Publications by authors named "Danny Vesprini"

90 Publications

Gantry-based 5-fraction Elective Nodal Irradiation in Unfavorable-Risk Prostate Cancer: Outcomes from 2 Prospective Studies comparing SABR Boost with MR Dose Painted HDR Brachytherapy Boost.

Int J Radiat Oncol Biol Phys 2021 Oct 9. Epub 2021 Oct 9.

Odette Cancer Centre, Sunnybrook Health Sciences Centre; Department of Radiation Oncology, University of Toronto; Institute of Health Policy, Management and Evaluation. Electronic address:

Background: ASCO/CCO guidelines recommend brachytherapy boost for intermediate-risk (IR) or high-risk (HR) prostate cancer (PCa) patients. Stereotactic ablative body radiotherapy (SABR) is an emerging technique for PCa but its use in HR disease is limited. We compare efficacy, toxicity, and quality-of-life (QoL) in patients treated on 2 prospective protocols that used SABR boost or MR-guided HDR brachytherapy boost (MR-HDR) with 6-18 months of androgen deprivation therapy (ADT).

Methods: In XXXXXX study (study 1), patients received 40Gy to prostate and 25Gy to pelvis in 5 weekly fractions. In XXXXXX (study 2), patients received HDR-BT 15Gy x 1 to the prostate and ≤22.5Gy to the MRI nodule, followed by 25Gy in 5 weekly fractions to pelvis. All patients received between 6 and 18 months of androgen deprivation therapy.

Results: Thirty patients (NCCN 7% unfavorable IR, and 93% HR) completed study 1 while 31 patients (NCCN 3% favorable IR, 47% Unfavorable IR and 50% HR) completed treatment as per study 2. Median follow-up was 72 and 62 months, respectively. In study 2, 6 patients had BF and all 6 developed metastatic disease. Actuarial 5-year BF was 0% for study 1 and 18.2% for study 2 (p=0.005). There was no significant difference in worst acute or late GI or GU toxicity. Grade 3 late GU toxicity was noted in 3% of the patients in study 2 (HDR-BT boost). There was no significant difference in QoL or minimally clinical important change.

Conclusions: In the context of 5-fraction pelvic radiotherapy and ADT, there does not appear to be a significant difference in toxicity or QoL between SABR vs. HDR BT boost. While efficacy favored the SABR boost cohort, this should be viewed in the context of limitations and biases associated with comparing two sequential phase II studies.
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http://dx.doi.org/10.1016/j.ijrobp.2021.10.003DOI Listing
October 2021

Factors Associated with Time to Conversion from Active Surveillance to Treatment for Prostate Cancer in a Multi-Institutional Cohort.

J Urol 2021 11 10;206(5):1147-1156. Epub 2021 Sep 10.

Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Purpose: We examined the demographic and clinicopathological parameters associated with the time to convert from active surveillance to treatment among men with prostate cancer.

Materials And Methods: A multi-institutional cohort of 7,279 patients managed with active surveillance had data and biospecimens collected for germline genetic analyses.

Results: Of 6,775 men included in the analysis, 2,260 (33.4%) converted to treatment at a median followup of 6.7 years. Earlier conversion was associated with higher Gleason grade groups (GG2 vs GG1 adjusted hazard ratio [aHR] 1.57, 95% CI 1.36-1.82; ≥GG3 vs GG1 aHR 1.77, 95% CI 1.29-2.43), serum prostate specific antigen concentrations (aHR per 5 ng/ml increment 1.18, 95% CI 1.11-1.25), tumor stages (cT2 vs cT1 aHR 1.58, 95% CI 1.41-1.77; ≥cT3 vs cT1 aHR 4.36, 95% CI 3.19-5.96) and number of cancerous biopsy cores (3 vs 1-2 cores aHR 1.59, 95% CI 1.37-1.84; ≥4 vs 1-2 cores aHR 3.29, 95% CI 2.94-3.69), and younger age (age continuous per 5-year increase aHR 0.96, 95% CI 0.93-0.99). Patients with high-volume GG1 tumors had a shorter interval to conversion than those with low-volume GG1 tumors and behaved like the higher-risk patients. We found no significant association between the time to conversion and self-reported race or genetic ancestry.

Conclusions: A shorter time to conversion from active surveillance to treatment was associated with higher-risk clinicopathological tumor features. Furthermore, patients with high-volume GG1 tumors behaved similarly to those with intermediate and high-risk tumors. An exploratory analysis of self-reported race and genetic ancestry revealed no association with the time to conversion.
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http://dx.doi.org/10.1097/JU.0000000000001937DOI Listing
November 2021

Elective nodal ultra hypofractionated radiation for prostate cancer: Safety and efficacy from four prospective clinical trials.

Radiother Oncol 2021 Sep 4;163:159-164. Epub 2021 Sep 4.

Odette Cancer Centre, Sunnybrook Health Sciences Centre, Canada; Department of Radiation Oncology, University of Toronto, Canada; Institute of Health Policy, Management and Evaluation, Canada. Electronic address:

Background And Purpose: The role of elective nodal irradiation (ENI) in localized prostate cancer (PCa) is controversial. With increasing use of SBRT to the prostate, data is needed regarding the safety and efficacy of ENI using ultra-hypofractionated radiation (UHRT).

Materials And Methods: Between 2013-2020, 4 prospective clinical trials of intermediate or high-risk PCa receiving dose-escalated RT to the prostate (via HDR brachytherapy or SBRT boost) and ENI using UHRT (25 Gy in 5 weekly fractions) were conducted. Primary endpoints included acute genitourinary and gastrointestinal toxicities (CTCAE v3.0/4.0), and secondary endpoints included late genitourinary and gastrointestinal toxicities, patient-reported quality of life (EPIC) and biochemical failure (Phoenix definition).

Results: One-hundred sixty-five patients were enrolled, of whom 98 (59%) had high-risk disease. ADT was used in 141 (85%). Median follow-up was 38 months (IQR 10-63). The worst acute genitourinary and gastrointestinal toxicities respectively were 48% and 7.5% for grade 2, and 2.7% and 0% for grade 3. Cumulative incidence of late grade 2+ genitourinary and gastrointestinal toxicities at 36 months were 58% and 11.3% and for late grade 3+ toxicities were 1% and 0%, respectively. No grade 4+ acute or late toxicities were observed. Bowel and sexual toxicity significantly worsened up to 1-year compared to baseline. Over time, urinary (p < 0.0001), bowel (p = 0.0018) and sexual (p < 0.0001) scores significantly improved. The 3-year biochemical recurrence-free survival was 98%.

Conclusion: ENI using UHRT is associated with low incidence of grade 3+ toxicity, while grade 1-2 acute genitourinary and gastrointestinal toxicity is common. Randomized phase 3 trials are needed.
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http://dx.doi.org/10.1016/j.radonc.2021.08.017DOI Listing
September 2021

Why do Older Women Avoid Breast Cancer Surgery? A Qualitative Analysis of Decision-making Factors.

J Surg Res 2021 Aug 30;268:623-633. Epub 2021 Aug 30.

Department of Surgery, University of Toronto, Toronto, Ontario, Canada; Division of Surgical Oncology, Department of Surgery, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. Electronic address:

Background: Few studies have explored why older women (≥70 years old) avoid breast cancer surgery. This study aimed to identify physician- and patient-perceived attitudes that influence the decision to avoid surgery among older women with invasive breast cancer.

Methods: Semi-structured in-depth interviews were conducted with multidisciplinary breast cancer specialists and older women (≥70 years old) with breast cancer who declined surgery. Transcripts were iteratively coded using a theoretical framework to guide identification of common themes. Thematic comparison was performed between patients and physicians.

Results: Ten breast cancer specialists and eleven patients participated. Physicians believed older women declined surgery because they did not perceive breast cancer as a life-threatening ailment compared to other medical comorbidities. Physicians did not discuss breast reconstruction, as it was perceived to be unimportant. Treatment side effects, length of treatment, impact on quality of life, and minimal survival benefit strongly influenced patients' decision to decline surgery. Patients valued independence and quality of life over quantity of life. Patients felt empowered to participate in the decision-making process but appreciated having support. Both phyisicians and patients had congruent beliefs with respect to age impacting treatment decision, cosmesis playing a minor factor in treatment decisions, and importance of quality of life; however, they were discordant in their perceptions about the amount of support that patients have from their families.

Conclusions: The decision to avoid surgery in older women stems from a variety of individual beliefs. Acknowledging patient values early in treatment planning may facilitate a patient-centered approach to the decision-making process.
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http://dx.doi.org/10.1016/j.jss.2021.06.088DOI Listing
August 2021

Proteomic discovery of non-invasive biomarkers of localized prostate cancer using mass spectrometry.

Nat Rev Urol 2021 Aug 27. Epub 2021 Aug 27.

Department of Medical Biophysics, University of Toronto, Toronto, Canada.

Prostate cancer is the second most frequently diagnosed non-skin cancer in men worldwide. Patient outcomes are remarkably heterogeneous and the best existing clinical prognostic tools such as International Society of Urological Pathology Grade Group, pretreatment serum PSA concentration and T-category, do not accurately predict disease outcome for individual patients. Thus, patients newly diagnosed with prostate cancer are often overtreated or undertreated, reducing quality of life and increasing disease-specific mortality. Biomarkers that can improve the risk stratification of these patients are, therefore, urgently needed. The ideal biomarker in this setting will be non-invasive and affordable, enabling longitudinal evaluation of disease status. Prostatic secretions, urine and blood can be sources of biomarker discovery, validation and clinical implementation, and mass spectrometry can be used to detect and quantify proteins in these fluids. Protein biomarkers currently in use for diagnosis, prognosis and relapse-monitoring of localized prostate cancer in fluids remain centred around PSA and its variants, and opportunities exist for clinically validating novel and complimentary candidate protein biomarkers and deploying them into the clinic.
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http://dx.doi.org/10.1038/s41585-021-00500-1DOI Listing
August 2021

Randomized Phase III Trial Evaluating Radiation Following Surgical Excision for Good-Risk Ductal Carcinoma In Situ: Long-Term Report From NRG Oncology/RTOG 9804.

J Clin Oncol 2021 Aug 18:JCO2101083. Epub 2021 Aug 18.

Ohio State University Comprehensive Cancer Center, Columbus, OH.

Purpose: To our knowledge, NRG/RTOG 9804 is the only randomized trial to assess the impact of whole breast irradiation (radiation therapy [RT]) versus observation (OBS) in women with good-risk ductal carcinoma in situ (DCIS), following lumpectomy. Long-term results focusing on ipsilateral breast recurrence (IBR), the primary outcome, are presented here.

Patients And Methods: Eligible patients underwent lumpectomy for DCIS that was mammogram detected, size ≤ 2.5 cm, final margins ≥ 3 mm, and low or intermediate nuclear grade. Consented patients were randomly assigned to RT or OBS. Tamoxifen use was optional. Cumulative incidence was used to estimate IBR, log-rank test and Gray's test to compare treatments, and Fine-Gray regression for hazard ratios (HRs).

Results: A total of six hundred thirty-six women were randomly assigned from 1999 to 2006. Median age was 58 years and mean pathologic DCIS size was 0.60 cm. Intention to use tamoxifen was balanced between arms (69%); however, actual receipt of tamoxifen varied, 58% RT versus 66% OBS ( = .05). At 13.9 years' median follow-up, the 15-year cumulative incidence of IBR was 7.1% (95% CI, 4.0 to 11.5) with RT versus 15.1% (95% CI, 10.8 to 20.2) OBS ( = .0007; HR = 0.36; 95% CI, 0.20 to 0.66); and for invasive LR was 5.4% (95% CI, 2.7 to 9.5) RT versus 9.5% (95% CI, 6.0 to 13.9) OBS ( = .027; HR = 0.44; 95% CI, 0.21 to 0.91). On multivariable analysis, only RT (HR = 0.34; 95% CI, 0.19 to 0.64; = .0007) and tamoxifen use (HR = 0.45; 95% CI, 0.25 to 0.78; = .0047) were associated with reduced IBR.

Conclusion: RT significantly reduced all and invasive IBR for good-risk DCIS with durable results at 15 years. These results are not an absolute indication for RT but rather should inform shared patient-physician treatment decisions about ipsilateral breast risk reduction in the long term following lumpectomy.
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http://dx.doi.org/10.1200/JCO.21.01083DOI Listing
August 2021

Elective pelvic nodal irradiation with a simultaneous hypofractionated integrated prostate boost for localized high risk prostate cancer: Long term results from a prospective clinical trial.

Radiother Oncol 2021 Jul 26;163:21-31. Epub 2021 Jul 26.

Department of Radiation Oncology, University of Toronto, Canada; Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Canada. Electronic address:

Background: To report on long-term results of elective pelvic nodal irradiation (EPNI) and a simultaneous hypofractionated prostate boost for high-risk prostate cancer.

Materials And Methods: This was a prospective single-arm study. Patients with high-risk disease (cT3, PSA >20 ng/mL, or Gleason score 8-10) were eligible. Patients received 45 Gy in 25 fractions to the prostate and pelvic lymph nodes with a simultaneous intensity-modulated radiotherapy boost of 22.5 Gy to the prostate (total dose 67.5 Gy in 25 fractions), with androgen deprivation therapy (ADT) for 2-3 years. The primary endpoint was biochemical failure. Secondary endpoints included distant metastases and overall survival. Multivariable analysis was performed to look for predictive factors. Late toxicity was assessed using CTCAE v3.0.

Results: 230 patients enrolled. Median follow-up was 11.2 years (IQR 8.1-12.9). At 10 years, cumulative incidence of biochemical failure was 33.4%, distant metastasis was 16.5%, and overall survival was 76.3%. On multivariable analysis, PSA nadir ≥0.05 ng/mL was associated with biochemical failure (HR 6.8, 95% CI 4-11.8, p < 0.001) and distant metastases (HR 7.5, 95% CI 3.9-14.5, p < 0.0001). PSA nadir ≥0.1 ng/mL (HR 5.2, 95% 2.2-12, p = 0.0001) and ADT use ≤12 months (versus >24 months) (HR 2.3, 95% CI 1.3-3.9, p = 0.004) were associated with worse survival. The 5-year cumulative incidence of any late grade ≥3 gastrointestinal and genitourinary toxicity was 2.3% and 7.5%, respectively.

Conclusion: EPNI and a simultaneous hypofractionated prostate boost combined with long-term ADT for high-risk prostate cancer resulted in acceptable 10-year biochemical control and survival with low grade ≥3 toxicity.
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http://dx.doi.org/10.1016/j.radonc.2021.07.018DOI Listing
July 2021

The evolving role of germline genetic testing and management in prostate cancer: Report from the Princess Margaret Cancer Centre International Retreat.

Can Urol Assoc J 2021 Jun 22. Epub 2021 Jun 22.

Division of Urology, University Health Network, Toronto, ON, Canada.

Introduction: Prostate cancer is a significant cause of cancer mortality. It has been well-established that certain germline pathogenic variants confer both an increased risk of being diagnosed with prostate cancer and dying of prostate cancer. There are exciting developments in both the availability of genetic testing and opportunities for improved treatment of patients. On August 19, 2020, the Princess Margaret Cancer Centre in Toronto, Ontario, hosted a virtual retreat, bringing together international experts in urology, medical oncology, radiation oncology, medical genetics, and translational research, as well as a patient representative. We are pleased to provide this manuscript as a review of those proceedings for Canadian clinicians.

Recommendations: We drafted several recommendations for future research and policy action based on this meeting:Need for increased access to funding for germline testing for the common genetic disorders associated with increased risk of prostate cancer.A need for increased research into identifying genetic factors influencing risk stratification, treatment response, and outcomes of prostate cancer within Canadian populations at increased genetic risk for prostate cancer.Need for increased awareness about genetic risk factors among the Canadian public.Need for research on patient perspectives and psychosocial outcomes in individuals identified to be at increased genetic risk of prostate cancer.We support the creation of specialized multidisciplinary clinics that specialize in tailored care for patients at increased genetic risk of prostate cancer.
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http://dx.doi.org/10.5489/cuaj.7383DOI Listing
June 2021

Three-antibody classifier for muscle invasive urothelial carcinoma and its correlation with p53 expression.

J Clin Pathol 2021 Jun 8. Epub 2021 Jun 8.

Division of Anatomic Pathology, Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada

Aims: To assess the utility of a three-antibody immunohistochemistry panel to classify muscle invasive bladder cancers (MIBCs) in correlation with morphological features and p53 status.

Methods: A retrospective review of 243 chemotherapy naïve MIBC cystectomy specimens was performed to assess morphological features. A tissue microarray was sequentially stained with CK5/6, GATA-3 and p16. Subgroups were assigned as basal-like (CK5/6+, GATA3-) and luminal (CK5/6-, GATA3+), with the latter subdivided into genomically unstable (GU, p16+) and urothelial like (Uro, p16-) subgroups. p53 staining was assessed as abnormal/wild type. Cases from the The Cancer Genome Atlas (TCGA) portal were assessed as external validation.

Results: We identified 78.8% luminal, 21.2% basal cases within our cohort and 63.4% luminal, 36.6% basal in the TCGA dataset. Divergent differentiation (p<0.001) was significantly associated with basal-subtype cases in both cohorts. Within the luminal subgroup (n=186), 81 cases were classified as GU and 105 as Uro. Abnormal p53 staining was noted in 48.0% of basal, 80.2% GU and 38.1% Uro cases. Further, basal-subtype tumours significantly correlated with disease-specific death compared with Uro cases in multivariate survival analysis.

Conclusions: This retrospective study demonstrates the potential utility of a three-antibody immunohistochemistry panel to differentiate luminal and basal MIBC.
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http://dx.doi.org/10.1136/jclinpath-2021-207573DOI Listing
June 2021

Stereotactic pelvic radiotherapy with HDR boost for dose escalation in intermediate and high-risk prostate cancer (SPARE): Efficacy, toxicity and quality of life.

Radiother Oncol 2021 08 3;161:40-46. Epub 2021 Jun 3.

Odette Cancer Centre, Sunnybrook Health Sciences Centre, Canada; Department of Radiation Oncology, University of Toronto, Canada; Institute of Health Policy, Management and Evaluation, Canada. Electronic address:

Background: The ASCO/CCO guidelines recommend brachytherapy (BT) boost for eligible intermediate- (IR) or high-risk (HR) prostate cancer (PCa) patients. We present efficacy, toxicity and quality-of-life (QoL) outcomes in patients treated on a prospective protocol of MRI dose-painted high-dose-rate BT boost (HDR-BT) followed by 5-fraction pelvic radiotherapy (RT) and 6-18 months of androgen deprivation therapy (ADT).

Methods: In this phase I/II study, IR or HR PCa patients received HDR-BT 15 Gy × 1 to prostate and up to 22.5 Gy to MRI nodule, followed by 25 Gy in 5, weekly fractions to pelvis. Toxicity was assessed using CTCAEv3.0, and QoL was captured using EPIC questionnaire. Biochemical failure (BF; nadir + 2.0), and proportion of patients with PSA < 0.4 ng/ml at 4-years (4yPSARR) were evaluated. A minimally clinically important change (MCIC) was recorded if QoL score decreased >0.5 standard deviation of baseline scores.

Results: Thirty-one patients (NCCN 3.2% favorable IR, 48.4% unfavorable IR and 48.4% HR) completed treatment with a median follow-up of 61 months. Median D90 to MR nodule was 19.0 Gy and median prostate V100% was 96.5%. The actuarial 5-year BF rate was 18.2%, and the 4yPSARR was 71%. One patient died of PCa. Acute grade 2 and 3 toxicities: GU: 50%, 7%, and GI: 3%, none, respectively. Late grade 2 and 3 toxicities were: GU: 23%, 3%, and GI: 7%, none, respectively. Proportion of patients with MCIC was 7.7% for urinary domain and 32.0% for bowel domain.

Conclusions: This novel treatment protocol incorporating MRI dose-painted HDR-BT boost and 5-fraction pelvic RT with ADT is well tolerated.
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http://dx.doi.org/10.1016/j.radonc.2021.05.024DOI Listing
August 2021

Can immune markers help identify fast relapse in patients with muscle invasive bladder cancer?

Pathol Res Pract 2020 Nov 5;216(11):153200. Epub 2020 Sep 5.

Division of Anatomic Pathology, Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Electronic address:

The aim of this pilot study was to assess the role of immune markers in fast relapse (<2 years) of high-grade muscle invasive urothelial carcinomas of the bladder (HGUC) treated by cystectomy. A series of 40 such cases was investigated for immune protein (CD3, CD4, CD8, CD20, CD68, CD163, FOXP3 and PD-1) status by immunohistochemistry. Decreased expression of all immune cell markers was observed in tumors of patients who relapsed quickly. In Kaplan-Meier (log-rank test) analysis, low CD3, CD4 and CD8 expression was associated with fast relapse (P = 0.005, 0.028, 0.036 respectively). Additional evaluation of the immune transcriptome by NanoString Human PanCancer Immune Panel v.1.1 has identified 5 differentially expressed genes significantly associated with fast relapse. Among these, KLRB1 and HLA-DQA1 were also significant on Kaplan-Meier analysis (log-rank test P = 0.007 and 0.006, respectively). These findings strengthen the potential clinical utility and, hence, the need for further evaluation of immune markers in HGUC prognostication.
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http://dx.doi.org/10.1016/j.prp.2020.153200DOI Listing
November 2020

When to biopsy Prostate Imaging and Data Reporting System version 2 (PI-RADSv2) assessment category 3 lesions? Use of clinical and imaging variables to predict cancer diagnosis at targeted biopsy.

Can Urol Assoc J 2021 Apr;15(4):115-121

Division of Urology, Department of Surgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.

Introduction: We aimed to determine if clinical and imaging features can stratify men at higher risk for clinically significant (CS, International Society of Urological Pathology [ISUP] grade group ≥2) prostate cancer (PCa) in equivocal Prostate Imaging and Data Reporting System (PI-RADS) category 3 lesions on magnetic resonance imaging (MRI).

Methods: Approved by the institutional review board, this retrospective study involved 184 men with 198 lesions who underwent 3T-MRI and MRI-directed transrectal ultrasound biopsy for PI-RADS 3 lesions. Men were evaluated including clinical stage, prostate-specific antigen density (PSAD), indication, and MRI lesion size. Diagnoses for all men and by indication (no cancer, any PCa, CSPCa) were compared using multivariate logistic regression, including stage, PSAD, and lesion size.

Results: We found an overall PCa rate of 31.8% (63/198) and 10.1% (20/198) CSPCa (13 grade group 2, five group 3, and two group 4). Higher stage (p=0.001), PSAD (p=0.007), and lesion size (p=0.015) were associated with CSPCa, with no association between CSPCa and age, PSA, or prostate volume (p>0.05). PSAD modestly predicted CSPCa area under the curve (AUC) 0.66 (95% confidence interval [CI] 0.518-0.794) in all men and 0.64 (0.487-0.799) for those on active surveillance (AS). Model combining clinical stage, PSAD, and lesion size improved accuracy for all men and AS (AUC 0.82 [0.736-0.910], p<0.001 and 0.785 [0.666-0.904], p<0.001). In men with prior negative biopsy and persistent suspicion, PSAD (0.90 [0.767-1.000]) was not different from the model (p>0.05), with optimal cutpoint of ≥0.215 ng/mL/cc achieving sensitivity/specificity of 85.7/84.4%.

Conclusions: PI-RADSv2 category 3 lesions are often not CSPCa. PSAD predicted CSPCa in men with a prior negative biopsy; however, PSAD alone had limited value, and accuracy improved when using a model incorporating PSAD with clinical stage and MRI lesion size.
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http://dx.doi.org/10.5489/cuaj.6781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021423PMC
April 2021

A Feasibility Study of Mepitel Film for the Prevention of Breast Radiation Dermatitis in a Canadian Center.

Pract Radiat Oncol 2021 Jan-Feb;11(1):e36-e45. Epub 2020 Sep 17.

Sunnybrook Health Sciences Center, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Purpose: Severe radiation dermatitis (RD) is distressing and may have adverse long-term effects including fibrosis and telangiectasia. Treatment interruptions due to severe RD may increase the risk of recurrence. Two randomized trials of Mepitel film demonstrated efficacy in preventing severe RD in breast cancer, but this product has not been widely adopted in North America. We aimed to assess the feasibility and efficacy of Mepitel film for prevention of breast RD at a Canadian center.

Methods And Materials: Patients were stratified based on breast size and receipt of postmastectomy radiation therapy. The primary outcome was RD grade using the Common Terminology Criteria for Adverse Events. Secondary outcomes included moist desquamation, patient- and clinician-reported symptoms of skin toxicity, and cosmetic outcomes.

Results: Thirty patients receiving external beam radiation therapy to the breast or chest wall were enrolled. Two patients (6.7%) discontinued use of the Mepitel film before completing radiation therapy. No patients developed grade 3 RD or higher. Five patients (17.9%) developed grade 2 RD: 3 (10.7%) had moist desquamation, and 2 (7.1%) had brisk erythema without moist desquamation.

Conclusions: Mepitel film completely prevented grade 3 RD. Rates of moist desquamation and grade 2 RD were lower with Mepitel film than in studies using aqueous cream, but unlike previous trials of Mepitel film we did not achieve complete prevention of moist desquamation. Further research is needed to confirm the efficacy of Mepitel film versus standard prophylaxis for RD and identify the patients who will benefit the most from the film.
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http://dx.doi.org/10.1016/j.prro.2020.09.004DOI Listing
August 2021

Reassessment of p53 immunohistochemistry thresholds in invasive high grade bladder cancer shows a better correlation with TP53 and FGFR3 mutations.

Pathol Res Pract 2020 Nov 23;216(11):153186. Epub 2020 Aug 23.

Division of Anatomic Pathology, Department of Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. Electronic address:

FGFR3 mutations are frequently mutually exclusive of TP53 mutations in invasive high grade urothelial carcinoma (HGUC) and p53 immunohistochemistry is often used as a surrogate for TP53 mutations. A 10 % staining cut off has been used in HGUC for designation as p53 positive or negative however, a novel contemporary method we have previously proposed (0% or >50 % - abnormal vs. 1-49 % - wild type) has shown significant correlation with oncologic outcome as well. We aimed to compare how a ≥10 % vs. 0 % and ≥ 50 % cut off p53 assessment method correlates with TP53 and FGFR3 mutation status. Tissue microarrays created from three retrospective cohorts (two cystectomy cohorts (cohort A, n = 206 and cohort B, n = 91; one T1 transurethral resection cohort (cohort C, n = 47)) were stained with p53 and scored by two blinded reviewers using both p53 scoring schemes. 50 cases from cohort A were assessed for TP53 and FGFR3 mutation status using next generation sequencing and FGFR3 mutation status was separately assessed in cohorts B and C using SNaPshot methodology. 202 (58.7 %) and 142 (41.3 %) cases showed abnormal and wild type p53 staining, respectively. Using the 10 % cut off, 254 cases were positive (73.8 %) and 90 cases were negative (26.2 %). 27 (14.4 %) and 15 (30 %) assessed cases demonstrated FGFR3 and TP53 mutations, respectively; 19/27 FGFR3 mutated showed a wild type pattern of p53 expression while 15/15 TP53 mutated tumours showed an abnormal pattern of p53 expression. There was a significant correlation between the contemporary p53 scoring scheme and TP53 and FGFR3 mutations (p < 0.0001 and p = 0.002, respectively). Improved sensitivity, specificity, positive predictive value, and negative predictive value for TP53 mutation was also seen compared to the 10 % cut off; specifically, the sensitivity and negative predictive value were 100 %. These findings might be of clinical relevance in the era of precision medicine.
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http://dx.doi.org/10.1016/j.prp.2020.153186DOI Listing
November 2020

Optimizing MR-Guided Radiotherapy for Breast Cancer Patients.

Front Oncol 2020 28;10:1107. Epub 2020 Jul 28.

Department of Radiotherapy, Royal Marsden NHS Foundation Trust and Institute of Cancer Research, Sutton, United Kingdom.

Current research in radiotherapy (RT) for breast cancer is evaluating neoadjuvant as opposed to adjuvant partial breast irradiation (PBI) with the aim of reducing the volume of breast tissue irradiated and therefore the risk of late treatment-related toxicity. The development of magnetic resonance (MR)-guided RT, including dedicated MR-guided RT systems [hybrid machines combining an MR scanner with a linear accelerator (MR-linac) or Co sources], could potentially reduce the irradiated volume even further by improving tumour visibility before and during each RT treatment. In this position paper, we discuss MR guidance in relation to each step of the breast RT planning and treatment pathway, focusing on the application of MR-guided RT to neoadjuvant PBI.
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http://dx.doi.org/10.3389/fonc.2020.01107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399349PMC
July 2020

Immune gene expression profiles in high-grade urothelial carcinoma of the bladder: a NanoString study.

J Clin Pathol 2021 Jan 29;74(1):53-57. Epub 2020 May 29.

Pathology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada

Aims: The advent of immune checkpoint inhibitor therapy has proven beneficial in a subset of high-grade urothelial carcinomas (HGUC) of the bladder. Although treatment selection is currently largely determined by programmed death-ligand 1 (PD-L1) status, multiple factors in the immune system may modulate the host immune response to HGUC and immunotherapy. In this pilot study, we used a transcriptomic approach to identify the immune milieu associated with PD-L1 expression to enhance our understanding of the HGUC immune evasion network.

Methods: The immune transcriptome of 40 HGUC cystectomy cases was profiled using the NanoString nCounter Human V.1.1 PanCancer Panel. All cases were assessed for associated PD-L1 status (SP263) using whole tissue sections. PD-L1 status was determined as high or low using 25% tumour and/or immune cell staining.

Results: The most significantly differentially expressed gene was PD-L1 messenger RNA (), which strongly correlated with protein expression (r=0.720, p<0.001). The sensitivity, specificity, positive and negative predictive values of for PD-L1 expression were 85%, 96%, 92% and 93%, respectively. The PD-L1 associated gene signature also included complement components and and (innate immune system), proinflammatory cytokines and along with the immune response mediator among others. Pathway analysis determined enrichment of these genes in interleukin-10 production, lymphocyte chemotaxis and aberrant IFNγ, NF-κB and ERK signalling networks.

Conclusions: We report key genes and pathways in the immune transcriptome and their association with PD-L1 status, which may be involved in immune evasion of HGUC and warrants further investigation.
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http://dx.doi.org/10.1136/jclinpath-2020-206631DOI Listing
January 2021

Accelerating prostate stereotactic ablative body radiotherapy: Efficacy and toxicity of a randomized phase II study of 11 versus 29 days overall treatment time (PATRIOT).

Radiother Oncol 2020 08 27;149:8-13. Epub 2020 Apr 27.

Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Canada; Institute of Health Policy Management and Evaluation, University of Toronto, Canada. Electronic address:

Background: Prostate stereotactic ablative radiotherapy (SABR) regimens differ in time, dose, and fractionation. We report an update of a multicentre, Canadian randomized phase II study to investigate the impact of overall treatment time on quality of life (QOL), efficacy, and toxicity.

Methods: Men with intermediate risk prostate cancer were randomized to 40 Gy in 5 fractions delivered every other day (EOD) versus once per week (QW). Primary outcome was proportion of patients experiencing a minimally clinically important change (MCIC) in acute bowel QOL using EPIC. Secondary outcomes were toxicity, biochemical failure (BF), other QOL domains, and the rate of salvage therapy.

Findings: 152 men from 3 centers were randomized; the median follow-up was 62 months. Results are described for EOD versus QW. Acute bowel and urinary QOL was reported previously. Late changes in QOL were not significantly different between the two arms. There were 1 (1.3%) vs 3 (2.7%) late grade 3 + GI toxicities (p = 0.36) and 5 (6.7%) vs 2 (2.7%) late grade 3 GU toxicities (p = 0.44). Two and 5 patients had BF (5-year failure rate 3.0 vs 7.2%, p = 0.22); 0 and 4 patients received salvage therapy (p = 0.04). 5-Year OS and CSS was 95.8% and 98.6% with no difference between arms (p = 0.49, p = 0.15). 3 patients in the QW arm developed metastases.

Interpretation: Although we previously reported that weekly prostate SABR had better bowel and urinary QOL compared to EOD, the updated results show no difference in late toxicity, QOL, BF, or PSA kinetics. Patients should be counseled that QW SABR reduces short-term toxicity compared to QW SABR.
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http://dx.doi.org/10.1016/j.radonc.2020.04.039DOI Listing
August 2020

Factors Affecting Mean Heart Dose in Patients Receiving Breast Radiotherapy from 2011 to 2018 in a Single Institution.

J Med Imaging Radiat Sci 2020 09 1;51(3):379-393. Epub 2020 May 1.

Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada. Electronic address:

Introduction: Breast cancer radiotherapy (RT) can increase the risk of cardiac disease with increasing dose; as such, reducing excessive dosage to the heart is a concern for clinicians. The purpose of the present study was to assess mean heart dose (MHD) in patients with breast cancer receiving RT, where it was hypothesized that MHD decreased over time.

Methods: Patients planned for adjuvant unilateral whole breast/chest wall RT from 2011 to 2018 were included for a retrospective chart-review at a single-institution, academic center. MHD (Gy) was summarized by laterality, fractionation, and heart-sparing techniques.

Results: A total of 4,687 patients were included. The median MHD for left-sided conventional RT (50 Gy in 25 fractions) was 2.16 Gy across all years, decreasing until 2015 and increasing after. Median MHD for left-sided hypofractionated RT (42.6 Gy in 16 fractions) was 1.47 Gy, also decreasing until 2015 and increasing after. The increase in MHD after 2015 was attributed to a significant increase in the use of wide tangents (including internal mammary chain) after 2015 (P < .0001). Several treatment factors were associated with higher MHD in both right- and left-sided cancers, including locoregional RT, high tangents, wide tangents, bolus, heart shielding, treatment to the chest wall, higher volume of tissue irradiated by tangential fields, higher baseline breast separation values, and smaller heart volume. After adjusting for laterality and fractionation in the multivariate analysis, locoregional RT, wide tangents, heart shielding, boost, treatment to the chest wall, higher volume of tissue irradiated by tangential fields, higher baseline breast separation, and lower heart volume were significantly associated with higher MHD (P < .0001).

Discussion/conclusions: MHD should be considered when determining the most appropriate RT techniques for both right- and left-sided cancers as higher MHD was significantly associated with various treatment techniques and patient factors.
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http://dx.doi.org/10.1016/j.jmir.2020.03.003DOI Listing
September 2020

Impact of Biopsy Compliance on Outcomes for Patients on Active Surveillance for Prostate Cancer.

J Urol 2020 11 24;204(5):934-940. Epub 2020 Apr 24.

Department of Radiation Oncology, Odette Cancer Center, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.

Purpose: Active surveillance for prostate cancer relies on regular prostate specific antigen tests and surveillance biopsies. Compliance rates with biopsies vary but the subsequent impact on oncologic outcomes is not known. The objective of this study was to determine whether noncompliance with the confirmatory biopsy negatively impacts prostate cancer specific outcomes.

Materials And Methods: A retrospective analysis was performed on a prospective single-arm cohort of men enrolled in active surveillance for prostate cancer between 1995 and 2018 with a median followup of 9.1 years. A total of 1,275 patients were enrolled and 1,043 had a minimum of 3 years of followup and were included in the analysis. Patients were stratified by compliance with a confirmatory biopsy within 24 months of enrollment in active surveillance. The primary outcome was recurrence-free survival. Secondary outcomes included metastatic-free survival and cause specific survival.

Results: A total of 1,275 patients were enrolled, and 1,043 had a minimum of 3 years of followup and were included in the analysis, of whom 425 were treated for localized prostate cancer. Patients noncompliant with the confirmatory biopsy had higher rates of recurrence after treatment (19% vs 12%, HR 1.64, 95% CI 1.19-2.26, p=0.003) and metastases (7% vs 2%, HR 3.56, 95% CI 1.8-7.0, p=0.0003) even after accounting for age, prostate specific antigen and Grade Group. Cause specific survival was not significantly different between the 2 groups. The results were consistent even in the subset of patients with Grade Group 1 disease at study entry.

Conclusions: Noncompliance with a confirmatory biopsy compromises the control of prostate cancer in men followed on active surveillance. Patients and physicians should be aware of the importance of adhering to protocol for men on active surveillance.
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http://dx.doi.org/10.1097/JU.0000000000001091DOI Listing
November 2020

Use of Adjuvant Breast Hypofractionation Radiation Treatment at a Cancer Center in Ontario From 2011 to 2018.

Clin Breast Cancer 2020 10 28;20(5):e612-e617. Epub 2020 Mar 28.

Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background: The adoption of hypofractionated radiotherapy (HFRT) into clinical practice varies widely despite randomized trials and guidelines supporting its equivalence to conventional fractionated radiotherapy (CFRT) for certain patient populations. We assessed the use of HFRT at a single institution from 2011 to 2018, as well as time-savings calculations.

Patients And Methods: A retrospective cohort study was conducted for patients with breast cancer receiving adjuvant radiotherapy by HFRT or CFRT. Trends in HFRT use (≤ 16 fractions) were stratified according to 4 subgroups: tangential breast RT, locoregional breast RT, tangential chest wall RT, and locoregional chest wall RT. Treatment time savings were approximated using the institutional median treatment time.

Results: A total of 5190 patients were included. HFRT use in all subgroups increased from 2011 to 2018. Tangential breast HFRT alone increased from 62.2% in 2011 to 96.9% in 2018. Locoregional breast HFRT and tangential chest wall HFRT use increased from less than 10% in 2011 to 76.2% and 76.9% in 2018. In locoregional chest wall RT, HFRT use of 44.9% was observed in 2018. Increased use of locoregional HFRT was mainly due to institutional policy changes. Time-savings calculations showed that 4002 hours of treatment or an additional 1402 HFRT courses could have been administered if all patients received HFRT.

Conclusion: The use of HFRT at our center increased in all patient subgroups. More evidence and guidelines for patients receiving chest wall or locoregional HFRT are required because the use of HFRT remains low in these patient cohorts.
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http://dx.doi.org/10.1016/j.clbc.2020.03.006DOI Listing
October 2020

Consensus on Contouring Primary Breast Tumors on MRI in the Setting of Neoadjuvant Partial Breast Irradiation in Trials.

Pract Radiat Oncol 2020 Nov - Dec;10(6):e466-e474. Epub 2020 Apr 18.

Department of Radiation Oncology, Amsterdam University Medical Center, Amsterdam, the Netherlands.

Purpose: Our purpose was to present and evaluate expert consensus on contouring primary breast tumors on magnetic resonance imaging (MRI) in the setting of neoadjuvant partial breast irradiation in trials.

Methods And Materials: Expert consensus on contouring guidelines for target definition of primary breast tumors on contrast-enhanced MRI in trials was developed by an international team of experienced breast radiation oncologists and a dedicated breast radiologist during 3 meetings. At the first meeting, draft guidelines were developed through discussing and contouring 2 cases. At the second meeting 6 breast radiation oncologists delineated gross tumor volume (GTV) in 10 patients with early-stage breast cancer (cT1N0) according to draft guidelines. GTV was expanded isotropically (20 mm) to generate clinical target volume (CTV), excluding skin and chest wall. Delineations were reviewed for disagreement and guidelines were clarified accordingly. At the third meeting 5 radiation oncologists redelineated 6 cases using consensus-based guidelines. Interobserver variation of GTV and CTV was assessed using generalized conformity index (CI). CI was calculated as the sum of volumes each pair of observers agreed upon, divided by the sum of encompassing volumes for each pair of observers.

Results: For the 2 delineation sessions combined, mean GTV ranged between 0.19 and 2.44 cm, CI for GTV ranged between 0.28 and 0.77, and CI for CTV between 0.77 and 0.94. The largest interobserver variation in GTV delineations was observed in cases with extended tumor spiculae, blood vessels near or markers within the tumor, or with increased enhancement of glandular breast tissue. Consensus-based guidelines stated to delineate all visible tumors on contrast enhanced-MRI scan 1 to 2 minutes after contrast injection and if a marker was inserted in the tumor to include this.

Conclusions: Expert-based consensus on contouring primary breast tumors on MRI in trials has been reached. This resulted in low interobserver variation for CTV in the context of a uniform 20 mm GTV to CTV expansion margin.
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http://dx.doi.org/10.1016/j.prro.2020.03.011DOI Listing
August 2021

Evaluating the Tolerability of a Simultaneous Focal Boost to the Gross Tumor in Prostate SABR: A Toxicity and Quality-of-Life Comparison of Two Prospective Trials.

Int J Radiat Oncol Biol Phys 2020 05 25;107(1):136-142. Epub 2020 Jan 25.

Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Purpose: Dose-escalated stereotactic ablative radiotherapy (SABR) to the whole prostate may be associated with better outcomes but has a risk of increased toxicity. An alternative approach is to focally boost the dominant intraprostatic lesion (DIL) seen on magnetic resonance imaging. We report the toxicity and quality-of-life (QOL) outcomes of 2 phase 2 trials of prostate and pelvic SABR, with or without a simultaneous DIL boost.

Methods And Materials: The first trial treated patients with high-risk prostate cancer to a dose of 40 Gy to the prostate and 25 Gy to the pelvis in 5 fractions. The second trial treated patients with intermediate-risk and high-risk prostate cancer to a dose of 35 Gy to the prostate, 25 Gy to the pelvis, and a DIL boost up to 50 Gy in 5 fractions. Acute toxicities, late toxicities, and QOL were assessed.

Results: Thirty patients were enrolled in each trial. In the focal boost cohort, the median DIL D90% was 48.3 Gy. There was no significant difference in acute grade ≥2 gastrointestinal or genitourinary toxicity between the 2 trials or in cumulative worst late gastrointestinal or genitourinary toxicity up to 24 months. There was no significant difference in QOL domain scores or minimally clinical important change between the 2 trials.

Conclusions: Prostate and pelvic SABR with a simultaneous DIL boost was feasible. Acute grade ≥2 toxicity, late toxicity, and QOL seemed to be comparable to a cohort that did not receive a focal boost. Further follow-up will be required to assess long-term outcomes, and randomized data are required to confirm these findings.
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http://dx.doi.org/10.1016/j.ijrobp.2019.12.044DOI Listing
May 2020

Correlation of mismatch repair protein deficiency, PD-L1 and CD8 expression in high-grade urothelial carcinoma of the bladder.

J Clin Pathol 2020 Aug 9;73(8):519-522. Epub 2020 Jan 9.

Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada

Mismatch repair-deficient (d-MMR) tumours have been reported to show susceptibility to immune checkpoint inhibitors targeting programmed death-1/PD ligand-1 (PD-1/PD-L1). In this study, we sought to correlate the association of d-MMR, PD-L1 and CD8 expression in muscle invasive, high-grade urothelial carcinoma (HGUC) of bladder. A tissue microarray (TMA) was constructed from 201 cases and sequentially stained with PD-L1, CD8, MSH2, MSH6, MLH1 and PMS2. PD-L1 was assessed in tumour and immune cells. CD8 was assessed in a hotspot fashion with results averaged across cores. Loss of nuclear MMR expression on TMA sections was further assessed using corresponding whole tissue sections. d-MMR was identified in four cases (2%). The mean CD8 count was significantly higher in d-MMR tumours (10 vs 35, p=0.007) as was the proportion of PD-L1 positivity (75% vs 20%, p=0.031). d-MMR is uncommon in HGUC of bladder but shows strong correlation with cytotoxic T lymphocyte infiltration and PD-L1 tissue expression.
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http://dx.doi.org/10.1136/jclinpath-2019-206256DOI Listing
August 2020

Dosimetric predictors of toxicity and quality of life following prostate stereotactic ablative radiotherapy.

Radiother Oncol 2020 03 3;144:135-140. Epub 2019 Dec 3.

Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Canada; Institute of Health Policy Management and Evaluation, University of Toronto, Canada. Electronic address:

Purpose: SABR offers an effective treatment option for clinically localized prostate cancer. Here we report the dosimetric predictors of late toxicity and quality of life (QOL) in a pooled cohort of patients from four phase II trials.

Methods: The combined cohort included all three prostate cancer risk groups. The prescription dose was 35-40 Gy in 5 fractions. Toxicity (CTCAE) and QOL (EPIC) were collected. Multiple dosimetric parameters for the bladder, rectum and penile bulb were collected. Univariate (UVA) followed by multivariate (MVA) logistic regression analysis was conducted to search for significant dosimetric predictors of late GI/GU toxicity, or minimal clinically important change in the relevant QOL domain.

Results: 258 patients were included with median follow up of 6.1 years. For QOL, bladder Dmax, V38, D1cc, D2cc, D5cc and rectal V35 were predictors of urinary and bowel MCIC on UVA. On MVA, only bladder V38 remained significant. For late toxicity, various parameters were significant on UVA but only rectal Dmax, V38 and bladder D2cc were significant predictors on MVA.

Conclusions: This report confirms that the high-dose regions in the bladder and rectum are more significant predictors of late toxicity and QOL after prostate SABR compared to low-dose regions. Caution must be taken to avoid high doses and hotspots in those organs.
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http://dx.doi.org/10.1016/j.radonc.2019.11.017DOI Listing
March 2020

Randomized Study of Systematic Biopsy Versus Magnetic Resonance Imaging and Targeted and Systematic Biopsy in Men on Active Surveillance (ASIST): 2-year Postbiopsy Follow-up.

Eur Urol 2020 03 8;77(3):311-317. Epub 2019 Nov 8.

Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada.

Background: The initial report from the ASIST trial showed little benefit from targeted biopsy for men on active surveillance (AS) for prostate cancer. Data after 2-yr follow-up are now available for analysis.

Objective: To determine if there was a difference in the AS failure rate in a 2-yr follow-up period among men undergoing magnetic resonance imaging (MRI) before initial confirmatory biopsy (CBx) compared to those who did not.

Design, Setting, And Participants: This is the 2-yr post-CBx follow-up for the ASIST trial, a prospective, randomized, multicenter, open-label study for men with Gleason grade group (GG) 1 cancer eligible for AS. Patients were randomized to CBx with 12-core systematic sampling or MRI with systematic and targeted sampling.

Outcome Measurements And Statistical Analysis: Patients with GG ≤ 1 on CBx were followed for 2 yr and had MRI and biopsy at that time point. Patients failed AS if they were no longer under AS because of grade progression, clinical progression, subject choice, clinical judgment, treatment, or lost to follow-up. Clinically significant cancer (CSC) was defined as GG ≥ 2.

Results And Limitations: In total, 259 men underwent CBx, 132 in the non-MRI and 127 in the MRI arm. After biopsy, 101 men in the non-MRI arm (76%) and 98 in the MRI arm (77%) continued AS. There were fewer men with AS failures in the MRI (19/98, 19%) compared to the non-MRI group (35/101, 35%; p =  0.017). At 2-yr biopsy there were fewer men with CSC in the MRI arm (9.9%, 8/81) than in the non-MRI arm (23%, 17/75; p =  0.048). Significant differences in AS failure rates were detected across the three centers in the MRI arm only (4.2% [2/48] vs 17% [4/24] vs 27% [7/26]; p =  0.019).

Conclusions: Baseline MRI before CBx during AS results in 50% fewer AS failures and less grade progression over 2 yr. The center where MRI and targeted biopsy is performed may influence AS failure rates.

Patient Summary: The ASIST trial randomized 273 men on active surveillance with low-grade prostate cancer diagnosed within the last year to systematic biopsy or magnetic resonance imaging (MRI) with systematic and targeted biopsy. The initial report showed little benefit from targeted biopsy. However, after 2 yr of follow-up we found that baseline MRI before confirmatory biopsy resulted in 50% fewer failures of surveillance and less progression to higher-grade cancer. This confirms the value of MRI in men on surveillance. This study is registered at ClinicalTrials.gov (NCT01354171).
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http://dx.doi.org/10.1016/j.eururo.2019.10.007DOI Listing
March 2020

A systematic review and meta-analysis of clinician-reported versus patient-reported outcomes of radiation dermatitis.

Breast 2020 Apr 19;50:125-134. Epub 2019 Sep 19.

Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Radiation dermatitis is a common adverse effect of radiotherapy (RT) in breast cancer patients. Although radiation dermatitis is reported by either the clinician or the patient, previous studies have shown disagreement between clinician-reported outcomes (CROs) and patient-reported outcomes (PROs). This review evaluated the extent of discordance between CROs and PROs for radiation dermatitis. Studies reporting both clinician and patient-reported outcomes for external beam RT were eligible. Nine studies met the inclusion criteria for the systematic review, while 8 of these studies were eligible for inclusion in a meta-analysis of acute and late skin toxicities. We found an overall agreement between CROs and PROs of acute skin colour change, fibrosis and/or retraction, and moist desquamation (p > 0.005). Reporting of late breast pain, breast edema, skin colour change, telangiectasia, fibrosis and/or retraction and induration/fibrosis alone (p > 0.005) were also in agreement between clinicians and patients. Our meta-analysis revealed a greater reporting of acute breast pain by patients (RR = 0.89, 95% CI 0.87-0.92, p < 0.001), greater reporting of acute breast edema by physicians (RR = 1.80, 95% CI 1.65-1.97, p < 0.001) and a greater reporting of late breast shrinkage by patients (RR = 0.61, 95% CI 0.44-0.86, p = 0.005). However, our review was limited by the discrepancies between PRO and CRO measurement tools as well as the absence of standard time points for evaluation of radiation dermatitis. Given potential discrepancies between CROs and PROs, both measures should be reported in future studies. Ultimately, we advocate for the development of a single tool to assess symptoms from both perspectives.
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http://dx.doi.org/10.1016/j.breast.2019.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375608PMC
April 2020

Two versus five stereotactic ablative radiotherapy treatments for localized prostate cancer: A quality of life analysis of two prospective clinical trials.

Radiother Oncol 2019 11 29;140:105-109. Epub 2019 Jun 29.

Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Canada; Department of Radiation Oncology, University of Toronto, Canada. Electronic address:

Purpose: Stereotactic ablative radiotherapy (SABR) is appealing for prostate cancer (PCa) due to low α/β, and increasing the dose per fraction could improve the therapeutic index and lead to a better quality of life (QOL). Here we report the outcomes of a QOL comparison between two phase II clinical trials: two vs. five fraction prostate SABR.

Methods: Patients had low or intermediate risk PCa. The doses prescribed were 26 Gy/2 and 40 Gy/5. Expanded prostate cancer index composite was collected. Urinary, bowel and sexual domains were analyzed. Minimal clinically important change (MCIC) was defined as >0.5 standard deviation.

Results: 30 and 152 patients were treated with 2-fraction and 5-fraction SABR. Median follow-up was 55 and 62 months. Five-year biochemical failure rate was 3.3% and 4.6%. The 2-fraction cohort had a significantly better mean QOL over time in the bowel domain (p = 0.0004), without a significant difference in the urinary or sexual domains. The 2-fraction cohort had a significantly lower rate of bowel MCIC (17.8% vs 42.3%, p = 0.01), but there was no difference in urinary (24.1% vs 35.7%) or sexual (15.3% vs 29.2%) MCIC. For MCIC x2 (moderate QOL change), the 2-fraction trial had significantly lower MCIC rates in both the bowel (7.1% vs 24%, p = 0.04) and sexual (0 vs 17.6%, p = 0.01) domains.

Conclusions: 2-Fraction SABR is feasible to deliver and well tolerated, with significant signals of improved bowel and sexual QOL. A randomized trial of two vs. five fractions for prostate SABR is needed to confirm the promising findings of this study.
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http://dx.doi.org/10.1016/j.radonc.2019.06.018DOI Listing
November 2019

prediction of breast tumour response to chemotherapy using quantitative ultrasound imaging and artificial neural networks.

Oncotarget 2019 Jun 11;10(39):3910-3923. Epub 2019 Jun 11.

Physical Sciences, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.

We demonstrate the clinical utility of combining quantitative ultrasound (QUS) imaging of the breast with an artificial neural network (ANN) classifier to predict the response of breast cancer patients to neoadjuvant chemotherapy (NAC) administration prior to the start of treatment. Using a 6 MHz ultrasound system, radiofrequency (RF) ultrasound data were acquired from 100 patients with biopsy-confirmed locally advanced breast cancer prior to the start of NAC. Quantitative ultrasound mean parameter intensity and texture features were computed from the tumour core and margin, and were compared to the clinical/pathological response and 5-year recurrence-free survival (RFS) of patients. A multi-parametric QUS model in conjunction with an ANN classifier predicted patient response with 96 ± 6% accuracy, and a 0.96 ± 0.08 area under the receiver operating characteristic curve (AUC), compared to 65 ± 10 % accuracy and 0.67 ± 0.14 AUC achieved using a K-Nearest Neighbour (KNN) algorithm. A separate ANN model predicted patient RFS with 85 ± 7% accuracy, and a 0.89 ± 0.11 AUC, whereas the KNN methodology achieved a 58 ± 6 % accuracy and a 0.64 ± 0.09 AUC. The application of ANN for classifying patient response based on tumour QUS features performs well in terms of predicting response to chemotherapy. The findings here provide a framework for developing personalized chemotherapy selection for patients that are candidates for NAC, potentially resulting in improved patient treatment outcomes and prognosis.
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http://dx.doi.org/10.18632/oncotarget.26996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6570472PMC
June 2019

Temporal Stability and Prognostic Biomarker Potential of the Prostate Cancer Urine miRNA Transcriptome.

J Natl Cancer Inst 2020 03;112(3):247-255

Ontario Institute for Cancer Research, Toronto, ON, Canada.

Background: The development of noninvasive tests for the early detection of aggressive prostate tumors is a major unmet clinical need. miRNAs are promising noninvasive biomarkers: they play essential roles in tumorigenesis, are stable under diverse analytical conditions, and can be detected in body fluids.

Methods: We measured the longitudinal stability of 673 miRNAs by collecting serial urine samples from 10 patients with localized prostate cancer. We then measured temporally stable miRNAs in an independent training cohort (n = 99) and created a biomarker predictive of Gleason grade using machine-learning techniques. Finally, we validated this biomarker in an independent validation cohort (n = 40).

Results: We found that each individual has a specific urine miRNA fingerprint. These fingerprints are temporally stable and associated with specific biological functions. We identified seven miRNAs that were stable over time within individual patients and integrated them with machine-learning techniques to create a novel biomarker for prostate cancer that overcomes interindividual variability. Our urine biomarker robustly identified high-risk patients and achieved similar accuracy as tissue-based prognostic markers (area under the receiver operating characteristic = 0.72, 95% confidence interval = 0.69 to 0.76 in the training cohort, and area under the receiver operating characteristic curve = 0.74, 95% confidence interval = 0.55 to 0.92 in the validation cohort).

Conclusions: These data highlight the importance of quantifying intra- and intertumoral heterogeneity in biomarker development. This noninvasive biomarker may usefully supplement invasive or expensive radiologic- and tissue-based assays.
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http://dx.doi.org/10.1093/jnci/djz112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073919PMC
March 2020
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