Publications by authors named "Richard Choo"

75 Publications

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

Comparison of Multimodal Therapies and Outcomes Among Patients With High-Risk Prostate Cancer With Adverse Clinicopathologic Features.

JAMA Netw Open 2021 Jul 1;4(7):e2115312. Epub 2021 Jul 1.

Department of Urology, Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland.

Importance: The optimal management strategy for high-risk prostate cancer and additional adverse clinicopathologic features remains unknown.

Objective: To compare clinical outcomes among patients with high-risk prostate cancer after definitive treatment.

Design, Setting, And Participants: This retrospective cohort study included patients with high-risk prostate cancer (as defined by the National Comprehensive Cancer Network [NCCN]) and at least 1 adverse clinicopathologic feature (defined as any primary Gleason pattern 5 on biopsy, clinical T3b-4 disease, ≥50% cores with biopsy results positive for prostate cancer, or NCCN ≥2 high-risk features) treated between 2000 and 2014 at 16 tertiary centers. Data were analyzed in November 2020.

Exposures: Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy (ADT), or EBRT plus brachytherapy boost (BT) with ADT. Guideline-concordant multimodal treatment was defined as RP with appropriate use of multimodal therapy (optimal RP), EBRT with at least 2 years of ADT (optimal EBRT), or EBRT with BT with at least 1 year ADT (optimal EBRT with BT).

Main Outcomes And Measures: The primary outcome was prostate cancer-specific mortality; distant metastasis was a secondary outcome. Differences were evaluated using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression models.

Results: A total of 6004 men (median [interquartile range] age, 66.4 [60.9-71.8] years) with high-risk prostate cancer were analyzed, including 3175 patients (52.9%) who underwent RP, 1830 patients (30.5%) who underwent EBRT alone, and 999 patients (16.6%) who underwent EBRT with BT. Compared with RP, treatment with EBRT with BT (subdistribution hazard ratio [sHR] 0.78, [95% CI, 0.63-0.97]; P = .03) or with EBRT alone (sHR, 0.70 [95% CI, 0.53-0.92]; P = .01) was associated with significantly improved prostate cancer-specific mortality; there was no difference in prostate cancer-specific mortality between EBRT with BT and EBRT alone (sHR, 0.89 [95% CI, 0.67-1.18]; P = .43). No significant differences in prostate cancer-specific mortality were found across treatment cohorts among 2940 patients who received guideline-concordant multimodality treatment (eg, optimal EBRT alone vs optimal RP: sHR, 0.76 [95% CI, 0.52-1.09]; P = .14). However, treatment with EBRT alone or EBRT with BT was consistently associated with lower rates of distant metastasis compared with treatment with RP (eg, EBRT vs RP: sHR, 0.50 [95% CI, 0.44-0.58]; P < .001).

Conclusions And Relevance: These findings suggest that among patients with high-risk prostate cancer and additional unfavorable clinicopathologic features receiving guideline-concordant multimodal therapy, prostate cancer-specific mortality outcomes were equivalent among those treated with RP, EBRT, and EBRT with BT, although distant metastasis outcomes were more favorable among patients treated with EBRT and EBRT with BT. Optimal multimodality treatment is critical for improving outcomes in patients with high-risk prostate cancer.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.15312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251338PMC
July 2021

The prognostic value, sensitivity, and specificity of multiparametric magnetic resonance imaging before salvage radiotherapy for prostate cancer.

Radiother Oncol 2021 08 21;161:9-15. Epub 2021 May 21.

Department of Radiation Oncology, Mayo Clinic, Rochester, USA.

Aim: To determine the operational characteristics of pelvic magnetic resonance imaging (MRI) prior to salvage radiation therapy (SRT) for biochemically recurrent prostate cancer following radical prostatectomy.

Methods And Materials: We reviewed the medical records of 386 patients who underwent MRI prior to SRT. We assessed associations of pre-SRT MRI findings with biochemical recurrence (BCR), distant metastasis (DM), prostate cancer-specific mortality (PCSM), and salvage androgen deprivation therapy (ADT) use following SRT. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of MRI for detecting local recurrence were also calculated.

Results: Pre-SRT MRI was positive for local recurrence in 216 patients (56%), indeterminate in 46 (12%), and negative in 124 (32%). On univariate analysis, BCR following SRT was significantly less likely for patients with positive (HR: 0.58, 95% CI: 0.42-0.8) or indeterminate (HR: 0.6: 0.36-1) MRI findings, compared to patients with negative imaging (p = 0.003). These associations remained significant on multivariate analysis (p < 0.05) and across pre-SRT PSA groups. For the entire cohort, the sensitivity of MRI for local recurrence was 61.0% (53.5-68.1%), specificity 60.0% (44.3-73.0%), PPV 86.1% (78.9-91.5%) and NPV 27.6% (19.0-37.5%). Sensitivity of MRI was better in men with higher pre-SRT PSA (80.0% for PSA > 1.0), and specificity was improved with lower pre-SRT PSA (73.9% for PSA 0.1-0.5).

Conclusions: Positive or indeterminate MRI findings prior to SRT were associated with improved biochemical control following SRT, across PSA levels. The sensitivity and specificity of MRI for local recurrence were 61% and 58.7%, respectively.
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http://dx.doi.org/10.1016/j.radonc.2021.05.015DOI Listing
August 2021

Patterns of Clinical Progression in Radiorecurrent High-risk Prostate Cancer.

Eur Urol 2021 Aug 10;80(2):142-146. Epub 2021 May 10.

Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

The natural history of radiorecurrent high-risk prostate cancer (HRPCa) is not well-described. To better understand its clinical course, we evaluated rates of distant metastases (DM) and prostate cancer-specific mortality (PCSM) in a cohort of 978 men with radiorecurrent HRPCa who previously received either external beam radiation therapy (EBRT, n = 654, 67%) or EBRT + brachytherapy (EBRT + BT, n = 324, 33%) across 15 institutions from 1997 to 2015. In men who did not die, median follow-up after treatment was 8.9 yr and median follow-up after biochemical recurrence (BCR) was 3.7 yr. Local and systemic therapy salvage, respectively, were delivered to 21 and 390 men after EBRT, and eight and 103 men after EBRT + BT. Overall, 435 men developed DM, and 248 were detected within 1 yr of BCR. Measured from time of recurrence, 5-yr DM rates were 50% and 34% after EBRT and EBRT + BT, respectively. Measured from BCR, 5-yr PCSM rates were 27% and 29%, respectively. Interval to BCR was independently associated with DM (p < 0.001) and PCSM (p < 0.001). These data suggest that radiorecurrent HRPCa has an aggressive natural history and that DM is clinically evident early after BCR. These findings underscore the importance of further investigations into upfront risk assessment and prompt systemic evaluation upon recurrence in HRPCa. PATIENT SUMMARY: High-risk prostate cancer that recurs after radiation therapy is an aggressive disease entity and spreads to other parts of the body (metastases). Some 60% of metastases occur within 1 yr. Approximately 30% of these patients die from their prostate cancer.
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http://dx.doi.org/10.1016/j.eururo.2021.04.035DOI Listing
August 2021

Predictors of Locoregional Recurrence and Delineation of Adjuvant Radiation Therapy Fields for Patients With Upper Tract Urothelial Carcinoma Receiving Nephroureterectomy.

Pract Radiat Oncol 2021 Sep-Oct;11(5):e468-e476. Epub 2021 Feb 23.

Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota. Electronic address:

Purpose: To identify factors predictive of locoregional recurrence (LRR) in upper tract urothelial carcinoma (UTUC) treated with nephroureterectomy and to propose adjuvant radiation therapy (ART) fields.

Methods And Materials: Clinical and pathologic variables for patients receiving nephroureterectomy for UTUC between 1995 and 2009 were analyzed for associations with outcomes. Sites of LRR from all patients with available imaging (39) were contoured on computed tomography image sets of patients with representative anatomy, and ART fields were proposed based on these distributions.

Results: A total of 279 patients with a median follow-up of 13.0 years were analyzed. The 5-year cumulative incidence of LRR was 16.7% (95% CI, 12.2-21). Pathologic risk factors (PRFs) associated with increased risk of LRR included tumor in both the renal pelvis and ureter, T stage ≥2, lymph node involvement, grade 3 histology, and positive surgical margins (P < .05). Patients with an increased number of PRFs had a significantly greater risk of LRR. The 5-year cumulative incidence estimates of LRR were 5.3% (95% CI, 1.8%-16.0%), 15.6% (95% CI, 9.5%-25.7%), and 43.9% (95% CI, 31.1%-62.1%) for those with 1, 2, and ≥3 PRFs, respectively. ART fields covering the renal fossa and retroperitoneal lymph nodes from the superior border of L1 through the aortic bifurcation would encompass all sites of LRR for 33 of 46 patients (72%). Non-LRR bladder and distant failure occurred in 101 (36.2%) and 73 (26.2%) of the patients, respectively. The 5-year cumulative incidence estimate of distant failure was 22.5% (95% CI, 17.4%-27.3%).

Conclusions: In patients receiving nephroureterectomy for UTUC, LRR is significantly increased in patients with 2 or more PRFs. These data provide clinically valuable insight into the selection of candidates for ART and the design of ART fields.
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http://dx.doi.org/10.1016/j.prro.2021.02.005DOI Listing
September 2021

Comparing bowel and urinary domains of patient-reported quality of life at the end of and 3 months post radiotherapy between intensity-modulated radiotherapy and proton beam therapy for clinically localized prostate cancer.

Cancer Med 2020 11 15;9(21):7925-7934. Epub 2020 Sep 15.

Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA.

Purpose: To prospectively assess acute differences in patient-reported outcomes in bowel and urinary domains between intensity-modulated radiotherapy (IMRT) and proton beam therapy (PBT) for prostate cancer.

Methods And Materials: Bowel function (BF), urinary irritative/obstructive symptoms (UO), and urinary incontinence (UI) domains of EPIC-26 were collected in patients with T1-T2 prostate cancer receiving IMRT or PBT at a tertiary cancer center (2015-2018). Mean changes in domain scores were analyzed from pretreatment to the end of and 3 months post-radiotherapy for each modality. A clinically meaningful change was defined as a score change >50% of the baseline standard deviation.

Results: A total of 157 patients receiving IMRT and 105 receiving PBT were included. There were no baseline differences in domain scores between cohorts. At the end of radiotherapy, there was significant and clinically meaningful worsening of BF and UO scores for patients receiving either modality. In the BF domain, the IMRT cohort experienced greater decrement (-13.0 vs -6.7, P < .01), and had a higher proportion of patients with clinically meaningful reduction (58.4% vs 39.5%, P = .01), compared to PBT. At 3 months post-radiotherapy, the IMRT group had significant and clinically meaningful worsening of BF (-9.3, P < .001), whereas the change in BF score of the PBT cohort was no longer significant or clinically meaningful (-1.2, P = .25). There were no significant or clinically meaningful changes in UO or UI 3 months post-radiotherapy.

Conclusions: PBT had less acute decrement in BF than IMRT following radiotherapy. There was no difference between the two modalities in UO and UI.
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http://dx.doi.org/10.1002/cam4.3414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643652PMC
November 2020

Outcomes and Profiles of Older Patients Receiving Definitive Radiation Therapy for Muscle-Invasive Bladder Cancer at a Tertiary Medical Center.

Pract Radiat Oncol 2020 Sep - Oct;10(5):e378-e387. Epub 2020 Feb 26.

Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota. Electronic address:

Purpose: Our purpose was to evaluate the outcomes and profiles of older patients with muscle-invasive bladder cancer (MIBC) treated with definitive radiation therapy (RT) with or without chemotherapy (CHT) at a tertiary medical center.

Methods And Materials: A retrospective study was conducted for older patients with MIBC who were ≥70 years old and underwent RT with or without CHT between 2000 and 2016. Overall survival (OS) was estimated using the Kaplan-Meier method. Disease-specific survival (DSS), cumulative incidence of progression, patterns of recurrence, and toxicities were examined. Univariate analyses were performed to identify variables associated with OS, DSS, and cumulative incidence of progression, using the Cox proportional hazards model.

Results: A total of 84 patients underwent definitive RT with or without CHT. Of these, only 29% were deemed medically fit to undergo radical cystectomy, and the remainder were medically unfit or had surgically unresectable disease. Median age was 81 years. Sixty-one percent, 29%, and 11% had clinical stage II, III, and IV disease, respectively. Eighty-six percent had maximal transurethral resection of bladder tumor before RT. Seventy-three percent received CHT with RT, and 27% had RT alone. Median follow-up was 5.7 years. Median OS was 1.9 years. OS was 42% and 25%, and DSS was 64% and 54% at 3 and 5 years, respectively. On univariate analysis, medical fitness to undergo radical cystectomy, receipt of CHT, lower T stage, and maximal transurethral resection of bladder tumor were associated with better OS; lower T stage was associated with better DSS. The cumulative incidence of progression was 44% and 49% at 3 and 5 years, respectively. Late grade 3 genitourinary and gastrointestinal toxicity were 15% and 4%, respectively. None had grade 4 or 5 toxicity.

Conclusions: Older patients with MIBC referred for RT were often medically unfit or had a surgically unresectable tumor. In these medically compromised patients, definitive RT with or without CHT was well tolerated and yielded encouraging treatment outcomes.
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http://dx.doi.org/10.1016/j.prro.2020.02.008DOI Listing
August 2021

IMPT versus VMAT for Pelvic Nodal Irradiation in Prostate Cancer: A Dosimetric Comparison.

Int J Part Ther 2019 21;5(3):11-23. Epub 2019 Mar 21.

Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA.

Purpose: To compare dosimetric data of the organs at risk (OARs) and clinical target volumes (CTVs) between intensity-modulated proton therapy (IMPT) and volumetric-modulated arc therapy (VMAT) for patients undergoing prostate and elective, pelvic lymph node radiotherapy in the setting of unfavorable, intermediate and high-risk prostate carcinoma.

Methods And Materials: A study of moderately hypofractionated proton therapy (6750 centigray [cGy] in 25 fractions) is in progress for unfavorable, intermediate and high-risk prostate cancer where treatment includes an elective pelvic nodal CTV (4500 cGy in 25 fractions). Ten consecutively accrued patients were the subjects for dose-volume histogram comparison between IMPT and VMAT. Two treatment plans (IMPT and VMAT) were prepared for each patient with predefined planning objectives for target volumes and OARs. The IMPT plans were prepared with 2 lateral beams and VMAT plans with 2 arcs.

Results: The CTV coverage was adequate for both plans with 99% of CTVs receiving ≥ 100% of the prescription doses. Mean doses to the bladder, rectum, large bowel, and small bowel were lower with IMPT versus VMAT. Mean femoral head dose was greater with IMPT. The percentage of volumes of rectum receiving ≤ 47.5 Gy, large bowel receiving ≤ 27.5 Gy, small bowel receiving ≤ 30 Gy, and bladder receiving ≤ 37.5 Gy was less with IMPT versus VMAT, largely because of reduction in the low-dose "bath" associated with VMAT.

Conclusions: In the setting of prostate and elective, pelvic nodal radiotherapy for prostate cancer, IMPT can significantly reduce the dose to OARs, in comparison to VMAT, and provide adequate target coverage.
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http://dx.doi.org/10.14338/IJPT-18-00048.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874187PMC
March 2019

Proton Therapy for Stage IIA-B Seminoma: A New Standard of Care for Treating Retroperitoneal Nodes.

Int J Part Ther 2018 30;5(2):50-57. Epub 2018 Nov 30.

Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA.

Currently there has been no published report describing the use of proton beam therapy for stage II testicular seminoma. A 31-year-old man presenting with a right testicular mass and a 2.7-cm aortocaval lymph node received a diagnosis of stage IIB testicular seminoma. He was treated with scanning proton beam therapy, as a means of improving the therapeutic ratio of radiation therapy over conventionally used x-ray radiation therapy. The patient achieved a complete response and remained free of relapse at 15 months post proton beam therapy. The advantageous dose deposition characteristics of proton beam, allowing much lower radiation doses to normal tissues, should be exploited when radiation therapy is applied for stage II testicular seminoma or for an isolated retroperitoneal lymph node relapse of stage I disease initially managed with surveillance.
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http://dx.doi.org/10.14338/IJPT-18-00001.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874188PMC
November 2018

C-Choline PET Guided Salvage Radiation Therapy for Isolated Pelvic and Paraortic Nodal Recurrence of Prostate Cancer After Radical Prostatectomy: Rationale and Early Genitourinary or Gastrointestinal Toxicities.

Adv Radiat Oncol 2019 Oct-Dec;4(4):659-667. Epub 2019 Jul 4.

Department of Radiation Oncology, Rochester, Minnesota.

Purpose: To assess gastrointestinal (GI) and genitourinary (GU) adverse events (AEs) of C-choline-positron emission tomography (CholPET) guided lymph node (LN) radiation therapy (RT) in patients who experience biochemical failure after radical prostatectomy.

Methods And Materials: From 2013 to 2016, 107 patients experienced biochemical failure of prostate cancer, had CholPET-detected pelvic and/or paraortic LN recurrence, and were referred for RT. Patients received androgen suppression and CholPET guided LN RT (median dose, 45 Gy) with a simultaneous integrated boost to CholPET-avid sites (median dose, 56.25 Gy), all in 25 fractions. RT-naïve patients had the prostatic fossa included in the initial treatment volumes followed by a sequential boost (median dose, 68 Gy). GI and GU AEs were reported per Common Terminology Criteria for Adverse Events (version 4.0) with data gathered retrospectively. Differences in maximum GI and GU AEs at baseline, immediately post-RT, and at early (median, 4 months) and late (median, 14 months) follow-up were assessed.

Results: Median follow-up was 16 months (interquartile range [IQR], 11-25). Median prostate-specific antigen at time of positive CholPET was 2.3 ng/mL (IQR, 1.3-4.8), with a median of 2 (IQR, 1-4) choline-avid LNs per patient. Most recurrences were within the pelvis (53%) or pelvis + paraortic (40%). Baseline rates of grade 1 to 2 GI AEs were 8.4% compared with 51.9% (4.7% grade 2) of patients post-RT ( < .01). These differences resolved by 4-month (12.2%,  = .65) and 14-month AE assessments (9.1%,  = .87). There was no significant change in grade 1 to 2 GU AEs post-RT (64.1%) relative to baseline (56.0%,  = .21), although differences did arise at 4-month (72.2%,  = .01) and 14-month (74.3%,  = .01) AE assessments.

Conclusions: Salvage CholPET guided nodal RT has acceptably low rates of acute GI and GU AEs and no significant detriment in 14-month GI AEs. These data are of value in counseling patients and designing prospective trials evaluating the oncologic efficacy of this treatment strategy.
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http://dx.doi.org/10.1016/j.adro.2019.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817538PMC
July 2019

Isolated biopsy-proven recurrence of prostate carcinoma in the spermatic cord after radical prostatectomy detected with 11C-Choline PET/CT.

Urol Case Rep 2019 Sep 31;26:100985. Epub 2019 Jul 31.

Department of Radiation Oncology, Mayo Clinic, Rochester, MN, 200 First Street SW, Rochester, MN, 55905, USA.

We report an unusual case of a solitary prostatic metastasis in the spermatic cord, following robotic-assisted laparoscopic radical prostatectomy with pelvic lymph node dissection and salvage radiotherapy, detected with the use of C-Choline PET/CT, heralded by a progressive rise in PSA. This lesion was biopsy-proven and surgically resected through radical left-sided orchiectomy. Postoperatively his PSA was undetectable and remained undetectable with no evidence of recurrent disease.
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http://dx.doi.org/10.1016/j.eucr.2019.100985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685691PMC
September 2019

Is there any benefit in adding postoperative adjuvant concurrent radiotherapy and chemotherapy for penile cancer with regional lymph node metastasis?

Minerva Urol Nefrol 2020 Aug 25;72(4):474-481. Epub 2019 Jul 25.

Department of Urology, Mayo Clinic, Rochester, MN, USA -

Background: The aim of this study was to evaluate whether there is any benefit in adding postoperative adjuvant concurrent radiotherapy and chemotherapy (RT-CHT) for penile cancer with regional lymph node metastasis (RLNM).

Methods: A single institution, retrospective study was conducted for a total of 23 patients with RLNM from penile squamous cell carcinoma. All underwent a definitive surgical intervention for both primary tumor and RLNM. Of these, 11 patients received adjuvant concurrent RT and CHT within 3 months after surgery (RT-CHT group), while 12 patients received no additional treatment (Surveillance Group). Overall survival was calculated with the Kaplan-Meier method. The difference in survival between the two groups was tested using the log-rank test. A potential prognostic factor for survival was evaluated using a univariate Cox-proportional hazards model.

Results: Median follow-up for the entire group was 15.8 months (17.1 months for the RT-CHT group and 10.7 months for the Surveillance Group). Overall survival at 1 and 2 years were 54.5% and 27.2%, respectively, for the RT-CHT Group, compared to 57.1% and 28.4% for the Surveillance Group (log-rank=0.68). On a univariate analysis, the number of involved lymph nodes and the presence of pN3 disease were associated with poor prognosis (P>0.001 and P=0.049, respectively). The RT-CHT Group had more extensive RLNM with a higher median number of positive nodes (5 vs. 3) and more pN3 disease (72.7% vs. 16.7%) than the Surveillance Group. The rate of complications requiring hospitalization was higher in the RT-CHT Group (63.6% vs. 16.6%; P=0.02), as was the rate of systemic complications (34.7% vs. 0%; P<0.01).

Conclusions: Penile cancer with extensive RLNM carries a poor prognosis. Despite having more extensive RLNM, the RT-CHT group had a similar overall survival as the Surveillance Group. This suggests a potential benefit of postoperative adjuvant concurrent RT-CHT for patients with extensive RLNM, although it carries an increased risk of complications. Further study is warranted to assess the benefit-to-risk ratio of this combined adjuvant therapy.
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http://dx.doi.org/10.23736/S0393-2249.19.03387-3DOI Listing
August 2020

Single-fraction Stereotactic Body Radiation Therapy versus Conventionally Fractionated Radiation Therapy for the Treatment of Prostate Cancer Bone Metastases.

Adv Radiat Oncol 2019 Apr-Jun;4(2):314-322. Epub 2019 Feb 19.

Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.

Purpose: This study aimed to compare outcomes of patients with prostate cancer with bone metastases treated with stereotactic body radiation therapy (SBRT) versus conventionally fractionated radiation therapy (CFRT).

Methods And Materials: An institutional, retrospective review was conducted of patients with prostate cancer receiving radiation therapy to bone metastases. In-field failure (IFF) was the primary outcome of the study, and distant failure (DF) and biochemical failure (BF) were secondary outcomes.

Results: A total of 249 metastases (191 SBRT; 58 CFRT) in 201 patients with a median follow-up of 2.2 years were analyzed. The SBRT prescription dose was predominantly 18 Gy (45.5%) or 20 Gy (46.6%) in a single fraction. CFRT was given either as 8 Gy in 1 fraction (56.9%) or 20 Gy in 5 fractions (41.4%). Imaging follow up was performed most frequently with C-choline positron emission tomography/computed tomography (79%) or bone scan (10%). The median time to IFF was 1.6 years for CFRT-treated lesions and not met (>4.4 years) for SBRT. The 1- and 3-year IFF estimates were 34.4% (95% confidence interval [CI], 19.9-46.2) and 53.3% (95% CI, 34.3-66.8) for lesions treated with CFRT compared with 4.5% (95% CI, 1.4-7.5) and 12.9% (95% CI, 6.6-18-8) for those treated with SBRT ( < .01). On multivariate regression, the hazard ratio (HR) for IFF with CFRT compared with SBRT was 6.8 (95% CI, 3.7-12.5;  < .01). There were nonsignificant reduced rates of BF (HR, 1.4; 95% CI, 1.0-2.1;  = .05) and DF (HR, 1.3; 95% CI, 1.0-1.8;  = .08) in patients who received SBRT. The 3-year BF and DF estimates in these patients were 88.6% (95% CI, 82.0-92.8) and 82.2% (95% CI, 74.5-87.6), respectively.

Conclusions: SBRT for the management of prostate cancer bone metastases significantly reduces radiographic IFF. However, the high rate of subsequent DF and BF highlights the challenges in selecting patients who may benefit from aggressive radiation therapy.
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http://dx.doi.org/10.1016/j.adro.2019.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460234PMC
February 2019

Reducing seed migration to near zero with stranded-seed implants: Comparison of seed migration rates to the chest in 1000 permanent prostate brachytherapy patients undergoing implants with loose or stranded seeds.

Brachytherapy 2019 May - Jun;18(3):306-312. Epub 2019 Mar 8.

Department of Radiation Oncology, Mayo Clinic, Rochester, MN.

Purpose: Pulmonary seed emboli to the chest may occur after permanent prostate brachytherapy (PPB). The purpose of this study is to analyze factors associated with seed migration to the chest in a large series of PPB patients from a single institution undergoing implant with either loose seeds (LS), mixed loose and stranded seeds (MS), or exclusively stranded seeds in an absorbable vicryl suture (VS).

Methods And Materials: Between May 1998 and July 2015, a total of 1000 consecutive PPB patients with postoperative diagnostic chest x-rays at 4 months after implant were analyzed for seed migration. Patients were grouped based on seed implant technique: LS = 391 (39.1%), MS = 43 (4.3%), or VS = 566 (56.6%). Univariate and multivariate analysis were performed using Cox proportional hazards regression models to determine predictors of seed migration.

Results: Overall, 18.8% of patients experienced seed migration to the chest. The incidence of seed migration per patient was 45.5%, 11.6%, and 0.9% (p < 0.0001), for patients receiving LS, MS, or VS PPB, respectively. The right and left lower lobes were the most frequent sites of pulmonary seed migration. On multivariable analysis, planimetry volume (p = 0.0002; HR = 0.7 per 10 cc [0.6-0.8]), number of seeds implanted (p < 0.0001, HR = 2.4 per 25 seeds [1.7-3.4]), LS implant (p < 0.0001, HR = 15.9 [5.9-42.1]), and MS implant (p = 0.001, HR = 7.9 [2.3-28.1]) were associated with seed migration to the chest.

Conclusions: In this large series, significantly higher rates of seed migration to the chest are observed in implants using any LS with observed hazard ratios of 15.9 and 7.9 for LS and MS respectively, as compared with implants using solely stranded seeds.
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http://dx.doi.org/10.1016/j.brachy.2019.01.007DOI Listing
December 2019

Permanent prostate brachytherapy monotherapy with I-125 for low- and intermediate-risk prostate cancer: Outcomes in 974 patients.

Brachytherapy 2019 Jan - Feb;18(1):1-7. Epub 2018 Oct 4.

Department of Radiation Oncology, Mayo Clinic, Rochester, MN. Electronic address:

Purpose: To report outcomes of patients undergoing low-dose-rate (LDR) brachytherapy and investigate factors associated with biochemical failure and survival.

Methods: Consecutive patients undergoing LDR with I-125 at our institution between 1998 through 2013 for primary intact prostate cancer were examined. Those with low- and intermediate-risk disease receiving LDR with a minimum of 2 years followup and at least one post-LDR prostate-specific antigen (PSA) were included.

Results: About 974 patients satisfied inclusion criteria. With median followup of 72 months, biochemical failure occurred in 45 patients. Freedom from biochemical failure as defined by the Phoenix criterion was 96% and 88% at 5 and 10 years, worse for intermediate risk as compared with low risk, with 10-year freedom from biochemical failure of 76% versus 92% (hazard ratio [HR] = 3.7, p < 0.001), respectively. On multivariable analysis, increased prebiopsy PSA, Gleason 4 + 3, and no androgen deprivation therapy were associated with biochemical failure. Gleason 4 + 3 was the factor most strongly associated with biochemical failure (HR = 7.01, p < 0.001). No examined factors were associated with local failure. Gleason 4 + 3 disease increased the likelihood of distant metastasis (HR = 12.4, p = 0.003) and prostate cancer-specific death (HR = 13.2, p < 0.001). No difference in outcomes between patients with Gleason 3 + 3 versus 3 + 4 was observed.

Conclusions: LDR brachytherapy provided excellent outcomes in this large series of patients treated for localized organ-confined prostate cancer. Local recurrence at 10 years was low at 2.1%. Primary Gleason 4 + 3, higher pretreatment PSA, and no receipt of androgen deprivation therapy were the only factors associated with biochemical failure. Primary Gleason 4 disease was also predictive of distant metastases and decreased prostate cancer-specific survival.
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http://dx.doi.org/10.1016/j.brachy.2018.09.003DOI Listing
April 2019

Increased utilization of external beam radiotherapy relative to cystectomy for localized, muscle-invasive bladder cancer: a SEER analysis.

Bladder (San Franc) 2018 23;5(3):e34. Epub 2018 Aug 23.

Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA.

Objective: To assess recent utilization patterns of radiotherapy (RT) relative to cystectomy for muscle-invasive bladder cancer (MIBC) and evaluate survival trends over time in patients receiving RT.

Materials And Methods: The surveillance, epidemiology, and end results program (SEER) was used to identify patients diagnosed between 1992 and 2013 with localized MIBC. Patients with a prior history of non-bladder malignancy, who received no treatment, or did not have available treatment information, were excluded. Treatment utilization patterns were assessed using Cochran-Armitage tests for trend, and patient characteristics were compared using chi-square tests. Overall survival (OS) and cause-specific survival (CSS) were estimated using the Kaplan-Meier method. All-cause (ACM) and cause-specific mortality (CSM) were evaluated with multivariable Cox proportional hazards regression.

Results: Of 16175 patients analyzed, 11917 (74%) underwent cystectomy, and 4258 (26%) were treated with RT. Patients who received RT were older (median age 79 . 68, < 0.01). Over time, the proportion of patients receiving RT relative to cystectomy increased (24% 1992-2002 . 28% 2003-2013, < 0.01), despite median patient age throughout the study period remaining unchanged (71 for each 1992-2002 and 2003-2013, = 0.41). For RT, compared with patients diagnosed earlier, those diagnosed from 2010-2013 showed improved OS (64% . 60% at 1 year, < 0.01; 38% . 29% at 3 years, < 0.01) and CSS (71% . 67% at 1 year, = 0.01; 51% . 40% at 3 years, < 0.01). On multivariable analysis, diagnosis from 2010-2013 was associated with a lower estimated risk of ACM (hazard ratio 0.77; 95% confidence interval 0.66-0.89, < 0.001) and CSM (hazard ratio 0.81; 95% confidence interval 0.67-0.97, = 0.02).

Conclusion: Utilization of RT for localized MIBC increased relative to cystectomy from 1992 to 2013, despite the median age of treated patients remaining unchanged. More recent survival outcomes for patients receiving RT were improved, supporting continued use of bladder preservation strategies utilizing RT.
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http://dx.doi.org/10.14440/bladder.2018.639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401988PMC
August 2018

Low dose rate prostate brachytherapy.

Transl Androl Urol 2018 Jun;7(3):341-356

Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA.

Low dose rate (LDR) prostate brachytherapy is an evidence based radiation technique with excellent oncologic outcomes. By utilizing direct image guidance for radioactive source placement, LDR brachytherapy provides superior radiation dose escalation and conformality compared to external beam radiation therapy (EBRT). With this level of precision, late grade 3 or 4 genitourinary or gastrointestinal toxicity rates are typically between 1% and 4%. Furthermore, when performed as a same day surgical procedure, this technique provides a cost effective and convenient strategy. A large body of literature with robust follow-up has led multiple expert consensus groups to endorse the use of LDR brachytherapy as an appropriate management option for all risk groups of non-metastatic prostate cancer. LDR brachytherapy is often effective when delivered as a monotherapy, although for some patients with intermediate or high-risk disease, optimal outcome are achieved in combination with supplemental EBRT and/or androgen deprivation therapy (ADT). In addition to reviewing technical aspects and reported clinical outcomes of LDR prostate brachytherapy, this article will focus on the considerations related to appropriate patient selection and other aspects of its use in the treatment of prostate cancer.
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http://dx.doi.org/10.21037/tau.2017.12.15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043740PMC
June 2018

Brachytherapy in the Management of Prostate Cancer.

Surg Oncol Clin N Am 2017 07 11;26(3):491-513. Epub 2017 May 11.

Department of Radiation Oncology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA.

Brachytherapy is performed by directly inserting radioactive sources into the prostate gland and is an important treatment option for appropriately selected men with prostate adenocarcinoma. Brachytherapy provides highly conformal radiotherapy and delivers tumoricidal doses that exceed those administered with external beam radiation therapy. There is a significant body of literature supporting the excellent long-term oncologic and safety outcomes achieved when brachytherapy is used for men in all risk categories of nonmetastatic prostate cancer. This article highlights some important considerations and published outcomes that relate to brachytherapy and its role in the treatment of prostate cancer.
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http://dx.doi.org/10.1016/j.soc.2017.01.008DOI Listing
July 2017

Factors Associated With Survival Following Radium-223 Treatment for Metastatic Castration-resistant Prostate Cancer.

Clin Genitourin Cancer 2017 12 26;15(6):e969-e975. Epub 2017 Apr 26.

Department of Radiation Oncology, Mayo Clinic Arizona, Phoenix, AZ.

Background: Radium-223 (Ra) improves survival in patients with metastatic castration-resistant prostate cancer (mCRPC). This retrospective analysis was performed to better understand its efficacy in routine clinical practice and identify factors associated with survival.

Materials And Methods: Sixty-four patients with mCRPC who received Ra between 2013 and 2015 were the basis of this retrospective study. Clinical outcomes and patient characteristics were obtained. Potential prognostic factors for survival were evaluated by univariate analysis using the log-rank test and multivariate analysis using the Cox proportional hazard method.

Results: The median survival was 12.9 months. Twenty-one patients (33%) developed a skeletal event, and the median time to the first skeletal event was 4.4 months. In univariate analysis, factors significantly associated with survival included: no prior chemotherapy, ≤ 5 bone metastases, baseline prostate-specific antigen (PSA) ≤ 36 ng/mL, baseline alkaline phosphatase (ALP) < 115 U/L, baseline hemoglobin > 12 g/dL, ALP response after Ra treatment, PSA decrease during Ra treatment, and absence of > 25% PSA increase during Ra treatment. In multivariate analysis, 4 factors remained significant: no prior chemotherapy, ≤ 5 bone metastases, baseline ALP < 115 U/L, and ALP response after Ra treatment.

Conclusion: When Ra is administered in routine clinical practice, clinical outcomes can be more variable than those reported in the randomized study owing to patient heterogeneity. Four factors were identified to be significantly associated with survival after Ra treatment. These pretreatment factors may be used as stratification factors in future studies to investigate whether Ra would be more effective for patients with newly diagnosed metastatic disease that is sensitive to androgen deprivation therapy.
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http://dx.doi.org/10.1016/j.clgc.2017.04.016DOI Listing
December 2017

Patterns of Recurrence After Postprostatectomy Fossa Radiation Therapy Identified by C-11 Choline Positron Emission Tomography/Computed Tomography.

Int J Radiat Oncol Biol Phys 2017 03 17;97(3):526-535. Epub 2016 Nov 17.

Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota. Electronic address:

Purpose: To evaluate C-11 choline positron emission tomography/computed tomography (CholPET) in staging and determining patterns of recurrence in prostate cancer patients with rising prostate-specific antigen levels after prostatectomy radiation therapy (RT).

Methods And Materials: The study includes patients with biochemical failure after postprostatectomy RT who underwent CholPET between 2008 and 2015. Patient and disease characteristics were examined in relation to sites of recurrence. All RT dosimetry records were reviewed, and recurrences were mapped on a representative computed tomography dataset with their relationship relative to the irradiated fossa field as out of field (OOF), edge of field (EOF; recurrence within <45-Gy isodose lines), or in field (IF; recurrence within ≥45-Gy isodose lines).

Results: Forty-one patients were identified with 121 sites of recurrence (median 2 sites; interquartile range [IQR], 1-4). The median prostate-specific antigen level at CholPET was 3.1 (IQR, 1.9-5.6) ng/mL. Median interval from RT to biochemical failure was 24 (IQR, 10-46) months, with recurrence identified on CholPET at a median of 15 (IQR, 7-28) months from biochemical failure. Histologic confirmation of recurrence was obtained in 20 patients (49%), with the remainder confirmed by treatment response. Five patients (12%) had IF recurrences, 10 patients (24%) had EOF recurrences (median dose 10 Gy; IQR, 5-30 Gy), and 36 patients (88%) had OOF recurrences. Ten patients had combination failures: 6 (15%) EOF/OOF and 4 (10%) IF/OOF. Fifty-seven recurrences (47%) were pelvic nodal sites inferior to the L5-S1 interspace, of which 52 (43%) were within a pelvic RT field. Eighty-one recurrences (67%) were nodal and inferior to the aortic bifurcation.

Conclusions: Using CholPET, we found that the majority of patients evaluated for biochemical failure recurred outside of the postprostatectomy RT field. Furthermore, most recurrence sites were nodal and inferior to the aortic bifurcation. These results provide data that may be useful for examining strategies that include elective lymph node irradiation in postprostatectomy patients.
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http://dx.doi.org/10.1016/j.ijrobp.2016.11.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5308881PMC
March 2017

Predictors of prostate volume reduction following neoadjuvant cytoreductive androgen suppression.

J Contemp Brachytherapy 2016 Oct 4;8(5):371-378. Epub 2016 Nov 4.

Department of Radiation Oncology.

Purpose: Limited duration cytoreductive neoadjuvant hormonal therapy (NHT) is used prior to definitive radiotherapeutic management of prostate cancer to decrease prostate volume. The purpose of this study is to examine the effect of NHT on prostate volume before permanent prostate brachytherapy (PPB), and determine associated predictive factors.

Material And Methods: Between June 1998 and April 2012, a total of 1,110 patients underwent PPB and 207 patients underwent NHT. Of these, 189 (91.3%) underwent detailed planimetric transrectal ultrasound before and after NHT prior to PPB. Regression analysis was used to assess predictors of absolute and percentage change in prostate volume after NHT.

Results: The median duration of NHT was 4.9 months with inter quartile range (IQR), 4.2-6.6 months. Prostate-specific antigen (PSA) reduced by a median of 97% following NHT. The mean prostate volume before NHT was 62.5 ± 22.1 cm (IQR: 46-76 cm), and after NHT, it was 37.0 ± 14.5 cm (IQR: 29-47 cm). The mean prostate volume reduction was 23.4 cm (35.9%). Absolute prostate volume reduction was positively correlated with initial volume and inversely correlated with T-stage, Gleason score, and NCCN risk group. In multivariate regression analyses, initial prostate volume ( < 0.001) remained as a significant predictor of absolute and percent prostate volume reduction. Total androgen suppression was associated with greater percent prostate volume reduction than luteinizing hormone releasing hormone agonist (LHRHa) alone ( = 0.001).

Conclusions: Prostate volume decreased by approximately one third after 4.9 months of NHT, with total androgen suppression found to be more efficacious in maximizing cytoreduction than LHRHa alone. Initial prostate volume is the greatest predictor for prostate volume reduction.
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http://dx.doi.org/10.5114/jcb.2016.63377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5116454PMC
October 2016

Identification of Site-specific Recurrence Following Primary Radiation Therapy for Prostate Cancer Using C-11 Choline Positron Emission Tomography/Computed Tomography: A Nomogram for Predicting Extrapelvic Disease.

Eur Urol 2017 03 3;71(3):340-348. Epub 2016 Sep 3.

Department of Urology, Mayo Clinic, Rochester, MN, USA.

Background: Management of recurrent prostate cancer (CaP) after radiotherapy (RT) is dependent on accurate localization of the site of recurrent disease.

Objective: To describe the anatomic patterns and clinical features associated with CaP recurrence following RT identified on advanced imaging.

Design, Setting, And Participants: Retrospective review of 184 patients with a rising prostate-specific antigen (PSA) after RT for CaP.

Intervention: C-11 choline positron emission tomography/computed tomography (CholPET).

Outcome Measurements And Statistical Analysis: Recurrence patterns were classified as pelvic soft tissue only (as a surrogate for potentially salvageable disease) versus any extrapelvic disease, and clinical features were compared between patterns. Multivariable logistic regression was used to generate a predictive nomogram for extrapelvic recurrence. Discrimination was assessed with a c-index.

Results And Limitations: Recurrence site was identified in 161 (87%) patients, with 95 (59%) sites histologically confirmed. Factors associated with the detection of recurrence included the difference between PSA nadir and PSA at CholPET (odds ratio: 1.30, p<0.01) and National Comprehensive Cancer Network high-risk classification (odds ratio: 10.83, p=0.03). One hundred (54.3%) patients recurred in the pelvic soft tissue only, while 61 (33%) had extrapelvic recurrence. Of 21 patients who underwent CholPET prior to meeting the Phoenix criteria of biochemical failure, 15 (71%) had recurrence identified on CholPET with 11 localized to the pelvis. On multivariable analysis, the difference between PSA nadir and PSA at CholPET, time from RT, and National Comprehensive Cancer Network risk group were predictive of recurrence outside of the pelvis, and a nomogram was generated with a c-index of 0.79.

Conclusions: CholPET identified the site of recurrence in 87% of patients with a rising PSA after RT; most commonly within the pelvis in potentially salvageable locations. A predictive nomogram was generated, and pending external validation, this may aid in assessing the risk of disease beyond the pelvis. These findings underscore the importance of advanced imaging when considering management strategies for patients with a rising PSA following primary RT.

Patient Summary: We identified anatomic patterns of recurrence in patients with a rising prostate-specific antigen after radiotherapy using C-11 choline positron emission tomography/computed tomography. Most recurrences were localized to the pelvis and we were able to generate a tool to aid in disease localization prior to evaluation with advanced imaging.
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http://dx.doi.org/10.1016/j.eururo.2016.08.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729924PMC
March 2017

Improved Metastasis-Free and Survival Outcomes With Early Salvage Radiotherapy in Men With Detectable Prostate-Specific Antigen After Prostatectomy for Prostate Cancer.

J Clin Oncol 2016 11;34(32):3864-3871

Bradley J. Stish, Thomas M. Pisansky, William S. Harmsen, Brian J. Davis, and Richard Choo, Mayo Clinic, Rochester MN; and Katherine S. Tzou and Steven J. Buskirk, Mayo Clinic, Jacksonville FL.

Purpose To describe outcomes of salvage radiotherapy (SRT) for men with detectable prostate-specific antigen (PSA) after radical prostatectomy for prostate cancer and identify associations with outcomes. Patients and Methods A total of 1,106 patients received SRT between January 1987 and July 2013, with median follow-up 8.9 years. Outcomes were estimated using Kaplan-Meier for overall survival (OS) and cumulative incidence for biochemical recurrence (BcR), distant metastases (DM), and cause-specific mortality (CSM). Variable associations with outcomes used Cox or Fine-Gray methods, as appropriate. Multiple variable analyses used backward selection with P < .05 for retention. Results In multiple variable analyses, pathologic tumor stage, Gleason score, and pre-SRT PSA were associated with BcR, DM, CSM, and OS; androgen suppression and SRT doses > 68 Gy were associated with BcR; and age was associated with OS. Each pre-SRT PSA doubling increased significantly the relative risk of BcR (hazard ratio [HR], 1.30; P < .001), DM (HR, 1.32; P < .001), CSM (HR, 1.40; P < .001), and all-cause mortality (HR, 1.12; P = .02). Using a pre-SRT PSA cutoff ≤ 0.5 versus > 0.5 ng/mL, 5-year and 10-year cumulative incidences for BcR were 42% versus 56% and 60% versus 68% ( P < .001), DM 7% versus 14% and 13% versus 25% ( P < .001), CSM 1% versus 4% and 6% versus 13% ( P < .001), and OS of 94% versus 92% and 83% versus 73% ( P > .05). Conclusion SRT outcomes are in part affected by factors associated with prostatectomy findings but may be positively affected by using SRT at lower PSA levels, including reductions in BcR, DM, CSM, and all-cause mortality. These findings argue against prolonged monitoring of detectable postprostatectomy PSA levels that delay initiation of SRT.
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http://dx.doi.org/10.1200/JCO.2016.68.3425DOI Listing
November 2016

Second malignancies after radiotherapy for prostate cancer: systematic review and meta-analysis.

BMJ 2016 Mar 2;352:i851. Epub 2016 Mar 2.

Division of Urology, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Room MG-406, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada

Objective: To determine the association between exposure to radiotherapy for the treatment of prostate cancer and subsequent second malignancies (second primary cancers).

Design: Systematic review and meta-analysis of observational studies.

Data Sources: Medline and Embase up to 6 April 2015 with no restrictions on year or language.

Study Selection: Comparative studies assessing the risk of second malignancies in patients exposed or unexposed to radiotherapy in the course of treatment for prostate cancer were selected by two reviewers independently with any disagreement resolved by consensus.

Data Extraction And Synthesis: Two reviewers independently extracted study characteristics and outcomes. Risk of bias was assessed with the Newcastle-Ottawa scale. Outcomes were synthesized with random effects models and Mantel-Haenszel weighting. Unadjusted odds ratios and multivariable adjusted hazard ratios, when available, were pooled.

Main Outcome Measures: Second cancers of the bladder, colorectal tract, rectum, lung, and hematologic system.

Results: Of 3056 references retrieved, 21 studies were selected for analysis. Most included studies were large multi-institutional reports but had moderate risk of bias. The most common type of radiotherapy was external beam; 13 studies used patients treated with surgery as controls and eight used patients who did not undergo radiotherapy as controls. The length of follow-up among studies varied. There was increased risk of cancers of the bladder (four studies; adjusted hazard ratio 1.67, 95% confidence interval 1.55 to 1.80), colorectum (three studies; 1.79, 1.34 to 2.38), and rectum (three studies; 1.79, 1.34 to 2.38), but not cancers of the hematologic system (one study; 1.64, 0.90 to 2.99) or lung (two studies; 1.45, 0.70 to 3.01), after radiotherapy compared with the risk in those unexposed to radiotherapy. The odds of a second cancer varied depending on type of radiotherapy: treatment with external beam radiotherapy was consistently associated with increased odds while brachytherapy was not. Among the patients who underwent radiotherapy, from individual studies, the highest absolute rates reported for bladder, colorectal, and rectal cancers were 3.8%, 4.2%, and 1.2%, respectively, while the lowest reported rates were 0.1%, 0.3%, and 0.3%.

Conclusion: Radiotherapy for prostate cancer was associated with higher risks of developing second malignancies of the bladder, colon, and rectum compared with patients unexposed to radiotherapy, but the reported absolute rates were low. Further studies with longer follow-up are required to confirm these findings.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4775870PMC
http://dx.doi.org/10.1136/bmj.i851DOI Listing
March 2016

Establishment of practice standards in nomenclature and prescription to enable construction of software and databases for knowledge-based practice review.

Pract Radiat Oncol 2016 Jul-Aug;6(4):e117-e126. Epub 2016 Jan 26.

Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.

Introduction: Establishment of standards within a practice and across disease site groups for nomenclatures, prescription formatting, and measured dose-volume histogram (DVH) metrics is a key enabling step for creating software and database solutions to make routine aggregation of dosimetric data for all patients treated in a practice, practical. A process of physician-driven, iterative dialogs coupled with development of technical tools is required to implement the cultural and procedural changes. The cumulative reward for this effort is a database that can be used for defining practice norms, benchmarking against national standards, and tracking dosimetric effects of longitudinal practice pattern changes.

Methods And Materials: A 4-year project was carried out to develop and introduce standardizations, modify processes, and develop computer-based tools for reporting, aggregation, and analysis of prescription and DVH metrics. Physician disease site groups developed 42 target and 81 normal tissue templates. From the database of 32,002 DVH metrics, benchmarking was illustrated for a subgroup of breast (281) and prostate (324) patients treated with conventional fractionation over a 16-month period. Breast patients were segregated according to prescription template used: simple (S, tangents only) vs complex (C, tangents + supraclavicular ± intramammary nodes) and left (S-L or C-L) versus right (S-R or C-R).

Results: Prostate patients' median and 50% confidence intervals (CIs) for bladder, stated according to the nomenclature: the percentage of bladder volume receiving doses of ≥40 Gy (V40[%]), V65Gy[%], V70Gy[%], V75Gy[%], and V80Gy[%] were 45.5 (24.9-57.0), 15.6 (9.0-23.8), 7.6 (3.3-13.6), 2.0 (0.0-7.9), and 0.0 (0.0-1.4), respectively. Values for rectum: V50Gy[%], V60 Gy[%], V65Gy[%], V70Gy[%], and V75Gy[%] were 37.1 (27.8-43.5), 21.8 (15.6-25.5), 14.6 (9.6-18.0), 7.7 (1.9-12.3), and 1.0 (0-7.0), respectively. For breast patients, heart:mean Gray values were 1.5 (1.0-2.0), 3.1 (2.2-4.8), 0.4 (0.3-0.7), and 1.1 (0.8-2.2) for S-L, C-L, S-R, and C-R, respectively. Longitudinal, moving window plots of median, 50% CI, and 90% CI for 6-month periods demonstrated the effect of practice changes to reduce heart doses.

Conclusions: Standardization was challenging as a practice change, but has resulted in significant improvements for both our clinical and research efforts.
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http://dx.doi.org/10.1016/j.prro.2015.11.001DOI Listing
March 2017

Surgery Versus Radiotherapy for Clinically-localized Prostate Cancer: A Systematic Review and Meta-analysis.

Eur Urol 2016 07 15;70(1):21-30. Epub 2015 Dec 15.

Division of Urology, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, Toronto, Canada; Division of Urology, Department of Surgery, University of Toronto, Toronto, ON, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada. Electronic address:

Context: To date, there is no Level 1 evidence comparing the efficacy of radical prostatectomy and radiotherapy for patients with clinically-localized prostate cancer.

Objective: To conduct a meta-analysis assessing the overall and prostate cancer-specific mortality among patients treated with radical prostatectomy or radiotherapy for clinically-localized prostate cancer.

Evidence Acquisition: We searched Medline, EMBASE, and the Cochrane Library through June 2015 without year or language restriction, supplemented with hand search, using Preferred Reporting Items for Systematic Reviews and Meta-Analysis and Meta-analysis of Observational Studies in Epidemiology guidelines. We used multivariable adjusted hazard ratios (aHRs) to assess each endpoint. Risk of bias was assessed using the Newcastle-Ottawa scale.

Evidence Synthesis: Nineteen studies of low to moderate risk of bias were selected and up to 118 830 patients were pooled. Inclusion criteria and follow-up length varied between studies. Most studies assessed patients treated with external beam radiotherapy, although some included those treated with brachytherapy separately or with the external beam radiation therapy group. The risk of overall (10 studies, aHR 1.63, 95% confidence interval 1.54-1.73, p<0.00001; I(2)=0%) and prostate cancer-specific (15 studies, aHR 2.08, 95% confidence interval 1.76-2.47, p < 0.00001; I(2)=48%) mortality were higher for patients treated with radiotherapy compared with those treated with surgery. Subgroup analyses by risk group, radiation regimen, time period, and follow-up length did not alter the direction of results.

Conclusions: Radiotherapy for prostate cancer is associated with an increased risk of overall and prostate cancer-specific mortality compared with surgery based on observational data with low to moderate risk of bias. These data, combined with the forthcoming randomized data, may aid clinical decision making.

Patient Summary: We reviewed available studies assessing mortality after prostate cancer treatment with surgery or radiotherapy. While the studies used have a potential for bias due to their observational design, we demonstrated consistently higher mortality for patients treated with radiotherapy rather than surgery.
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http://dx.doi.org/10.1016/j.eururo.2015.11.010DOI Listing
July 2016

Neuroendocrine differentiation in prostate cancer: a mechanism of radioresistance and treatment failure.

Front Oncol 2015 14;5:90. Epub 2015 Apr 14.

Department of Pathology, David Geffen School of Medicine at UCLA , Los Angeles, CA , USA.

Neuroendocrine differentiation (NED) in prostate cancer is a well-recognized phenotypic change by which prostate cancer cells transdifferentiate into neuroendocrine-like (NE-like) cells. NE-like cells lack the expression of androgen receptor and prostate specific antigen, and are resistant to treatments. In addition, NE-like cells secrete peptide hormones and growth factors to support the growth of surrounding tumor cells in a paracrine manner. Accumulated evidence has suggested that NED is associated with disease progression and poor prognosis. The importance of NED in prostate cancer progression and therapeutic response is further supported by the fact that therapeutic agents, including androgen-deprivation therapy, chemotherapeutic agents, and radiotherapy, also induce NED. We will review the work supporting the overall hypothesis that therapy-induced NED is a mechanism of resistance to treatments, as well as discuss the relationship between therapy-induced NED and therapy-induced senescence, epithelial-to-mesenchymal transition, and cancer stem cells. Furthermore, we will use radiation-induced NED as a model to explore several NED-based targeting strategies for development of novel therapeutics. Finally, we propose future studies that will specifically address therapy-induced NED in the hope that a better treatment regimen for prostate cancer can be developed.
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http://dx.doi.org/10.3389/fonc.2015.00090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396194PMC
April 2015

Long-term results of a study using individualized planning target volumes for hypofractionated intensity-modulated radiotherapy boost for prostate cancer.

Radiat Oncol 2015 Apr 18;10:95. Epub 2015 Apr 18.

Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, 2075 Bayview Ave., Toronto, ON, M4N 3 M5, Canada.

Background: This is the final report of a prospective phase I study which evaluated the feasibility, toxicities, and biochemical control in prostate cancer patients treated with a hypofractionated boost utilizing a fiducial marker-based daily image guidance strategy and small patient-specific PTV margins.

Methods: Low- and intermediate-risk prostate cancer patients underwent transperineal ultrasound-guided implantation of three gold fiducial markers and were treated with three-dimensional conformal radiotherapy to 42 Gy (2 Gy/day). During the first nine fractions of treatment, pre- and post-treatment electronic portal imaging was performed to calculate intrafraction prostate motion. Patient-specific PTV margins were derived and a 30 Gy (3 Gy/day) intensity modulated radiotherapy boost was delivered (Total dose = 72 Gy in 31 fractions; EQD2 = 81 Gy, α/β = 1.4).

Results: Thirty-three patients completed treatment and were followed for a median of 7.2 years (range, 1.2 - 9.5). Seven patients (21%) developed Radiation Therapy Oncology Group (RTOG) late grade 2 GI toxicity and 1 patient (3%) developed late grade 2 GU toxicity. No patients developed late grade 3 GI or GU toxicity. To date, nine patients developed PSA relapse according to the Phoenix criteria. The actuarial five, seven and nine year biochemical control (BC) rates were 87% (95% confidence interval: 69-95), 77% (95% confidence interval: 56-89) and 66% (95% confidence interval: 42-82).

Conclusions: Our study demonstrates that the use of prostate fiducial markers in combination with a daily online image guidance protocol permits reduced, patient-specific PTV margins in a hypofractionated treatment scheme. This treatment planning and delivery strategy was well tolerated in the intermediate time frame. The use of very small PTV margins did not result in excessive failures when compared to other radiation regimens of similar radiobiological intensity.
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http://dx.doi.org/10.1186/s13014-015-0400-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407385PMC
April 2015

Comparison of biochemical failure rates between permanent prostate brachytherapy and radical retropubic prostatectomy as a function of posttherapy PSA nadir plus 'X'.

Radiat Oncol 2014 Jul 29;9:171. Epub 2014 Jul 29.

Department of Radiation Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.

Background: Prostate-specific antigen (PSA) nadir + 2 ng/mL, also known as the Phoenix definition, is the definition most commonly used to establish biochemical failure (BF) after external beam radiotherapy for prostate cancer management. The purpose of this study is to compare BF rates between permanent prostate brachytherapy (PPB) and radical retropubic prostatectomy (RRP) as a function of PSA nadir plus varying values of X and examine the associated implications.

Methods And Materials: We retrospectively searched for patients who underwent PPB or RRP at our institution between 1998 and 2004. Only primary patients not receiving androgen-deprivation therapy were included in the study. Three RRP patients were matched to each PPB patient on the basis of prognostic factors. BF rates were estimated for PSA nadirs + different values of X.

Results: A total of 1,164 patients were used for analysis: 873 in the RRP group and 291 in the PPB group. Patients were equally matched by clinical stage, biopsy Gleason sum, primary Gleason grade, and pretherapy PSA value. Median follow-up was 3.1 years for RRP patients and 3.6 years in the PPB group (P = .01). Using PSA nadir + 0.1 ng/mL for the definition of BF, the 5-year BF rate was 16.3% for PPB patients and 13.5% for RRP patients (P = .007), whereas at nadir + 2 ng/mL or greater, the BF rates were less than 3% and were indistinguishable between PPB and RRP patients.

Conclusions: In a cohort of well-matched patients who had prostatectomy or brachytherapy, we examined BF as a function of nadir + X, where X was treated as a continuous variable. As X increases from 0.1 to 2.0 ng/mL, the BF curves converge, and above 2.0 ng/mL they are essentially indistinguishable. The data presented are of interest as BF definitions continue to evolve.
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http://dx.doi.org/10.1186/1748-717X-9-171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123307PMC
July 2014

Outcomes in a multi-institutional cohort of patients treated with intraoperative radiation therapy for advanced or recurrent renal cell carcinoma.

Int J Radiat Oncol Biol Phys 2014 Mar 8;88(3):618-23. Epub 2014 Jan 8.

Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Purpose/objective(s): This study aimed to analyze outcomes in a multi-institutional cohort of patients with advanced or recurrent renal cell carcinoma (RCC) who were treated with intraoperative radiation therapy (IORT).

Methods And Materials: Between 1985 and 2010, 98 patients received IORT for advanced or locally recurrent RCC at 9 institutions. The median follow-up time for surviving patients was 3.5 years. Overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were estimated with the Kaplan-Meier method. Chained imputation accounted for missing data, and multivariate Cox hazards regression tested significance.

Results: IORT was delivered during nephrectomy for advanced disease (28%) or during resection of locally recurrent RCC in the renal fossa (72%). Sixty-nine percent of the patients were male, and the median age was 58 years. At the time of primary resection, the T stages were as follows: 17% T1, 12% T2, 55% T3, and 16% T4. Eighty-seven percent of the patients had a visibly complete resection of tumor. Preoperative or postoperative external beam radiation therapy was administered to 27% and 35% of patients, respectively. The 5-year OS was 37% for advanced disease and 55% for locally recurrent disease. The respective 5-year DSS was 41% and 60%. The respective 5-year DFS was 39% and 52%. Initial nodal involvement (hazard ratio [HR] 2.9-3.6, P<.01), presence of sarcomatoid features (HR 3.7-6.9, P<.05), and higher IORT dose (HR 1.3, P<.001) were statistically significantly associated with decreased survival. Adjuvant systemic therapy was associated with decreased DSS (HR 2.4, P=.03). For locally recurrent tumors, positive margin status (HR 2.6, P=.01) was associated with decreased OS.

Conclusions: We report the largest known cohort of patients with RCC managed by IORT and have identified several factors associated with survival. The outcomes for patients receiving IORT in the setting of local recurrence compare favorably to similar cohorts treated by local resection alone suggesting the potential for improved DFS with IORT.
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http://dx.doi.org/10.1016/j.ijrobp.2013.11.207DOI Listing
March 2014
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