also experienced serious dose-limiting gastrointestinal toxicities. Conclusion/Impact/Outcomes: Reconstruction of delivered doses was performed to increase accuracy of dosimetry estimates in an effort to interpret SBRT-related toxicities. Because delivered normal tissue doses can vary substantially, conservative approaches may be required at planning, such as the use of planning risk volumes, or during treatment delivery, such as monitoring delivered doses online. This may be particularly important when novel targeted biologic agents are used that may lead to unexpected anatomical and functional changes in critical normal tissues.
Acute Toxicity and Early Patient Reported Outcomes in a Randomized Phase II Trial of High Dose-Rate Brachytherapy as Monotherapy in Low and Intermediate Risk Prostate Cancer Gerard Mortonab, Hans Chungab, Merrylee McGuffinc, Laura D’Alimontebc, Liying Zhangd, Ananth Ravibe, Joelle Helouab and Andrew Loblawab a - Department of Radiation Oncology, Sunnybrook Health Sciences Centre
S14
b - Department of Radiation Oncology, University of Toronto c - Department of Radiation Therapy, Sunnybrook Health Sciences Centre d - Biostatistics, Sunnybrook Health Sciences Centre e - Department of Medical Physics, Sunnybrook Health Sciences Centre Purpose/Aim: High dose-rate (HDR) brachytherapy is most commonly combined with external beam radiotherapy (EBRT) to treat intermediate and high risk prostate cancer. HDR monotherapy (without EBRT) is emerging as a safe and effective alternative to low dose-rate brachytherapy for selected patients with organ-confined disease. However, there is currently no standard fractionation schedule for HDR monotherapy. Our purpose is to compare the acute effects of one vs two fractions of HDR monotherapy in the setting of a prospective randomized clinical trial. Method/Process: All participants were accrued from a single metropolitan cancer centre in Ontario. Eligible participants had stage T1c/T2a adenocaricoma of the prostate, Gleason 6/7, PSA <20 ng/ml and prostate volume <60cc. Consenting participants were randomly assigned to receive either one 19Gy fraction (Arm1) or two 13.5Gy fractions (Arm2) of HDR delivered using an outpatient ultrasound-based technique. Assessments were completed using CTCAE v4 and the International Prostate Symptom Score (IPSS) at baseline, 6 and 12 weeks post-treatment. Results/Benefits/Challenges: 170 participants were accrued, 87 randomized to Arm1 and 83 to Arm2. Median age of participants was 65, median prostate volume was 35cc and the majority of patients were classified as intermediate risk (77%). The highest acute GI toxicity was Grade2 with only 4 patients (2.4%) experiencing any Grade2 GI toxicity. The highest acute GU toxicity was Grade3 with a single patient experiencing hematuria requiring bladder irrigation. The most common Grade2 GU toxicities were retention (50%) and frequency (21%). There was no significant difference between treatment arms for any acute GI or GU toxicities. A significant association was found between prostate volume and Grade2 urinary retention (p¼0.0036). Mean IPSS scores were significantly different from baseline at week 6 (5.5vs10.4,p<0.001) and week 12 (5.5vs7.4,p<0.001). When compared between treatment arms, IPSS scores were significantly higher in Arm2 (p¼0.036). Conclusion/Impact/Outcomes: Overall, both fractionation schedules were well tolerated with minimal acute GI and GU toxicities experienced by participants. Patients in Arm2 reported more acute urinary symptoms with significantly higher IPSS scores. These patients continue on long-term follow-up to determine late effects and outcomes of one and two fraction HDR monotherapy.
Patient-reported Adverse Events Following Trans-rectal Ultrasound-guided Intra-prostatic Marker Insertion Tara Rosewallab, Andrew Bayleyab, Peter Chungab and Charles Cattonab a - Princess Margaret Cancer Centre b - Department of Radiation Oncology, University of Toronto Purpose/Aim: Significant improvements in the precision of radiotherapy delivery have been made using radio-opaque intra-prostatic markers (IPM). Despite widespread clinical implementation, there is little information available on the frequency and severity of adverse events associated with IPM insertion. The purpose of this study was to quantify patient-reported adverse events following ultrasound-guided, trans-rectal implantation of IPM and to determine the factors that may influence the frequency and severity of those adverse events. Method/Process: A cohort of 100 prostate cancer patients was prospectively accrued. Procedural parameters that may be associated with the risk of adverse events were documented in a data collection form by the interventional radiologist immediately after the IPM insertion. All patients completed an adverse events questionnaire immediately after IPM insertion and approximately 3 to 5 days later. Results/Benefits/Challenges: All patients were successfully implanted with 3 IPM following a course of prophylactic antibiotics. Local anaesthetic was used in only 2% of patients, and the radiologist reported that only 4% of patients complained of pain. Conversely, 49% of patients reported that the procedure
Conference Proceedings from RTi3 2017/Journal of Medical Imaging and Radiation Sciences 48 (2017) S1-S22