Publications by authors named "Patrick A Kupelian"

138 Publications

Identifying the Best Candidates for Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography as the Primary Staging Approach Among Men with High-risk Prostate Cancer and Negative Conventional Imaging.

Eur Urol Oncol 2021 Feb 15. Epub 2021 Feb 15.

Department of Radiation Oncology, UCLA Medical Center, Los Angeles, CA, USA. Electronic address:

Prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) is an emerging imaging modality with greater sensitivity and specificity over conventional imaging for prostate cancer (PCa) staging. Using data from two prospective trials (NCT03368547 and NCT04050215), we explored predictors of overall upstaging (nodal and metastatic) by PSMA PET/CT among patients with cN0M0 National Comprehensive Cancer Network high-risk PCa on conventional imaging (n = 213). Overall, 21.1%, 8.9%, and 23.9% of patients experienced nodal, metastatic, and overall upstaging, respectively, without histologic confirmation. On multivariable analysis, Gleason grade group (GG) and percent positive core (PPC) on systematic biopsy significantly predict overall upstaging (odds ratio [OR] 2.15, 95% confidence interval [CI] 1.33-3.45; p =  0.002; and OR 1.03, 95% CI 1.01-1.04; p <  0.001). Overall upstaging was significantly more frequent among men with GG 5 disease (33.0% vs. 17.6%; p =  0.0097) and PPC ≥50% (33.0% vs 15.0%; p =  0.0020). We constructed a nomogram that predicts overall upstaging using initial prostate-specific antigen, PPC, GG, and cT stage, with coefficients estimated from a standard logistic regression model (using maximum likelihood estimation). It is internally validated with a tenfold cross-validated area under the receiver operating characteristic curve estimated at 0.74 (95% CI 0.67-0.82). In our cohort, 90% of patients who had a nomogram-estimated risk below the cutoff of 22% for overall upstaging could have been spared PSMA PET/CT as our model correctly predicted no upstaging. In other words, the predictive model only missed 10% of patients who would otherwise have benefitted from PSMA PET/CT. PATIENT SUMMARY: We analyzed predictors of overall upstaging (lymph node or/and metastasis) by prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) from conventional imaging in men with high-risk prostate cancer undergoing initial staging deemed free of disease in the lymph nodes and distant metastasis by conventional imaging techniques. We found that the pathologic grade and disease burden in a prostate biopsy are associated with upstaging. We also developed a tool that predicts the probability of upstaging according to an individual patient's characteristics. Our study may help in defining patient groups who are most likely to benefit from the addition of a PSMA PET/CT scan.
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http://dx.doi.org/10.1016/j.euo.2021.01.006DOI Listing
February 2021

Stereotactic Body Radiotherapy for High-Risk Localized Carcinoma of the Prostate (SHARP) Consortium: Analysis of 344 Prospectively Treated Patients.

Int J Radiat Oncol Biol Phys 2021 Jan 23. Epub 2021 Jan 23.

Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, California. Electronic address:

Purpose: To explore the efficacy and toxicity of stereotactic body radiation therapy (SBRT) in high-risk prostate cancer (HRPCa) in a consortium of 7 institutional phase 2 trials and prospective registries.

Methods And Materials: Individual patient data were pooled for 344 patients with a minimum follow-up of 24 months. Biochemical recurrence-free survival (BCRFS) and distant metastasis-free survival (DMFS) were estimated using a Kaplan-Meier framework. Fine and Gray competing risk and Cox proportional hazards regression models were developed to assess the association between time to BCR and time to distant metastasis and prespecified variables of interest. Logistic regression models were developed to evaluate associations between acute and late grade ≥2 genitourinary and gastrointestinal and the following a priori-specified variables: age, dose per fraction, ADT use, and nodal radiation therapy.

Results: Median follow-up was 49.5 months. Seventy-two percent of patients received ADT, with a median duration of 9 months, and 19% received elective nodal radiation therapy. Estimated 4-year BCRFS and DMFS rates were 81.7% (95% CI, 77.2%-86.5%) and 89.1% (95% CI, 85.3%-93.1%). The crude incidences of late grade ≥3 genitourinary and gastrointestinal toxicity were 2.3% and 0.9%.

Conclusions: These data support a favorable toxicity and efficacy profile for SBRT for HRPCa. Further prospective studies are needed to evaluate the optimal dose and target volume in the context of SBRT for HRPCa.
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http://dx.doi.org/10.1016/j.ijrobp.2021.01.016DOI Listing
January 2021

Dose-response with stereotactic body radiotherapy for prostate cancer: A multi-institutional analysis of prostate-specific antigen kinetics and biochemical control.

Radiother Oncol 2020 Oct 7;154:207-213. Epub 2020 Oct 7.

Department of Radiation Oncology, University of California, Los Angeles, USA; Department of Urology, University of California, Los Angeles, USA. Electronic address:

Background And Purpose: The optimal dose for prostate stereotactic body radiotherapy (SBRT) is still unknown. This study evaluated the dose-response relationships for prostate-specific antigen (PSA) decay and biochemical recurrence (BCR) among 4 SBRT dose regimens.

Materials And Methods: In 1908 men with low-risk (50.0%), favorable intermediate-risk (30.9%), and unfavorable intermediate-risk (19.1%) prostate cancer treated with prostate SBRT across 8 institutions from 2003 to 2018, we examined 4 regimens (35 Gy/5 fractions [35/5, n = 265, 13.4%], 36.25 Gy/5 fractions [36.25/5, n = 711, 37.3%], 40 Gy/5 fractions [40/5, n = 684, 35.8%], and 38 Gy/4 fractions [38/4, n = 257, 13.5%]). Between dose groups, we compared PSA decay slope, nadir PSA (nPSA), achievement of nPSA ≤0.2 and ≤0.5 ng/mL, and BCR-free survival (BCRFS).

Results: Median follow-up was 72.3 months. Median nPSA was 0.01 ng/mL for 38/4, and 0.17-0.20 ng/mL for 5-fraction regimens (p < 0.0001). The 38/4 cohort demonstrated the steepest PSA decay slope and greater odds of nPSA ≤0.2 ng/mL (both p < 0.0001 vs. all other regimens). BCR occurred in 6.25%, 6.75%, 3.95%, and 8.95% of men treated with 35/5, 36.25/5, 40/5, and 38/4, respectively (p = 0.12), with the highest BCRFS after 40/5 (vs. 35/5 hazard ratio [HR] 0.49, p = 0.026; vs. 36.25/5 HR 0.42, p = 0.0005; vs. 38/4 HR 0.55, p = 0.037) including the entirety of follow-up, but not for 5-year BCRFS (≥93% for all regimens, p ≥ 0.21).

Conclusion: Dose-escalation was associated with greater prostate ablation and PSA decay. Dose-escalation to 40/5, but not beyond, was associated with improved BCRFS. Biochemical control remains excellent, and prospective studies will provide clarity on the benefit of dose-escalation.
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http://dx.doi.org/10.1016/j.radonc.2020.09.053DOI Listing
October 2020

Prostate-specific antigen kinetics and biochemical control following stereotactic body radiation therapy, high dose rate brachytherapy, and low dose rate brachytherapy: A multi-institutional analysis of 3502 patients.

Radiother Oncol 2020 Oct 11;151:26-32. Epub 2020 Jul 11.

Department of Radiation Oncology, University of California Los Angeles, Los Angeles, United States. Electronic address:

Background And Purpose: Stereotactic body radiation therapy (SBRT), low dose rate brachytherapy (LDR-BT) and high dose rate brachytherapy (HDR-BT) are ablative-intent radiotherapy options for prostate cancer (PCa). These vary considerably in dose delivery, which may impact post-treatment prostate-specific antigen (PSA) patterns and biochemical control. We compared PSA kinetics between SBRT, HDR-BT, and LDR-BT, and assessed their relationships to biochemical recurrence-free survival (BCRFS).

Methods And Materials: Retrospective PSA data were analyzed for 3502 men with low-risk (n = 2223; 63.5%), favorable intermediate-risk (n = 869; 24.8%), and unfavorable intermediate-risk (n = 410; 11.7%) PCa treated with SBRT (n = 1716; 49.0%), HDR-BT (n = 512; 14.6%), or LDR-BT (n = 1274; 36.4%) without upfront androgen deprivation therapy at 10 institutions from 1990 to 2017. We compared nadir PSA (nPSA), time to nPSA, achievement of nPSA <0.2 ng/mL and <0.5 ng/mL, rates of nPSA <0.4 ng/mL at 4 years, and BCRFS.

Results: Median follow-up was 72 months. Median nPSA and nPSA <0.2 ng/mL were stratified by risk group (interaction p ≤ 0.001). Median nPSA and time to nPSA were 0.2 ng/mL at 44 months after SBRT, 0.1-0.2 ng/mL at 37 months after HDR-BT, and 0.01-0.2 ng/mL at 51 months after LDR-BT (mean log nPSA p ≤ 0.009 for LDR-BT vs. SBRT or HDR-BT for low/favorable intermediate-risk). There were no differences in nPSA <0.4 ng/mL at 4 years (p ≥ 0.51). BCRFS was similar for all three modalities (p ≥ 0.27). Continued PSA decay beyond 4 years was predictive of durable biochemical control.

Conclusion: LDR-BT led to lower nPSAs with longer continued decay compared to SBRT and HDR-BT, but no differences in BCRFS.
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http://dx.doi.org/10.1016/j.radonc.2020.07.014DOI Listing
October 2020

The intraprostatic immune environment after stereotactic body radiotherapy is dominated by myeloid cells.

Prostate Cancer Prostatic Dis 2020 Jul 9. Epub 2020 Jul 9.

Radiation Oncology at UCLA, Los Angeles, CA, USA.

Background: Hundreds of ongoing clinical trials combine radiation therapy, mostly delivered as stereotactic body radiotherapy (SBRT), with immune checkpoint blockade. However, our understanding of the effect of radiotherapy on the intratumoral immune balance is inadequate, hindering the optimal design of trials that combine radiation therapy with immunotherapy. Our objective was to characterize the intratumoral immune balance of the malignant prostate after SBRT in patients.

Methods: Sixteen patients with high-risk, non-metastatic prostate cancer at comparable Gleason Grade disease underwent radical prostatectomy with (n = 9) or without (n = 7) neoadjuvant SBRT delivered in three fractions of 8 Gy over 5 days completed 2 weeks before surgery. Freshly resected prostate specimens were processed to obtain single-cell suspensions, and immune-phenotyped for major lymphoid and myeloid cell subsets by staining with two separate 14-antibody panels and multicolor flow cytometry analysis.

Results: Malignant prostates 2 weeks after SBRT had an immune infiltrate dominated by myeloid cells, whereas malignant prostates without preoperative treatment were more lymphoid-biased (myeloid CD45 cells 48.4 ± 19.7% vs. 25.4 ± 7.0%; adjusted p-value = 0.11; and CD45 lymphocytes 51.6 ± 19.7% vs. 74.5 ± 7.0%; p = 0.11; CD3 T cells 35.2 ± 23.8% vs. 60.9 ± 9.7%; p = 0.12; mean ± SD).

Conclusion: SBRT drives a significant lymphoid to myeloid shift in the prostate-tumor immune infiltrate. This may be of interest when combining SBRT with immunotherapies, particularly in prostate cancer.
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http://dx.doi.org/10.1038/s41391-020-0249-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794088PMC
July 2020

Phase 1 Trial of Stereotactic Body Radiation Therapy Neoadjuvant to Radical Prostatectomy for Patients With High-Risk Prostate Cancer.

Int J Radiat Oncol Biol Phys 2020 Nov 17;108(4):930-935. Epub 2020 Jun 17.

Department of Radiation Oncology, University of California Los Angeles, Los Angeles, California; Department of Urology, University of California Los Angeles, Los Angeles, California; Radiation Therapy Service, VA Greater Los Angeles Healthcare System, Los Angeles, California. Electronic address:

Purpose: This study aimed to evaluate the feasibility and safety of prostate stereotactic body radiation therapy (SBRT) neoadjuvant to radical prostatectomy (RP) in a phase 1 trial. The primary endpoint was treatment completion rate without severe acute surgical complications. Secondary endpoints included patient-reported quality of life and physician-reported toxicities.

Methods And Materials: Patients with nonmetastatic high-risk or locally advanced prostate cancer received 24 Gy in 3 fractions to the prostate and seminal vesicles over 5 days, completed 2 weeks before RP. Patients with pN1 disease were treated after multidisciplinary discussion and shared decision making. Patient-reported quality of life (International Prostate Symptom Score and Expanded Prostate Cancer Index Composite 26-item version questionnaires) and physician-reported toxicity (Common Terminology Criteria for Adverse Events, version 4.03) were assessed before SBRT, immediately before surgery, and at 3-month intervals for 1 year.

Results: Twelve patients were enrolled, and 11 completed treatment (1 patient had advanced disease on prostate-specific membrane antigen positron emission tomography after enrollment but before treatment). There were no significant surgical complications. After RP, 2 patients underwent additional radiation therapy to nodes with androgen suppression for pN1 disease. Median follow-up after completion of treatment was 20.1 months, with 9 of 11 patients having a follow-up period of >12 months. Two patients had biochemical recurrence (prostate-specific antigen ≥0.05) within the first 12 months, with an additional 2 patients found to have biochemical recurrence after the 12-month period. The highest Common Terminology Criteria for Adverse Events genitourinary grades were 0, 1, 2, and 3 (n = 1, 4, 4, and 2, respectively), and the highest gastrointestinal grades were 0, 1, and 2 (n = 9, 1, and 1, respectively). At 12 months, incontinence was the only grade ≥2 toxicity. One and 2 of 9 patients had grade 2 and 3 incontinence, respectively. On the Expanded Prostate Cancer Index Composite (26-item version), the mean/median changes in scores from baseline to 12 months were -32.8/-31.1 for urinary incontinence, -1.6/-6.2 for urinary irritative/obstructive, -2.1/0 for bowel, -34.4/-37.5 for sexual function, and -10.6/-2.5 for hormonal. The mean/median change in International Prostate Symptom Score from baseline to 12 months was 0.5/0.5.

Conclusions: RP after neoadjuvant SBRT appears to be feasible and safe at the dose tested. The severity of urinary incontinence may be higher than RP alone.
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http://dx.doi.org/10.1016/j.ijrobp.2020.06.010DOI Listing
November 2020

Gantry-Mounted Linear Accelerator-Based Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer.

Adv Radiat Oncol 2020 May-Jun;5(3):404-411. Epub 2019 Oct 14.

Department of Radiation Oncology, University of California, Los Angeles, California.

Purpose: To establish the safety and efficacy of gantry-mounted linear accelerator-based stereotactic body radiation therapy (SBRT) for low- and intermediate-risk prostate cancer.

Methods: We pooled 921 patients enrolled on 7 single-institution prospective phase II trials of gantry-based SBRT from 2006 to 2017. The cumulative incidences of biochemical recurrence (defined by the Phoenix definition) and physician-scored genitourinary (GU) and gastrointestinal (GI) toxicities (defined per the original trials using Common Terminology Criteria for Adverse Events) were estimated using a competing risk framework. Multivariable logistic regression was used to evaluate the relationship between late toxicity and prespecified covariates: biologically effective dose, every other day versus weekly fractionation, intrafractional motion monitoring, and acute toxicity.

Results: Median follow-up was 3.1 years (range, 0.5-10.8 years). In addition, 505 (54.8%) patients had low-risk disease, 236 (25.6%) had favorable intermediate-risk disease, and 180 (19.5%) had unfavorable intermediate-risk disease. Intrafractional motion monitoring was performed in 78.0% of patients. The 3-year cumulative incidence of biochemical recurrence was 0.8% (95% confidence interval [CI], 0-1.7%), 2.2% (95% CI, 0-4.3%), and 5.1% (95% CI, 1.0-9.2%) for low-, favorable intermediate-, and unfavorable intermediate-risk disease. Acute grade ≥2 GU and GI toxicity occurred in 14.5% and 4.6% of patients, respectively. Three-year cumulative incidence estimates of late grade 2 GU and GI toxicity were 4.1% (95% CI, 2.6-5.5%) and 1.3% (95% CI, 0.5-2.1%), respectively, with late grade ≥3 GU and GI toxicity estimates of 0.7% (95% CI, 0.1-1.3%) and 0.4% (95% CI, 0-0.8%), respectively. The only identified significant predictors of late grade ≥2 toxicity were acute grade ≥2 toxicity ( < .001) and weekly fractionation ( < .01), although only 12.4% of patients were treated weekly.

Conclusions: Gantry-based SBRT for prostate cancer is associated with a favorable safety and efficacy profile, despite variable intrafractional motion management techniques. These findings suggest that multiple treatment platforms can be used to safely deliver prostate SBRT.
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http://dx.doi.org/10.1016/j.adro.2019.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276661PMC
October 2019

Development and Validation of a Comprehensive Multivariate Dosimetric Model for Predicting Late Genitourinary Toxicity Following Prostate Cancer Stereotactic Body Radiotherapy.

Front Oncol 2020 20;10:786. Epub 2020 May 20.

Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, CA, United States.

Dosimetric predictors of toxicity after Stereotactic Body Radiation Therapy (SBRT) are not well-established. We sought to develop a multivariate model that predicts Common Terminology Criteria for Adverse Events (CTCAE) late grade 2 or greater genitourinary (GU) toxicity by interrogating the entire dose-volume histogram (DVH) from a large cohort of prostate cancer patients treated with SBRT on prospective trials. Three hundred and thirty-nine patients with late CTCAE toxicity data treated with prostate SBRT were identified and analyzed. All patients received 40 Gy in five fractions, every other day, using volumetric modulated arc therapy. For each patient, we examined 910 candidate dosimetric features including maximum dose, volumes of each organ [CTV, organs at risk (OARs)], V100%, and other granular volumetric/dosimetric indices at varying volumetric/dosimetric values from the entire DVH as well as ADT use to model and predict toxicity from SBRT. Training and validation subsets were generated with 90 and 10% of the patients in our cohort, respectively. Predictive accuracy was assessed by calculating the area under the receiver operating curve (AROC). Univariate analysis with student -test was first performed on each candidate DVH feature. We subsequently performed advanced machine-learning multivariate analyses including classification and regression tree (CART), random forest, boosted tree, and multilayer neural network. Median follow-up time was 32.3 months (range 3-98.9 months). Late grade ≥2 GU toxicity occurred in 20.1% of patients in our series. No single dosimetric parameter had an AROC for predicting late grade ≥2 GU toxicity on univariate analysis that exceeded 0.599. Optimized CART modestly improved prediction accuracy, with an AROC of 0.601, whereas other machine learning approaches did not improve upon univariate analyses. CART-based machine learning multivariate analyses drawing from 910 dosimetric features and ADT use modestly improves upon clinical prediction of late GU toxicity alone, yielding an AROC of 0.601. Biologic predictors may enhance predictive models for identifying patients at risk for late toxicity after SBRT.
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http://dx.doi.org/10.3389/fonc.2020.00786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251156PMC
May 2020

Clinical Assessment of Prostate Displacement and Planning Target Volume Margins for Stereotactic Body Radiotherapy of Prostate Cancer.

Front Oncol 2020 16;10:539. Epub 2020 Apr 16.

Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, CA, United States.

To assess the optimal planning target volume (PTV) margins for stereotactic body radiotherapy (SBRT) of prostate cancer based on inter- and intra-fractional prostate motion determined from daily image guidance. Two hundred and five patients who were enrolled on two prospective studies of SBRT (8 Gy × 5 fractions) for localized prostate cancer treated at a single institution between 2012 and 2017 had complete inter- and intra-fractional shift data available. All patients had scheduled kilovoltage planar imaging during SBRT with rigid registration to intraprostatic fiducials prior to each of four half-arcs delivered per fraction, as well as cone beam CT verification of anatomy prior to each fraction. Inter- and intra- fractional shift data were obtained to estimate the required PTV margins based on the classic van Herk formula. Inter- and intra-fractional motion were compared between patients with and without severe toxicities using the independent two-sample Wilcoxon test. The margins required to account for inter-fractional motion were estimated to be 0.99, 1.52, and 1.45 cm in lateral (LR), longitudinal (SI), and vertical (AP) directions, respectively. The margins required to account for intra-fractional motion were estimated to be 0.19, 0.27, and 0.31 cm in LR, SI and AP directions, respectively. Large intra-fractional shifts were mostly observed in the SI and AP directions, with 2.0 and 5.4% of patients experiencing average intra-fractional motion >3 mm in the SI and AP directions, respectively, compared with none experiencing mean shifts >3 mm in the LR direction. Six patients experienced grade 3 gastrointestinal or genitourinary toxicity. There were no significant differences in mean inter- or intra-fractional motion in any of the cardinal directions compared to patients without severe toxicity (inter-fractional = 0.46-0.99, intra-fractional = 0.10-0.84). The inter- and intra-fractional margins estimated from this study are in line with prior reported values. Intra-fractional prostate motion was generally small with larger margins required for the SI and AP directions, notably just slightly exceeding the commonly used 3 mm posterior PTV margin even with realignment between half-arcs. Development of severe toxicity was not significantly associated with the degree of inter- or intra-fractional motion.
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http://dx.doi.org/10.3389/fonc.2020.00539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177009PMC
April 2020

A Prospective Multi-Institutional Phase I/II Trial of Step-Wise Dose-per-Fraction Escalation in Low and Intermediate Risk Prostate Cancer.

Pract Radiat Oncol 2020 Sep - Oct;10(5):345-353. Epub 2020 Mar 10.

Karmanos Cancer Institute, Detroit, Michigan.

Purpose: This phase I/II, multi-institutional trial explored the tolerance and efficacy of stepwise increasing hypofractionation (HPFX) radiation therapy regimens for fraction sizes up to 4.3 Gy in localized prostate cancer.

Methods And Materials: Three escalating dose-per-fraction schedules were designed to yield similar predicted tumor control while maintaining equivalent predicted late toxicity. HPFX levels I, II, and III were carried out sequentially and delivered schedules of 64.7 Gy/22 fx/2.94 Gy, 58.08 Gy/16 fx/3.63 Gy, and 51.6 Gy/12 fx/4.3 Gy, respectively with next level escalations contingent upon acceptable gastrointestinal (GI) toxicity. The primary endpoints were biochemical control and toxicity.

Results: A total of 347 patients were recruited by 5 institutions with 101, 111, and 135 patients treated on HPFX levels I, II, and III with median follow-ups of 100, 85.5, and 61.7 months, respectively (83.2 months combined). The National Comprehensive Cancer Network low- or intermediate-risk group distribution was 46% and 54%, respectively. Sixteen percent of patients, primarily intermediate risk, received 6 months of androgen deprivation therapy. The 8-year nadir + 2 actuarial biochemical control rates for HPFX levels I, II, and III were 91.1% ± 3.0%, 92.7% ± 2.7%, and 88.5% ± 4.6%, respectively (Kaplan-Meier log rank, 0.903). Among clinical covariates, only Gleason score reached near significance in multivariate analysis (P = .054). Twenty-six patients failed biochemically (crude incidence of 7.5%), and there were 5 cause-specific deaths. GI and genitourinary toxicities were acceptable and similar across the 3 HPFX levels. The combined actuarial cumulative incidence of grade 2+ GI and genitourinary toxicities at 7 years were 16.3% ± 2.1% and 22.1% ± 2.4%, respectively.

Conclusions: HPFX employing fraction sizes extending into the 3.6 to 4.3 Gy/fraction range can be delivered with excellent oncologic outcomes. Such schedules, positioned between moderate and ultra-HPFX, may provide additional options for patients wishing to avoid prolonged treatment schedules associated with conventionally fractionated radiation therapy for prostate cancer.
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http://dx.doi.org/10.1016/j.prro.2020.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483248PMC
March 2020

Local Failure and Survival After Definitive Radiotherapy for Aggressive Prostate Cancer: An Individual Patient-level Meta-analysis of Six Randomized Trials.

Eur Urol 2020 02 10;77(2):201-208. Epub 2019 Nov 10.

Department of Radiation Oncology, Cedars Sinai, Los Angeles, CA, USA.

Background: The importance of local failure (LF) after treatment of high-grade prostate cancer (PCa) with definitive radiotherapy (RT) remains unknown.

Objective: To evaluate the clinical implications of LF after definitive RT.

Design, Setting, And Participants: Individual patient data meta-analysis of 992 patients (593 Gleason grade group [GG] 4 and 399 GG 5) enrolled in six randomized clinical trials.

Outcome Measurements And Statistical Analysis: Multivariable Cox proportional hazard models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), and distant metastasis (DM)-free survival (DMFS) and LF as a time-dependent covariate. Markov proportional hazard models were developed to evaluate the impact of specific transitions between disease states on these endpoints.

Results And Limitations: Median follow-up was 6.4 yr overall and 7.2 yr for surviving patients. LF was significantly associated with OS (hazard ratio [HR] 1.70 [95% confidence interval {CI} 1.37-2.10]), PCSS (3.10 [95% CI 2.33-4.12]), and DMFS (HR 1.92 [95% CI 1.54-2.39]), p < 0.001 for all). Patients who had not transitioned to the LF state had a significantly lower hazard of transitioning to a PCa-specific death state than those who transitioned to the LF state (HR 0.13 [95% CI 0.04-0.41], p < 0.001). Additionally, patients who transitioned to the LF state had a greater hazard of DM or death (HR 2.46 [95% CI 1.22-4.93], p = 0.01) than those who did not.

Conclusions: LF is an independent prognosticator of OS, PCSS, and DMFS in high-grade localized PCa and a subset of DM events that are anteceded by LF events. LF events warrant consideration for intervention, potentially suggesting a rationale for upfront treatment intensification. However, whether these findings apply to all men or just those without significant comorbidity remains to be determined.

Patient Summary: Men who experience a local recurrence of high-grade prostate cancer after receiving upfront radiation therapy are at significantly increased risks of developing metastases and dying of prostate cancer.
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http://dx.doi.org/10.1016/j.eururo.2019.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008470PMC
February 2020

Association between Long-Term Second Malignancy Risk and Radiation: A Comprehensive Analysis of the Entire Surveillance, Epidemiology, and End Results Database (1973-2014).

Adv Radiat Oncol 2019 Oct-Dec;4(4):738-747. Epub 2019 May 15.

Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, California.

Purpose: Second malignancies (SMs) after radiation therapy are rare but serious sequelae of treatment. This study investigates whether radiation therapy use is associated with changes in baseline SM risk.

Methods And Materials: We extracted all patients with cancer, with or without SM, in the Surveillance, Epidemiology, and End Results database from 1973 to 2014. Cumulative incidence of SM for patients stratified by radiation therapy status was calculated using a competing risk model, both for the entire cohort and for subgroups based on the primary tumor's anatomic location.

Results: We identified 2,872,063 patients with cancer, including 761,289 patients who received radiation therapy and 2,110,774 who did not. The SM rate at 20 years for patients receiving radiation therapy versus no radiation therapy was 21.4% versus 18.8%. The relative risk for SM associated with radiation therapy for the overall group was 1.138 at 20 years. The relative risks for SM associated with radiation therapy to malignancies arising from central nervous system and orbits, head and neck, thorax, abdomen, and pelvis at 20 years were 0.704, 1.011, 0.559, 0.646, and 1.106 for men and 0.792, 1.298, 1.265, 0.780, and 0.988 for women, respectively.

Conclusions: The association between SM and radiation therapy varies with both sex and disease anatomic location, with the largest increase in SM seen in females irradiated to the head and neck region. Overall, the absolute change in SM rates associated with radiation therapy remains small, with differences in various clinical contexts.
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http://dx.doi.org/10.1016/j.adro.2019.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817555PMC
May 2019

Underutilization of Androgen Deprivation Therapy with External Beam Radiotherapy in Men with High-grade Prostate Cancer.

Eur Urol Oncol 2019 Feb 1. Epub 2019 Feb 1.

Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, CA, USA; Department of Urology, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address:

Multiple randomized trials have shown a survival benefit to long durations of androgen deprivation therapy (ADT) in patients with Gleason grade group (GG) 4-5 (ie, Gleason score 8-10) prostate cancer (PCa) undergoing definitive external beam radiotherapy (EBRT). We conducted a population-based retrospective study utilizing the complete Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database from 2008 to 2011, extracting PCa patients of non-Hispanic white (NHW) and African-American (AA) race diagnosed with GG 4-5PCa who received EBRT with or without concomitant ADT. Of 961 patients receiving definitive EBRT, 225 (23.4%) received no ADT, 297 (30.9%) received 1-6mo of ADT, 313 (32.6) received 7-23mo of ADT, and 126 (13.1%) received ≥24mo of ADT. On multinomial logistic regression after inverse probability treatment weighting to balance for differences in other covariates, AA men still had significantly lower odds of receiving 1-6mo of ADT versus no ADT compared with NHW men (odds ratios 0.519 [95% confidence interval, 0.384-0.700]). In conclusion, long-duration ADT is underutilized, with nearly 90% of patients with GG 4-5PCa receiving <24mo of concomitant ADT, and AA men are less likely to receive ADT than NHW men. PATIENT SUMMARY: In this report, we examined the utilization of concomitant androgen deprivation therapy (ADT) among men with high-grade prostate cancer undergoing definitive external beam radiotherapy. We found that long-duration ADT was underutilized overall; moreover, African-American men were less likely to receive concomitant ADT than non-Hispanic white men.
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http://dx.doi.org/10.1016/j.euo.2019.01.006DOI Listing
February 2019

Multi-Institutional Analysis of Prostate-Specific Antigen Kinetics After Stereotactic Body Radiation Therapy.

Int J Radiat Oncol Biol Phys 2019 11 2;105(3):628-636. Epub 2019 Jul 2.

Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, California. Electronic address:

Purpose: Understanding prostate-specific antigen (PSA) kinetics after radiation therapy plays a large role in the management of patients with prostate cancer (PCa). This is particularly true in establishing expectations regarding PSA nadir (nPSA) and PSA bounces, which can be disconcerting. As increasingly more patients are being treated with stereotactic body radiation therapy (SBRT) for low- and intermediate-risk PCa, it is imperative to understand the PSA response to SBRT.

Methods And Materials: PSA data from 5 institutions were retrospectively analyzed for patients with localized PCa treated definitively with SBRT alone from 2004 to 2016. Patients received 35 to 40 Gy in 5 fractions, per institutional standards. Patients who had less than 12 months of PSA data or received androgen deprivation therapy were excluded from this study. Linear and logistic multivariable analysis were performed to identify predictors of nPSA, bounce, and biochemical recurrence, and joint latent class models were developed to identify significant predictors of time to biochemical failure.

Results: A total of 1062 patients were included in this study. Median follow-up was 66 months (interquartile range [IQR], 36.4-89.9 months). Biochemical failure per the Phoenix criteria occurred in 4% of patients. Median nPSA was 0.2 ng/mL, median time to nPSA was 40 months, 84% of patients had an nPSA ≤0.5 ng/mL, and 54% of patients had an nPSA ≤0.2 ng/mL. On multivariable analysis, nPSA was a significant predictor of biochemical failure. Benign PSA bounce was noted in 26% of patients. The median magnitude of PSA bounce was 0.52 ng/mL (IQR, 0.3-1.0 ng/mL). Median time to PSA bounce was 18.1 months (IQR, 12.0-31.1 months). On multivariable analysis, age and radiation dose were significantly associated with a lower incidence of bounce. Joint latent class models modeling found that nPSA and radiation dose were significantly associated with longer time to biochemical failure.

Conclusions: In this multi-institutional cohort of patients with long-term follow-up, we found that SBRT led to low nPSAs. In turn, lower nPSAs are associated with reduced incidence of, and longer time to, biochemical failure. Benign PSA bounces occurred in a quarter of patients, as late as several years after treatment. Further studies are needed to directly compare the PSA response of patients who receive SBRT versus other treatment modalities.
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http://dx.doi.org/10.1016/j.ijrobp.2019.06.2539DOI Listing
November 2019

Testosterone Levels and Sexual Quality of Life After Stereotactic Body Radiation Therapy for Prostate Cancer: A Multi-Institutional Analysis of Prospective Trials.

Int J Radiat Oncol Biol Phys 2019 09 17;105(1):149-154. Epub 2019 May 17.

Department of Radiation Oncology, UCLA, Los Angeles, California. Electronic address:

Purpose: The impact of higher scatter doses per fraction on testicular function and quality of life after prostate stereotactic body radiation therapy (SBRT) is poorly studied.

Methods And Materials: Six hundred thirty-six patients treated with SBRT for low- to intermediate-risk prostate cancer from 2009 to 2014 were included. Changes in testosterone and in sexual and hormonal domain scores on the Expanded Prostate Cancer Index Composite-26 (EPIC) questionnaire over a 24-month period were evaluated via a 1-sided t test. EPIC score changes were evaluated in comparison with a distribution-based minimal clinically important difference threshold, wherein changes of greater than one half or greater than one third of the standard deviation in each domain were considered as medium-sized or small-sized effects, respectively.

Results: Median and mean percent changes in testosterone at the 3- to 6-month, 7- to 12-month, 13- to 18-month, and 19- to 24-month time periods were -13.41% and -4.49% (P = .02); -12.23% and -2.77% (P = .13); -11.20% and -0.29% (P = .47); -5.00% and + 1.20% (P = .65). When analyzed after dividing the cohort into 3 groups based on baseline testosterone values using tertiles, testosterone tended to increase in patients in the first group and decrease in patients in the third group. Overall, the decline in EPIC hormonal domain scores never exceeded the threshold for a small-sized effect, though the decline in EPIC sexual domain scores did pass this threshold at the 19- to 24-month time period (mean 10.90 point decline). This decline was not present when groups were examined individually.

Conclusions: In this large cohort of prospectively followed patients, there was a transient decline in testosterone shortly after SBRT that normalized by 24 months posttreatment. There was no significant change in EPIC hormonal domain scores. A significant decline in EPIC sexual domain scores, consistent with a small-sized clinically detectable difference, manifested between 19 and 24 months of follow-up. These results are consistent with testosterone decline patterns and sexual function changes seen after other forms of photon-based radiation therapy.
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http://dx.doi.org/10.1016/j.ijrobp.2019.05.014DOI Listing
September 2019

Prostate-only Versus Whole-pelvis Radiation with or Without a Brachytherapy Boost for Gleason Grade Group 5 Prostate Cancer: A Retrospective Analysis.

Eur Urol 2020 01 13;77(1):3-10. Epub 2019 Apr 13.

Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address:

Background: The role of elective whole-pelvis radiotherapy (WPRT) remains controversial. Few studies have investigated it in Gleason grade group (GG) 5 prostate cancer (PCa), known to have a high risk of nodal metastases.

Objective: To assess the impact of WPRT on patients with GG 5 PCa treated with external-beam radiotherapy (EBRT) or EBRT with a brachytherapy boost (EBRT+BT).

Design, Setting, And Participants: We identified 1170 patients with biopsy-proven GG 5 PCa from 11 centers in the United States and one in Norway treated between 2000 and 2013 (734 with EBRT and 436 with EBRT+BT).

Outcome Measurements And Statistical Analysis: Biochemical recurrence-free survival (bRFS), distant metastasis-free survival (DMFS), and prostate cancer-specific survival (PCSS) were compared using Cox proportional hazards models with propensity score adjustment.

Results And Limitations: A total of 299 EBRT patients (41%) and 320 EBRT+BT patients (73%) received WPRT. The adjusted 5-yr bRFS rates with WPRT in the EBRT and EBRT+BT groups were 66% and 88%, respectively. Without WPRT, these rates for the EBRT and EBRT+BT groups were 58% and 78%, respectively. The median follow-up was 5.6yr. WPRT was associated with improved bRFS among patients treated with EBRT+BT (hazard ratio [HR] 0.5, 95% confidence interval [CI] 0.2-0.9, p=0.02), but no evidence for improvement was found in those treated with EBRT (HR 0.8, 95% CI 0.6-1.2, p=0.4). WPRT was not significantly associated with improved DMFS or PCSS in the EBRT group (HR 1.1, 95% CI 0.7-1.7, p=0.8 for DMFS and HR 0.7, 95% CI 0.4-1.1, p=0.1 for PCSS), or in the EBRT+BT group (HR 0.6, 95% CI 0.3-1.4, p=0.2 for DMFS and HR 0.5 95% CI 0.2-1.2, p=0.1 for PCSS).

Conclusions: WPRT was not associated with improved PCSS or DMFS in patients with GG 5 PCa who received either EBRT or EBRT+BT. However, WPRT was associated with a significant improvement in bRFS among patients receiving EBRT+BT. Strategies to optimize WPRT, potentially with the use of advanced imaging techniques to identify occult nodal disease, are warranted.

Patient Summary: When men with a high Gleason grade prostate cancer receive radiation with external radiation and brachytherapy, the addition of radiation to the pelvis results in a longer duration of prostate-specific antigen control. However, we did not find a difference in their survival from prostate cancer or in their survival without metastatic disease. We also did not find a benefit for radiation to the pelvis in men who received radiation without brachytherapy.
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http://dx.doi.org/10.1016/j.eururo.2019.03.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521828PMC
January 2020

Long-term Outcomes of Stereotactic Body Radiotherapy for Low-Risk and Intermediate-Risk Prostate Cancer.

JAMA Netw Open 2019 02 1;2(2):e188006. Epub 2019 Feb 1.

Department of Radiation Oncology, University of California, Los Angeles.

Importance: Stereotactic body radiotherapy harnesses improvements in technology to allow the completion of a course of external beam radiotherapy treatment for prostate cancer in the span of 4 to 5 treatment sessions. Although mounting short-term data support this approach, long-term outcomes have been sparsely reported.

Objective: To assess long-term outcomes after stereotactic body radiotherapy for low-risk and intermediate-risk prostate cancer.

Design, Setting, And Participants: This cohort study analyzed individual patient data from 2142 men enrolled in 10 single-institution phase 2 trials and 2 multi-institutional phase 2 trials of stereotactic body radiotherapy for low-risk and intermediate-risk prostate cancer between January 1, 2000, and December 31, 2012. Statistical analysis was performed based on follow-up from January 1, 2013, to May 1, 2018.

Main Outcomes And Measures: The cumulative incidence of biochemical recurrence was estimated using a competing risk framework. Physician-scored genitourinary and gastrointestinal toxic event outcomes were defined per each individual study, generally by Radiation Therapy Oncology Group or Common Terminology Criteria for Adverse Events scoring systems. After central review, cumulative incidences of late grade 3 or higher toxic events were estimated using a Kaplan-Meier method.

Results: A total of 2142 men (mean [SD] age, 67.9 [9.5] years) were eligible for analysis, of whom 1185 (55.3%) had low-risk disease, 692 (32.3%) had favorable intermediate-risk disease, and 265 (12.4%) had unfavorable intermediate-risk disease. The median follow-up period was 6.9 years (interquartile range, 4.9-8.1 years). Seven-year cumulative rates of biochemical recurrence were 4.5% (95% CI, 3.2%-5.8%) for low-risk disease, 8.6% (95% CI, 6.2%-11.0%) for favorable intermediate-risk disease, 14.9% (95% CI, 9.5%-20.2%) for unfavorable intermediate-risk disease, and 10.2% (95% CI, 8.0%-12.5%) for all intermediate-risk disease. The crude incidence of acute grade 3 or higher genitourinary toxic events was 0.60% (n = 13) and of gastrointestinal toxic events was 0.09% (n = 2), and the 7-year cumulative incidence of late grade 3 or higher genitourinary toxic events was 2.4% (95% CI, 1.8%-3.2%) and of late grade 3 or higher gastrointestinal toxic events was 0.4% (95% CI, 0.2%-0.8%).

Conclusions And Relevance: In this study, stereotactic body radiotherapy for low-risk and intermediate-risk disease was associated with low rates of severe toxic events and high rates of biochemical control. These data suggest that stereotactic body radiotherapy is an appropriate definitive treatment modality for low-risk and intermediate-risk prostate cancer.
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http://dx.doi.org/10.1001/jamanetworkopen.2018.8006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484596PMC
February 2019

Ten-Year Outcomes of Moderately Hypofractionated (70 Gy in 28 fractions) Intensity Modulated Radiation Therapy for Localized Prostate Cancer.

Int J Radiat Oncol Biol Phys 2019 06 2;104(2):325-333. Epub 2019 Feb 2.

Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio. Electronic address:

Purpose: Long-term outcomes with hypofractionated radiation therapy for prostate cancer are limited. We report 10-year outcomes for patients treated with intensity modulated radiation therapy (IMRT) for localized prostate cancer with 70 Gy in 28 fractions at 2.5 Gy per fraction.

Methods And Materials: The study included 854 consecutive patients with localized prostate cancer treated with moderately hypofractionated IMRT and daily image guidance at a single institution between 1998 and 2012. Patients with a single intermediate risk factor were considered to have favorable intermediate-risk (FIR) disease, and those with multiple intermediate risk factors were considered unfavorable (UIR). Biochemical relapse-free survival, clinical relapse-free survival, and overall survival were analyzed using Kaplan-Meier analysis. Prostate cancer-specific mortality (PCSM) was analyzed using competing risk regression. All grade ≥3 genitourinary (GU) and gastrointestinal (GI) toxicities were recorded using Common Terminology Criteria for Adverse Event version 4.03, and cumulative incidence rates of GU and GI toxicity were calculated.

Results: The median follow-up was 11.3 years (maximum, 19 years). For patients with low-risk (LR), FIR, UIR, and high-risk (HR) disease, the 10-year biochemical relapse free survival rates were 88%, 78%, 71%, and 42%, respectively, (P < .0001). The 10-year clinical relapse free survival were 95%, 91%, 85%, and 72% for patients with LR, FIR, UIR, and HR, respectively, (P < .0001). For all patients, the 10-year actuarial overall survival rate was 69% (95% confidence interval, 66%-73%), and the 10-year PCSM was 6.8% (95% confidence interval, 5.1%-8.6%) overall. For patients with LR, FIR, UIR and HR disease, the 10-year PCSM rates were 2%, 5%, 5%, and 15%. Long-term grade ≥3 GU or GI toxicity remained low with 10-year cumulative incidences of 2% and 1%, respectively.

Conclusions: High-dose moderately hypofractionated IMRT with daily image guidance for localized prostate cancer demonstrates favorable 10-year oncologic outcomes with a low incidence of toxicity. This fractionation schedule appears to be acceptable for patients across all risk groups.
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http://dx.doi.org/10.1016/j.ijrobp.2019.01.091DOI Listing
June 2019

Development of a Radiation Oncology-Specific Prospective Data Registry for Research and Quality Improvement: A Clinical Workflow-Based Solution.

JCO Clin Cancer Inform 2018 12;2:1-9

All authors: University of California, Los Angeles-David Geffen School of Medicine, Los Angeles, CA.

Purpose: The computerized paperless medical recording system has transformed the modern health information system and serves as an idea platform for registry development, particularly in a specialty such as radiation oncology, where technologic advances continue to generate unprecedented amounts of complex data. We present our single-institution experience with the development of a real-time observational registry fully integrated into the process of routine clinical workflow and show how this has the potential to transform research and quality assurance.

Materials And Methods: From May 2011 to May 2016, physicians prospectively inputted data during the process of routine charting on patients seen in clinic. Using a customized interface established between an in-house registry and a commercially available, hospital-based electronic medical record system (Epic Systems, Verona, WI), a departmentally based parser was created for automatic data deposition, which was also linked to the Aria Treatment Planning Station (Varian Medical Systems, Palo Alto, CA). The total number of data fields embedded per disease site ranged from nine to 73 (median, 21 fields).

Results: A total of 12,341 patients were logged into the registry, of whom 6,911 completed a course of radiation therapy. Primary disease sites were prostate (n = 2,340), breast (n = 2,159), head or neck (n = 1,426), primary CNS (n = 1,338), lung (n = 749), brain metastasis (n = 739), GI (n = 638), gynecologic (n = 534), and other or benign (n = 3,618). A total of 54 independent, investigator-initiated research studies have been initiated using queries supported by the registry from multiple access points, of which 23 were published in peer-reviewed journals.

Conclusion: The development of a radiation oncology-specific registry enhanced research efficiency and facilitated quality assurance by producing clear and quality information to guide clinical practice.
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http://dx.doi.org/10.1200/CCI.17.00036DOI Listing
December 2018

Association of Gleason Grade With Androgen Deprivation Therapy Duration and Survival Outcomes: A Systematic Review and Patient-Level Meta-analysis.

JAMA Oncol 2019 01;5(1):91-96

Department of Radiation Oncology, University of California, Los Angeles, Los Angeles.

Importance: Androgen deprivation therapy (ADT) improves survival outcomes in patients with high-risk prostate cancer (PCa) treated with radiotherapy (RT). Whether this benefit differs between patients with Gleason grade group (GG) 4 (formerly Gleason score 8) and GG 5 (formerly Gleason score 9-10) disease remains unknown.

Objective: To determine whether the effectiveness of ADT duration varies between patients with GG 4 vs GG 5 PCa.

Design, Setting, And Participants: Traditional and network individual patient data meta-analyses of 992 patients (593 GG 4 and 399 GG 5) who were enrolled in 6 randomized clinical trials were carried out.

Main Outcomes And Measures: Multivariable Cox proportional hazard models were used to obtain hazard ratio (HR) estimates of ADT duration effects on overall survival (OS) and distant metastasis-free survival (DMFS). Cause-specific competing risk models were used to estimate HRs for cancer-specific survival (CSS). The interaction of ADT with GS was incorporated into the multivariable models. Traditional and network meta-analysis frameworks were used to compare outcomes of patients treated with RT alone, short-term ADT (STADT), long-term ADT (LTADT), and lifelong ADT.

Results: Five hundred ninety-three male patients (mean age, 70 years; range, 43-88 years) with GG 4 and 399 with GG 5 were identified. Median follow-up was 6.4 years. Among GG 4 patients, LTADT and STADT improved OS over RT alone (HR, 0.43; 95% CI, 0.26-0.70 and HR, 0.59; 95% CI, 0.38-0.93, respectively; P = .03 for both), whereas lifelong ADT did not (HR, 0.84; 95% CI, 0.54-1.30; P = .44). Among GG 5 patients, lifelong ADT improved OS (HR, 0.48; 95% CI, 0.31-0.76; P = .04), whereas neither LTADT nor STADT did (HR, 0.80; 95% CI, 0.45-1.44 and HR, 1.13; 95% CI, 0.69-1.87; P = .45 and P = .64, respectively). Among all patients, and among those receiving STADT, GG 5 patients had inferior OS compared with GG 4 patients (HR, 1.25; 95% CI, 1.07-1.47 and HR, 1.40; 95% CI, 1.05-1.88, respectively; P = .02). There was no significant OS difference between GG 5 and GG 4 patients receiving LTADT or lifelong ADT (HR, 1.21; 95% CI, 0.89-1.65 and HR, 0.85; 95% CI, 0.53-1.37; P = .23 and P = .52, respectively).

Conclusions And Relevance: These data suggest that prolonged durations of ADT improve survival outcomes in both GG 4 disease and GG 5 disease, albeit with different optimal durations. Strategies to maintain the efficacy of ADT while minimizing its duration (potentially with enhanced potency agents) should be investigated.
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http://dx.doi.org/10.1001/jamaoncol.2018.3732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440243PMC
January 2019

Content Validity of Anatomic Site-Specific Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Item Sets for Assessment of Acute Symptomatic Toxicities in Radiation Oncology.

Int J Radiat Oncol Biol Phys 2018 09 5;102(1):44-52. Epub 2018 Jun 5.

Department of Radiation Oncology, University of California, Los Angeles, California. Electronic address:

Purpose: To improve assessment of symptomatic toxicity in cancer clinical trials and complement clinician-based toxicity reporting, the US National Cancer Institute developed a measurement system called the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). The objective of this study was to examine the content validity of PRO-CTCAE in patients undergoing radiation therapy and to establish anatomic site-specific item sets for implementation in cancer research.

Methods And Materials: Patients receiving radiation to the brain, head and neck, breast, thorax, abdomen, or pelvis were recruited during the final week of radiation. Participants described side effects qualitatively and completed anatomic site-specific checklists indicating the presence or absence of symptomatic toxicities drawn from the PRO-CTCAE library. Items endorsed by ≥20% of participants were selected for inclusion. Symptomatic toxicities described qualitatively were content analyzed and summarized. Symptomatic toxicities not reflected in the PRO-CTCAE item library were tabulated.

Results: We conducted 389 interviews of patients receiving radiation to the brain (n = 46), head and neck (n = 69), breast (n = 134), thorax (n = 30), abdomen (n = 27), female pelvis (n = 36), or male pelvis (n = 47). Median age was 62 years; 62% were female. The 53 solicited PRO-CTCAE symptoms reflected all reported radiation-induced toxicities with the exception of phlegm/mucus production and mouth/throat pain with swallowing in patients receiving head and neck radiation, eye dryness/irritation in patients undergoing brain radiation, and obstructive urinary symptoms in men receiving pelvic radiation. The PRO-CTCAE items "skin burns" and "pain" require greater specificity to adequately reflect toxicities experienced during radiation.

Conclusions: PRO-CTCAE demonstrates strong content validity as a measure of symptomatic toxicities in patients receiving radiation. These results provide empirical support for the definition of site-specific PRO-CTCAE item sets to assess the symptomatic toxicities of radiation therapy. The site-specific PRO-CTCAE item sets developed herein are currently being deployed in our department via an electronic platform to capture treatment-related toxicity.
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http://dx.doi.org/10.1016/j.ijrobp.2018.04.048DOI Listing
September 2018

Image-guided radiotherapy for prostate cancer.

Transl Androl Urol 2018 Jun;7(3):308-320

Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, California, USA.

Intensity-modulated radiotherapy (IMRT) has become the standard radiotherapy technology utilized for the treatment of prostate cancer, as it permits the delivery of highly conformal radiation dose distributions. Image-guided radiotherapy (IGRT) is an essential companion to IMRT that allows the treatment team to account for daily changes in target anatomy and positioning. In the present review, we will discuss the different sources of geometric uncertainty and review the rationale behind using IGRT in the treatment of prostate cancer. We will then describe commonly employed IGRT techniques and review their benefits and drawbacks. Additionally, we will review the evidence suggesting a potential clinical benefit to utilizing IGRT.
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http://dx.doi.org/10.21037/tau.2017.12.37DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043755PMC
June 2018

Clinical Outcomes for Patients With Gleason Score 10 Prostate Adenocarcinoma: Results From a Multi-institutional Consortium Study.

Int J Radiat Oncol Biol Phys 2018 07 5;101(4):883-888. Epub 2018 Apr 5.

Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, California. Electronic address:

Purpose: Gleason score (GS) 10 disease is the most aggressive form of clinically localized prostate adenocarcinoma (PCa). The long-term clinical outcomes and overall prognosis of patients presenting with GS 10 PCa are largely unknown because of its rarity.

Methods And Materials: The study included 112 patients with biopsy-determined GS 10 PCa who received treatment with radical prostatectomy (RP, n = 26), external beam radiation therapy (EBRT, n = 48), or EBRT with a brachytherapy boost (EBRT-BT, n = 38) between 2000 and 2013. Propensity scores were included as covariates for comparative analysis. Overall survival, prostate cancer-specific survival, and distant metastasis-free survival (DMFS) were estimated by the Kaplan-Meier method with inverse probability of treatment weighting to control for confounding.

Results: The median follow-up period was 4.9 years overall (3.9 years for RP, 4.8 years for EBRT, and 5.7 years for EBRT-BT). Significantly more EBRT patients than EBRT-BT patients received upfront androgen deprivation therapy (98% vs 79%, P < .01 by χ test), though the durations were similar (median, 24 months vs 22.5 months). Of the RP patients, 34% received postoperative EBRT, and 35% received neoadjuvant systemic therapy. The propensity score-adjusted 5-year overall survival rate was 80% for the RP group, 73% for the EBRT group, and 83% for the EBRT-BT group. The corresponding adjusted 5-year prostate cancer-specific survival rates were 87%, 75%, and 94%, respectively. The EBRT-BT group trended toward superior DMFS when compared with the RP group (hazard ratio, 0.3; 95% confidence interval 0.1-1.06; P = .06) and had superior DMFS when compared with the EBRT group (hazard ratio, 0.4; 95% confidence interval 0.1-0.99; P = .048).

Conclusions: To our knowledge, this is the largest series ever reported on the clinical outcomes of patients with biopsy-determined GS 10 PCa. These data provide useful prognostic benchmark information for physicians and patients. Aggressive therapy with curative intent is warranted, as >50% of patients remain free of systemic disease 5 years after treatment.
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http://dx.doi.org/10.1016/j.ijrobp.2018.03.060DOI Listing
July 2018

Radical Prostatectomy, External Beam Radiotherapy, or External Beam Radiotherapy With Brachytherapy Boost and Disease Progression and Mortality in Patients With Gleason Score 9-10 Prostate Cancer.

JAMA 2018 03;319(9):896-905

Department of Radiation Oncology, University of California, Los Angeles.

Importance: The optimal treatment for Gleason score 9-10 prostate cancer is unknown.

Objective: To compare clinical outcomes of patients with Gleason score 9-10 prostate cancer after definitive treatment.

Design, Setting, And Participants: Retrospective cohort study in 12 tertiary centers (11 in the United States, 1 in Norway), with 1809 patients treated between 2000 and 2013.

Exposures: Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy, or EBRT plus brachytherapy boost (EBRT+BT) with androgen deprivation therapy.

Main Outcomes And Measures: The primary outcome was prostate cancer-specific mortality; distant metastasis-free survival and overall survival were secondary outcomes.

Results: Of 1809 men, 639 underwent RP, 734 EBRT, and 436 EBRT+BT. Median ages were 61, 67.7, and 67.5 years; median follow-up was 4.2, 5.1, and 6.3 years, respectively. By 10 years, 91 RP, 186 EBRT, and 90 EBRT+BT patients had died. Adjusted 5-year prostate cancer-specific mortality rates were RP, 12% (95% CI, 8%-17%); EBRT, 13% (95% CI, 8%-19%); and EBRT+BT, 3% (95% CI, 1%-5%). EBRT+BT was associated with significantly lower prostate cancer-specific mortality than either RP or EBRT (cause-specific HRs of 0.38 [95% CI, 0.21-0.68] and 0.41 [95% CI, 0.24-0.71]). Adjusted 5-year incidence rates of distant metastasis were RP, 24% (95% CI, 19%-30%); EBRT, 24% (95% CI, 20%-28%); and EBRT+BT, 8% (95% CI, 5%-11%). EBRT+BT was associated with a significantly lower rate of distant metastasis (propensity-score-adjusted cause-specific HRs of 0.27 [95% CI, 0.17-0.43] for RP and 0.30 [95% CI, 0.19-0.47] for EBRT). Adjusted 7.5-year all-cause mortality rates were RP, 17% (95% CI, 11%-23%); EBRT, 18% (95% CI, 14%-24%); and EBRT+BT, 10% (95% CI, 7%-13%). Within the first 7.5 years of follow-up, EBRT+BT was associated with significantly lower all-cause mortality (cause-specific HRs of 0.66 [95% CI, 0.46-0.96] for RP and 0.61 [95% CI, 0.45-0.84] for EBRT). After the first 7.5 years, the corresponding HRs were 1.16 (95% CI, 0.70-1.92) and 0.87 (95% CI, 0.57-1.32). No significant differences in prostate cancer-specific mortality, distant metastasis, or all-cause mortality (≤7.5 and >7.5 years) were found between men treated with EBRT or RP (cause-specific HRs of 0.92 [95% CI, 0.67-1.26], 0.90 [95% CI, 0.70-1.14], 1.07 [95% CI, 0.80-1.44], and 1.34 [95% CI, 0.85-2.11]).

Conclusions And Relevance: Among patients with Gleason score 9-10 prostate cancer, treatment with EBRT+BT with androgen deprivation therapy was associated with significantly better prostate cancer-specific mortality and longer time to distant metastasis compared with EBRT with androgen deprivation therapy or with RP.
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http://dx.doi.org/10.1001/jama.2018.0587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885899PMC
March 2018

Use of the Electronic Medical Record to Facilitate Intervention for Patients With Rising Prostate-Specific Antigen Values After Radical Prostatectomy: A Feasibility Study.

JCO Clin Cancer Inform 2017 11;1:1-6

All authors: University of California, Los Angeles, Los Angeles, CA.

Purpose: Salvage radiotherapy (SRT) is the standard of care offered when postprostatectomy prostate-specific antigen (PSA) levels are ≥ 0.2 ng/mL. However, emerging evidence suggests that early SRT (ie, SRT delivered at PSA values < 0.2 ng/mL, but generally ≥ 0.05 ng/mL) improves oncologic outcomes. We evaluated the feasibility of improving referral rates for discussion of early SRT by using a dynamic registry that identifies through the electronic medical record patients with rising postprostatectomy PSA levels.

Methods: We developed an iteratively updated registry that identifies patients who fall within two postoperative PSA strata: ≥ 0.05 to < 0.1 ng/mL and ≥ 0.1 to < 0.2 ng/mL. We compared referral rates to radiation oncology during a 3-year period before use of this registry with those during a 1-year period after promotion of the registry in multidisciplinary tumor board settings.

Results: Before promotion of the registry, referral rates for patients with PSA values ≥ 0.05 to < 0.1 ng/mL and ≥ 0.1 to < 0.2 ng/mL were 35% and 65%, respectively. After promotion of the registry, referral rates within each stratum increased significantly to 82% and 94%, respectively ( P < .05 for both by Fisher's exact test). The overall rate of referral for patients with PSA values ≥ 0.05 to < 0.2 ng/mL rose from 48% to 90% ( P < .001).

Conclusion: The creation of a registry of patients with rising postprostatectomy PSA values can facilitate increased referral rates for early SRT without burdening providers with a clinical support tool embedded within the EMR itself. This is true even in the case of already high baseline rates of referral for early SRT. The changes reported herein most likely reflect a Hawthorne effect wherein the ability to track referrals rather than a direct function of the registry influenced practice patterns. Nonetheless, the registry provided an integral framework to allow for tracking.
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http://dx.doi.org/10.1200/CCI.17.00046DOI Listing
November 2017

Prospective radiotherapy for patients with oropharyngeal carcinoma - Authors' reply.

Lancet Oncol 2017 08 26;18(8):e426. Epub 2017 Jul 26.

University of California, Davis, CA, USA.

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http://dx.doi.org/10.1016/S1470-2045(17)30534-XDOI Listing
August 2017

Considerations for Quality Improvement in Radiation Oncology Therapy for Patients with Uncomplicated Painful Bone Metastases.

J Palliat Med 2017 May 23;20(5):478-486. Epub 2017 Feb 23.

Department of Radiation Oncology, David Geffen School of Medicine at University of California, Los Angeles, California.

There is an increasing need for evidence-based efficiency in providing a growing amount of cancer care. One example of a quality gap is the use of multiple-fraction palliative radiation for patients with advanced cancer who have uncomplicated bone metastases; evidence suggests similar pain outcomes for treatment regimens with a lower burden of treatments. During the first phase of quality improvement work, we used RAND/UCLA appropriateness methodology to understand how radiation oncologists at one academic medical center rate the appropriateness of different treatment regimens for painful uncomplicated bone metastases. We compared radiation oncologist appropriateness ratings for radiation treatments with radiation therapy provided by these oncologists to patients with painful bone metastases between July 2012 and June 2013. Appropriateness ratings showed that single-fraction (8 Gy) treatment (a low burden treatment) was consistently considered an appropriate option to treat a variety of uncomplicated bone metastases. The use of >10 fractions was consistently rated as inappropriate regardless of other factors. Eighty-one patients receiving radiation therapy for painful bone metastases during the study period had an available medical record for chart abstraction. Almost one-third of metastases were considered complicated because of a concern of spinal cord compression, a history of prior irradiation, or an associated pathological fracture. Among uncomplicated bone metastases, 25% were treated with stereotactic body radiation treatment (SBRT). Among the 54 uncomplicated bone metastases treated with conformal radiation, only one was treated with single-fraction treatment and 32% were treated with greater than 10 fractions. Treatment at the study site demonstrates room for improvement in providing low-burden radiation oncology treatments for patients with painful bone metastases. Choosing a radiation treatment schedule for patients with advanced cancer and painful bone metastases requires consideration of many medical and patient-centered factors. Our experience suggests that it will take more than the existence of guidelines to change practice in this area.
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http://dx.doi.org/10.1089/jpm.2016.0339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5421511PMC
May 2017

Reduced-dose radiotherapy for human papillomavirus-associated squamous-cell carcinoma of the oropharynx: a single-arm, phase 2 study.

Lancet Oncol 2017 06 20;18(6):803-811. Epub 2017 Apr 20.

Department of Radiation Oncology, University of California, Davis, School of Medicine, Sacramento, CA, USA.

Background: Head and neck cancers positive for human papillomavirus (HPV) are exquisitely radiosensitive. We investigated whether chemoradiotherapy with reduced-dose radiation would maintain survival outcomes while improving tolerability for patients with HPV-positive oropharyngeal carcinoma.

Methods: We did a single-arm, phase 2 trial at two academic hospitals in the USA, enrolling patients with newly diagnosed, biopsy-proven stage III or IV squamous-cell carcinoma of the oropharynx, positive for HPV by p16 testing, and with Zubrod performance status scores of 0 or 1. Patients received two cycles of induction chemotherapy with 175 mg/m paclitaxel and carboplatin (target area under the curve of 6) given 21 days apart, followed by intensity-modulated radiotherapy with daily image guidance plus 30 mg/m paclitaxel per week concomitantly. Complete or partial responders to induction chemotherapy received 54 Gy in 27 fractions, and those with less than partial or no responses received 60 Gy in 30 fractions. The primary endpoint was progression-free survival at 2 years, assessed in all eligible patients who completed protocol treatment. This study is registered with ClinicalTrials.gov, numbers NCT02048020 and NCT01716195.

Findings: Between Oct 4, 2012, and March 3, 2015, 45 patients were enrolled with a median age of 60 years (IQR 54-67). One patient did not receive treatment and 44 were included in the analysis. 24 (55%) patients with complete or partial responses to induction chemotherapy received 54 Gy radiation, and 20 (45%) with less than partial responses received 60 Gy. Median follow-up was 30 months (IQR 26-37). Three (7%) patients had locoregional recurrence and one (2%) had distant metastasis; 2-year progression-free survival was 92% (95% CI 77-97). 26 (39%) of 44 patients had grade 3 adverse events, but no grade 4 events were reported. The most common grade 3 events during induction chemotherapy were leucopenia (17 [39%]) and neutropenia (five [11%]), and during chemoradiotherapy were dysphagia (four [9%]) and mucositis (four [9%]). One (2%) of 44 patients was dependent on a gastrostomy tube at 3 months and none was dependent 6 months after treatment.

Interpretation: Chemoradiotherapy with radiation doses reduced by 15-20% was associated with high progression-free survival and an improved toxicity profile compared with historical regimens using standard doses. Radiotherapy de-escalation has the potential to improve the therapeutic ratio and long-term function for these patients.

Funding: University of California.
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http://dx.doi.org/10.1016/S1470-2045(17)30246-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488353PMC
June 2017

Pattern of solid and hematopoietic second malignancy after local therapy for prostate cancer.

Radiother Oncol 2017 04 7;123(1):133-138. Epub 2017 Feb 7.

Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, CA, United States.

Background And Purpose: Second malignancies (SM) after external beam radiotherapy (EBRT) or brachytherapy (BT) for prostate cancer (PCa) are rare but serious sequelae.

Materials And Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify men diagnosed with cT1-2N0M0 PCa between 1999 and 2005, who underwent EBRT, BT or radical prostatectomy (RP). Patients with time interval to second malignancy or follow-up shorter than five and two years were excluded for solid and hematopoietic SM analyses respectively. Risks for solid and hematopoietic SM were evaluated via the multivariate Fine and Gray proportional hazards model.

Results: EBRT and BT resulted in similar increases in solid and hematopoietic SM compared to RP. In subgroup analysis stratified by treatment modality, only the EBRT cohort demonstrated significantly decreased solid and hematopoietic SM in years 2002-2005 compared to years 1999-2001, with adjusted-hazard ratios of 0.752 (p=0.001) and 0.815 (p=0.018) respectively.

Conclusions: EBRT and BT resulted in statistically equivalent increase in both solid and hematopoietic SM compared to RP. EBRT in more recent years resulted in significantly decreased solid and hematopoietic SM, coinciding with increased utilization of IMRT.
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http://dx.doi.org/10.1016/j.radonc.2017.01.009DOI Listing
April 2017