Publications by authors named "Paul L Nguyen"

414 Publications

Development and Validation of a Genomic Tool to Predict Seminal Vesicle Invasion in Adenocarcinoma of the Prostate.

Authors:
William A Hall Nick Fishbane Yang Liu Melody J Xu Elai Davicioni Brandon A Mahal Robert B Den Robert T Dess William C Jackson Anthony C Wong Edward M Schaeffer R Jeffrey Karnes Peter R Carroll Matthew R Cooperberg Tarek A Bismar Hyung L Kim Eric A Klein John W Davis Ashley E Ross Jeffrey J Tosoian Todd M Morgan Rohit Mehra Simpa S Salami Paul L Nguyen Colleen A F Lawton Daniel E Spratt Felix Feng

JCO Precis Oncol 2020 Nov;4:1228-1238

Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA.

Purpose: Pretreatment estimates of seminal vesicle invasion (SVI) are challenging and significantly influence the management of prostate cancer. We sought to improve current models to predict SVI through the development of an SVI prediction genomic signature.

Patients And Methods: A total of 15,889 patients who underwent radical prostatectomy (RP) with available baseline clinical, pathology, and transcriptome data were retrieved from the GRID registry (ClinicalTrials.gov identifier: NCT02609269) and other retrospective cohorts. These data were divided into a training (n = 6,766), test (n = 3,363), and two validation (n = 5,062 and 698) cohorts. Multivariable logistic regression was performed to assess the predictive effect of the genomic SVI (gSVI) classifier in the presence of established nomograms (Partin Tables and Memorial Sloan Kettering Cancer Center [MSKCC]).

Results: In the training cohort, univariable filtering identified 2,132 genes that were differentially expressed between RP tumors with and without SVI. Model parameters were tuned to maximize the area under the curve (AUC) in the testing cohort, resulting in a logistic generalized linear model with 581 genes. The gSVI model scores range from 0 to 1. In the first validation set, gSVI showed superior discrimination of patients with and without SVI at RP compared with other prognostic signatures trained to predict distant metastasis or clinical recurrence. Of the 698 patients in the second validation set, gSVI combined with the MSKCC nomogram had a superior AUC (0.86) compared with either nomogram individually (0.81).

Conclusion: The gSVI represents a novel and validated expression signature to predict the presence of SVI before treatment with surgery. This genomic tool adds discriminatory power to existing clinical predictive nomograms and may help with pretreatment counseling and decision making.
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http://dx.doi.org/10.1200/PO.20.00013DOI Listing
November 2020

Comparison of Response to Definitive Radiotherapy for Localized Prostate Cancer in Black and White Men: A Meta-analysis.

Authors:
Ting Martin Ma Tahmineh Romero Nicholas G Nickols Matthew B Rettig Isla P Garraway Mack Roach Jeff M Michalski Thomas M Pisansky W Robert Lee Christopher U Jones Seth A Rosenthal Chenyang Wang Holly Hartman Paul L Nguyen Felix Y Feng Paul C Boutros Christopher Saigal Karim Chamie William C Jackson Todd M Morgan Rohit Mehra Simpa S Salami Randy Vince Edward M Schaeffer Brandon A Mahal Robert T Dess Michael L Steinberg David Elashoff Howard M Sandler Daniel E Spratt

JAMA Netw Open 2021 12 1;4(12):e2139769. Epub 2021 Dec 1.

Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Cleveland Medical Center, Cleveland, Ohio.

Importance: Black men have a 2-fold increased risk of dying from prostate cancer compared with White men. However, race-specific differences in response to initial treatment remain unknown.

Objective: To compare overall and treatment-specific outcomes of Black and White men with localized prostate cancer receiving definitive radiotherapy (RT).

Data Sources: A systematic search was performed of relevant published randomized clinical trials conducted by the NRG Oncology/Radiation Therapy Oncology Group between January 1, 1990, and December 31, 2010. This meta-analysis was performed from July 1, 2019, to July 1, 2021.

Study Selection: Randomized clinical trials of definitive RT for patients with localized prostate cancer comprising a substantial number of Black men (self-identified race) enrolled that reported on treatment-specific and overall outcomes.

Data Extraction And Synthesis: Individual patient data were obtained from 7 NRG Oncology/Radiation Therapy Oncology Group randomized clinical trials evaluating definitive RT with or without short- or long-term androgen deprivation therapy. Unadjusted Fine-Gray competing risk models, with death as a competing risk, were developed to evaluate the cumulative incidences of end points. Cox proportional hazards models were used to evaluate differences in all-cause mortality and the composite outcome of distant metastasis (DM) or death. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed.

Main Outcomes And Measures: Subdistribution hazard ratios (sHRs) of biochemical recurrence (BCR), DM, and prostate cancer-specific mortality (PCSM).

Results: A total of 8814 patients (1630 [18.5%] Black and 7184 [81.5%] White) were included; mean (SD) age was 69.1 (6.8) years. Median follow-up was 10.6 (IQR, 8.0-17.8) years for surviving patients. At enrollment, Black men were more likely to have high-risk disease features. However, even without adjustment, Black men were less likely to experience BCR (sHR, 0.88; 95% CI, 0.58-0.91), DM (sHR, 0.72; 95% CI, 0.58-0.91), or PCSM (sHR, 0.72; 95% CI, 0.54-0.97). No significant differences in all-cause mortality were identified (HR, 0.99; 95% CI, 0.92-1.07). Upon adjustment, Black race remained significantly associated with improved BCR (adjusted sHR, 0.79; 95% CI, 0.72-0.88; P < .001), DM (adjusted sHR, 0.69; 95% CI, 0.55-0.87; P = .002), and PCSM (adjusted sHR, 0.68; 95% CI, 0.50-0.93; P = .01).

Conclusions And Relevance: The findings of this meta-analysis suggest that Black men enrolled in randomized clinical trials present with more aggressive disease but have better BCR, DM, and PCSM with definitive RT compared with White men, suggesting that other determinants of outcome, such as access to care, are important factors of achieving racial equity.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.39769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8717118PMC
December 2021

Radiation Dose to the Intraprostatic Urethra Correlates Strongly With Urinary Toxicity After Prostate Stereotactic Body Radiation Therapy: A Combined Analysis of 23 Prospective Clinical Trials.

Authors:
Jonathan E Leeman Yu-Hui Chen Paul Catalano Jeremy Bredfeldt Martin King Kent W Mouw Anthony V D'Amico Peter Orio Paul L Nguyen Neil Martin

Int J Radiat Oncol Biol Phys 2022 Jan 25;112(1):75-82. Epub 2021 Oct 25.

Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Purpose: Clinical trials assessing evaluation prostate stereotactic body radiation therapy (SBRT) have used a wide range of allowed doses to the intraprostatic urethra, but the relationship between urethral dose and urinary toxicity has not been thoroughly evaluated. The goal of this study was to characterize urinary toxicity outcomes according to urethral dose administered during prostate SBRT.

Methods And Materials: The MEDLINE (PubMed) database was searched for published prospective studies of prostate SBRT through August 2020 that documented a maximum urethral dose metric (MUDM). Reported acute and late urinary toxicity rates were collected. Logistic regression and weighted Pearson correlation models were used to assess associations between urinary toxicity rates and MUDM.

Results: Twenty-three unique studies (n = 2232 patients) met the inclusion criteria and included a wide range of MUDMs (equivalent dose in 2 Gy fractions [EQD]: 69-141.75 Gy; α/β = 3 Gy). The median follow-up ranged from 3 to 67 months (median, 32 months). On logistic regression analysis, the MUDM EQD was significantly associated with multiple urinary toxicity endpoints, including acute grade (G) 2+ (odds ratio [OR], 1.02; P < .001), late G2+ (OR, 1.03; P < .0001), and late G3+ (OR, 1.04; P = .003) urinary toxicity. On weighted Pearson correlation analysis, the MUDM was more closely associated with all evaluated urinary toxicity endpoints than prescription dose, including acute G2+ (r = 0.51; P = .02), late G2+ (r = 0.9; P < .0001), and late G3+ toxicity (r = 0.7; P = .003). Multivariate analysis accounting for age, prostate size, bladder dosimetry, and baseline urinary function confirmed associations between urinary outcomes and MUDM. Within the studied dose range, each increase of 1 Gy to the MUDM corresponded to a 0.8% and 1.0% increase in acute G2+ and late G2+ toxicity, respectively.

Conclusions: Radiation dose to the urethra correlates closely with urinary toxicity in patients with prostate cancer treated with SBRT. Attention should be paid to the urethral dose when delivering prostate SBRT to high doses, and approaches for urethral dose reduction warrant further investigation.
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http://dx.doi.org/10.1016/j.ijrobp.2021.06.037DOI Listing
January 2022

Prostate Cancer Disparities in Risk Group at Presentation and Access to Treatment for Asian Americans, Native Hawaiians, and Pacific Islanders: A Study With Disaggregated Ethnic Groups.

Authors:
Bhav Jain Kenrick Ng Patricia Mae G Santos Kekoa Taparra Vinayak Muralidhar Brandon A Mahal Neha Vapiwala Quoc-Dien Trinh Paul L Nguyen Edward Christopher Dee

JCO Oncol Pract 2022 Jan 28;18(1):e204-e218. Epub 2021 Oct 28.

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: We identified (1) differences in localized prostate cancer (PCa) risk group at presentation and (2) disparities in access to initial treatment for Asian American, Native Hawaiian, and Pacific Islander (AANHPI) men with PCa after controlling for sociodemographic factors.

Methods: We assessed all patients in the National Cancer Database with localized PCa with low-, intermediate-, and high-risk disease who identified as Thai, White, Asian Indian, Chinese, Vietnamese, Korean, Japanese, Filipino, Hawaiian, Pacific Islander, Laotian, Pakistani, Kampuchean, and Hmong. Multivariable logistic regression defined adjusted odds ratios (AORs) with 95% CI of (1) presenting at progressively higher risk group and (2) receiving treatment or active surveillance with intermediate- or high-risk disease, adjusting for sociodemographic and clinical factors.

Results: Among 980,889 men (median age 66 years), all AANHPI subgroups with the exception of Thai (AOR = 0.84 [95% CI, 0.58 to 1.21], > .05), Asian Indian (AOR = 1.12 [95% CI, 1.00 to 1.25], > .05), and Pakistani (AOR = 1.34 [95% CI, 0.98 to 1.83], > .05) men had greater odds of presenting at a progressively higher PCa risk group compared with White patients (Chinese AOR = 1.18 [95% CI, 1.11 to 1.25], < .001; Japanese AOR = 1.36 [95% CI, 1.26 to 1.47], < .001; Filipino AOR = 1.37 [95% CI, 1.29 to 1.46], < .001; Korean AOR = 1.32 [95% CI, 1.18 to 1.48], < .001; Vietnamese AOR = 1.20 [95% CI, 1.07 to 1.35], = .002; Laotian AOR = 1.60 [95% CI, 1.08 to 2.36], = .018; Hmong AOR = 4.07 [95% CI, 1.54 to 10.81], = .005; Kampuchean AOR = 1.55 [95% CI, 1.03 to 2.34], = .036; Asian Indian or Pakistani AOR = 1.15 [95% CI, 1.07 to 1.24], < .001; Native Hawaiians AOR = 1.58 [95% CI, 1.38 to 1.80], < .001; and Pacific Islanders AOR = 1.58 [95% CI, 1.37 to 1.82], < .001). Additionally, Japanese Americans (AOR = 1.46 [95% CI, 1.09 to 1.97], = .013) were more likely to receive treatment compared with White patients.

Conclusion: Our findings suggest that there are differences in PCa risk group at presentation by race or ethnicity among Asian American, Native Hawaiian, and Pacific Islander subgroups and that there exist disparities in treatment patterns. Although AANHPI are often studied as a homogenous group, heterogeneity upon subgroup disaggregation underscores the importance of further study to assess and address barriers to PCa care.
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http://dx.doi.org/10.1200/OP.21.00412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8758129PMC
January 2022

The Clinical Cell-Cycle Risk (CCR) score Is Associated With Metastasis After Radiation Therapy and Provides Guidance on When to Forgo Combined Androgen Deprivation Therapy With Dose-Escalated Radiation.

Authors:
Jonathan Tward Lauren Lenz Darl D Flake Saradha Rajamani Carl Olsson Deepak A Kapoor Constantine Mantz Stanley L Liauw Tatjana Antic Neal Shore Dan Albertson Jonathan Henderson Steve P Lee Hiram A Gay Jeff Michalski Arthur Hung David Raben Isla Garraway Michael S Lewis Paul L Nguyen David T Marshall Michael K Brawer Steven Stone Todd Cohen

Int J Radiat Oncol Biol Phys 2021 Oct 3. Epub 2021 Oct 3.

Myriad Genetics, Inc, Salt Lake City, Utah.

Purpose: The clinical cell-cycle risk (CCR) score, which combines the University of California, San Francisco's Cancer of the Prostate Risk Assessment (CAPRA) and the cell cycle progression (CCP) molecular score, has been validated to be prognostic of disease progression for men with prostate cancer. This study evaluated the ability of the CCR score to prognosticate the risk of metastasis in men receiving dose-escalated radiation therapy (RT) with or without androgen deprivation therapy (ADT).

Methods And Materials: This retrospective, multi-institutional cohort study included men with localized National Comprehensive Cancer Network (NCCN) intermediate-, high-, and very high-risk prostate cancer (N = 741). Patients were treated with dose-escalated RT with or without ADT. The primary outcome was time to metastasis.

Results: The CCR score prognosticated metastasis with a hazard ratio (HR) per unit score of 2.22 (95% confidence interval [CI], 1.71-2.89; P < .001). The CCR score better prognosticated metastasis than NCCN risk group (CCR, P < .001; NCCN, P = .46), CAPRA score (CCR, P = .002; CAPRA, P = .59), or CCP score (CCR, P < .001; CCP, P = .59) alone. In bivariable analyses, CCR score remained highly prognostic when accounting for ADT versus no ADT (HR, 2.18; 95% CI, 1.61-2.96; P < .001), ADT duration as a continuous variable (HR, 2.11; 95% CI, 1.59-2.79; P < .001), or ADT given at or below the recommended duration for each NCCN risk group (HR, 2.19; 95% CI, 1.69-2.86; P < .001). Men with CCR scores below or above the multimodality threshold (CCR score, 2.112) had a 10-year risk of metastasis of 3.7% and 21.24%, respectively. Men with below-threshold scores receiving RT alone had a 10-year risk of metastasis of 3.7%, and for men receiving RT plus ADT, the 10-year risk of metastasis was also 3.7%.

Conclusions: The CCR score accurately and precisely prognosticates metastasis and adds clinically actionable information relative to guideline-recommended therapies based on NCCN risk in men undergoing dose-escalated RT with or without ADT. For men with scores below the multimodality threshold, adding ADT may not significantly reduce their 10-year risk of metastasis.
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http://dx.doi.org/10.1016/j.ijrobp.2021.09.034DOI Listing
October 2021

Exercise: A Treatment That Should Be Prescribed With Radiation Therapy.

Authors:
Nicholas G Zaorsky Sara Garrett Daniel E Spratt Paul L Nguyen Chris Sciamanna Kathryn Schmitz

Int J Radiat Oncol Biol Phys 2022 Jan 21;112(1):96-98. Epub 2021 Sep 21.

Department of Public Health Sciences, Penn State College of Medicine, Hershey, Pennsylvania.

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http://dx.doi.org/10.1016/j.ijrobp.2021.08.005DOI Listing
January 2022

High-flow nasal cannula therapy in a predominantly African American population with COVID-19 associated acute respiratory failure.

Authors:
Paul L Nguyen Heba Osman Donovan Watza Suman Khicher Aditi Sharma Greg Dyson Ghulam Saydain Ayman Soubani

BMJ Open Respir Res 2021 09;8(1)

Division of Pulmonary and Critical Care, Wayne State University School of Medicine, Detroit, Michigan, USA.

Importance: Use of non-invasive respiratory modalities in COVID-19 has the potential to reduce rates of intubation and mortality in severe disease however data regarding the use of high-flow nasal cannula (HFNC) in this population is limited.

Objective: To interrogate clinical and laboratory features of SARS-CoV-2 infection associated with high-flow failure.

Design: We conducted a retrospective cohort study to evaluate characteristics of high-flow therapy use early in the pandemic and interrogate factors associated with respiratory therapy failure.

Setting: Multisite single centre hospital system within the metropolitan Detroit region.

Participants: Patients from within the Detroit Medical Center (n=104, 89% African American) who received HFNC therapy during a COVID-19 admission between March and May of 2020.

Primary Outcome: HFNC failure is defined as death or intubation while on therapy.

Results: Therapy failure occurred in 57% of the patient population, factors significantly associated with failure centred around markers of multiorgan failure including hepatic dysfunction/transaminitis (OR=6.1, 95% CI 1.9 to 19.4, p<0.01), kidney injury (OR=7.0, 95% CI 2.7 to 17.8, p<0.01) and coagulation dysfunction (OR=4.5, 95% CI 1.2 to 17.1, p=0.03). Conversely, comorbidities, admission characteristics, early oxygen requirements and evaluation just prior to HFNC therapy initiation were not significantly associated with success or failure of therapy.

Conclusions: In a population disproportionately affected by COVID-19, we present key indicators of likely HFNC failure and highlight a patient population in which aggressive monitoring and intervention are warranted.
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http://dx.doi.org/10.1136/bmjresp-2021-000875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457999PMC
September 2021

Novel genomic signature predictive of response to immune checkpoint blockade: A pan-cancer analysis from project Genomics Evidence Neo-plasia Information Exchange (GENIE).

Authors:
Nishwant Swami William L Hwang Jimmy A Guo Hannah Hoffman Matthew C Abramowitz Ziad Elbakouny Himisha Beltran Fallon Chipidza Toni Choueiri Alan Dal Pra Franklin Huang Salma Kaochar Philip Kantoff Daniel W Kim Amar U Kishan Erin Kobetz Catherine Marinac Lorelei A Mucci Vinayak Muralidhar Alan Pollack Nina N Sanford Edward M Schaeffer Daniel E Spratt Shuang G Zhao Timothy R Rebbeck Paul L Nguyen Felix Y Feng Brandon A Mahal Mohammed Alshalalfa

Cancer Genet 2021 11 28;258-259:61-68. Epub 2021 Aug 28.

University of California at San Francisco, San Francisco, CA, USA; Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA, USA. Electronic address:

Background: High tumor mutation burden (TMB) and total mutation count (TMC) can be predictive of better response to immune checkpoint blockade (ICB). Nevertheless, TMB and TMC are limited by variation across cancers and inconsistent definitions due to different profiling methods (targeted vs whole genome sequencing). Our objective was to identify genomic alterations (GAs) associated with ICB response and builds a novel genomic signature predictive of ICB response, independent of TMB/TMC.

Methods: This was a pan-cancer next generation sequencing (NGS)-association study using January 2014-May 2016 data from AACR Project Genomics Evidence Neo-plasia Information Exchange (GENIE). Participants included 6619 patients with metastatic or un-resectable cancer across 9 cancer types (including 1572 ICB-treated patients). GA data was collected using next-generation sequencing (NGS) assays and downloaded from cbioportal.org. Predictive analyses for ICB response were performed to develop the signature (ImmGA).

Results: GAs in 16 genes were associated with improved OS in ICB-treated patients (p < 0.005). 13 GAs were associated with an OS benefit in ICB-treated patients (P < 0.05); these genes composed the ImmGA signature. High ImmGA score (≥2 alterations out of 13 predictive GAs) was associated with better OS in ICB-treated patients (AHR:0.67, 95%CI [0.6-0.75], p = 1.4e), even after accounting for TMC (P = 8e). High ImmGA was associated with better OS in ICB-treated patients across most cancers and across different ICB treatment modalities.

Conclusion: A novel signature predictive of ICB response (ImmGA) was developed from 13 GAs. Further investigation of the utility of ImmGA for treatment and trial selection is warranted.
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http://dx.doi.org/10.1016/j.cancergen.2021.08.004DOI Listing
November 2021

Trends in Incidence, and Mortality of Acute Exacerbation of Chronic Obstructive Pulmonary Disease in the United States Emergency Department (2010-2018).

Authors:
Paul L Nguyen Mohammed M Uddin Tanveer Mir Amir Khalil Neelambuj Regmi Amina Pervaiz Tanveer Hussain Mohammed Amir Babu Irfan Ullah Pragnesh Patel Prateek Lohia Ghulam Saydain Parvaiz A Koul Ayman O Soubani

COPD 2021 10 16;18(5):567-575. Epub 2021 Sep 16.

Division of Pulmonary and Critical Care Medicine, Wayne State University, Detroit, MI, USA.

Literature regarding trends of incidence, mortality, and complications of acute exacerbation of chronic obstructive pulmonary disease (COPD) in the emergency departments (ED) is limited. What are trends of COPD exacerbation in ED? Data were obtained from the Nationwide Emergency Department Sample (NEDS) that constitutes a 20% sample of hospital-owned EDs and inpatient sample in the US. All ED encounters were included in the analysis. Complications of AECOPD were obtained by using ICD codes. Out of 1.082 billion ED encounters, 5,295,408 (mean age 63.31 ± 12.63 years, females 55%) presented with COPD exacerbation. Among these patients, 353,563(6.7%) had AECOPD-plus (features of pulmonary embolism, acute heart failure and/or pneumonia) while 4,941,845 (93.3%) had exacerbation without associated features or precipitating factors which we grouped as AECOPD. The AECOPD-plus group was associated with statistically significantly higher proportion of cardiovascular complications including AF (5.6% vs 3.5%;  < 0.001), VT/VF (0.14% vs 0.06%;  < 0.001), STEMI (0.22% vs 0.11%;  < 0.001) and NSTEMI (0.65% vs 0.2%;  < 0.001). The in-hospital mortality rates were greater in the AECOPD-plus population (0.7% vs 0.1%;  < 0.001). The incidence of both AECOPD and AECOPD-plus had worsened (-trend 0.004 and 0.0003) and the trend of mortality had improved (-trend 0.0055 and 0.003, respectively). The prevalence of smoking for among all COPD patients had increased (-value 0.004), however, the prevalence trend of smoking among AECOPD groups was static over the years 2010-2018. There was an increasing trend of COPD exacerbation in conjunction with smoking; however, mortality trends improved significantly. Moreover, the rising burden of AECOPD would suggest improvement in diagnostics and policy making regarding management.
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http://dx.doi.org/10.1080/15412555.2021.1979500DOI Listing
October 2021

Boosting the Abscopal Effect Using Immunogenic Biomaterials With Varying Radiation Therapy Field Sizes.

Authors:
Sayeda Yasmin-Karim Bashkim Ziberi Johanna Wirtz Noella Bih Michele Moreau Romy Guthier Victoria Ainsworth Juergen Hesser G Mike Makrigiorgos Michael D Chuong Xiao Wei Paul L Nguyen Wilfred Ngwa

Int J Radiat Oncol Biol Phys 2022 Feb 13;112(2):475-486. Epub 2021 Sep 13.

Dana Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; University of Massachusetts, Lowell, Massachusetts; Department of Radiation Oncology and Molecular Radiation Sciences, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

Purpose: Persistent immunosuppression in the tumor microenvironment is a major limitation to boosting the abscopal effect, whereby radiation therapy at 1 site can lead to regression of tumors at distant sites. Here, we investigate the use of radiation and immunogenic biomaterials (IBM) targeting only the gross tumor volume/subvolume for boosting the abscopal effect in immunologically cold tumors.

Methods And Materials: To evaluate the abscopal effect, 2 syngeneic contralateral tumors were implanted in each mouse, where only 1 tumor was treated. IBM was administered to the treated tumor with 1 fraction of radiation and results were compared, including as a function of different radiation therapy field sizes. The IBM was designed similar to fiducial markers using immunogenic polymer components loaded with anti-CD40 agonist. Tumor volumes of both treated and untreated tumors were measured over time, along with survival and corresponding immune cell responses.

Results: Results showed that radiation with IBM administered to the gross tumor subvolume can effectively boost abscopal responses in both pancreatic and prostate cancers, significantly increasing survival (P < .0001 and P < .001, respectively). Results also showed equal or superior abscopal responses when using field sizes smaller than the gross tumor volume compared with irradiating the whole tumor volume. These results were buttressed by observation of higher infiltration of cytotoxic CD8+ T-lymphocytes in the treated tumors (P < .0001) and untreated tumors (P < .0001) for prostate cancer. Significantly higher infiltration was also observed in treated tumors (P < .0001) and untreated tumors P < .01) for pancreatic cancer. Moreover, the immune responses were accompanied by a positive shift of proinflammatory cytokines in both prostate and pancreatic tumors.

Conclusions: The approach targeting gross tumor subvolumes with radiation and IBM offers opportunity for boosting the abscopal effect while significantly minimizing healthy tissue toxicity. This approach proffers a radioimmunotherapy dose-painting strategy that can be developed for overcoming current barriers of immunosuppression especially for immunologically cold tumors.
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http://dx.doi.org/10.1016/j.ijrobp.2021.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8750216PMC
February 2022

Second malignancy probabilities in prostate cancer patients treated with SBRT and other contemporary radiation techniques.

Authors:
Edward Christopher Dee Vinayak Muralidhar Martin T King Neil E Martin Anthony V D'Amico Kent W Mouw Peter F Orio Paul L Nguyen Jonathan E Leeman

Radiother Oncol 2021 08 24;161:241-250. Epub 2021 Jun 24.

Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Harvard Medical School, Boston, United States. Electronic address:

Background: Prostate radiotherapy has been associated with an increased risk of developing a second malignancy (SM). However, relative SM probabilities following treatment with contemporary radiation techniques such as stereotactic body radiotherapy (SBRT) or moderately hypofractionated intensity modulated radiotherapy (HF-IMRT) remain unknown.

Methods: A cohort analysis was performed of men from a nationally representative database with localized prostate cancer with at least 60 months of follow-up comparing SM probability amongst men receiving either radical prostatectomy (RP), conventionally fractionated intensity-modulated radiotherapy (CF-IMRT), HF-IMRT, brachytherapy (BT), or SBRT, using multivariable logistic models, which were used to generate predicted probabilities. Additionally, propensity score-adjusted pairwise assessments of modalities were performed.

Results: For 303,432 patients included in the study, median follow-up was 9.08 years (IQR 7.01-11.21). Predicted rates of SM by treatment modality and adjusted odds ratios (AOR) for development of SM (referent: RP) were: 6.0% for RP (AOR n/a), 7.1% for CF-IMRT (AOR 1.20, 95%CI 1.14-1.25, P < 0.001), 7.3% for HF-IMRT (AOR 1.25, 95%CI 1.01-1.55, P = 0.045), 6.6% for BT (AOR 1.11, 95%CI 1.07-1.16, P < 0.001), and 5.7% for SBRT (AOR 0.95, 95%CI 0.81-1.12, P = 0.567). On propensity score-adjusted analysis, SBRT was associated with lower odds of SM compared to CF-IMRT (AOR 0.78, 95%CI 0.66-0.93, P = 0.005); no significant difference was found when SBRT was compared to RP (AOR 0.86, 95%CI 0.73-1.03, P = 0.102).

Conclusions: Conventionally fractionated intensity-modulated radiotherapy, moderately hypofractionated intensity-modulated radiotherapy, and brachytherapy but not stereotactic body radiotherapy were associated with increased probability of a second malignancy compared to radical prostatectomy. Patients treated with SBRT may be at lower risk of second malignancy due to improved conformality, radiobiological differences or patient selection. The possibility that SBRT in select patients may minimize the probability of SM underscores the need for assessment of second malignancy risk in prospective studies of SBRT.
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http://dx.doi.org/10.1016/j.radonc.2021.06.023DOI Listing
August 2021

Elective Pelvic Lymph Node Radiation in Prostate Cancer Revisited.

Authors:
David D Yang Paul L Nguyen Anthony V D'Amico

J Clin Oncol 2021 09 4;39(25):2845-2846. Epub 2021 Jun 4.

David D. Yang, MD, Paul L. Nguyen, MD, and Anthony V. D'Amico, MD, PhD, Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.

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http://dx.doi.org/10.1200/JCO.21.00621DOI Listing
September 2021

Comparative analysis of 1152 African-American and European-American men with prostate cancer identifies distinct genomic and immunological differences.

Authors:
Walter Rayford Alp Tuna Beksac Jordan Alger Mohammed Alshalalfa Mohsen Ahmed Irtaza Khan Ugo G Falagario Yang Liu Elai Davicioni Daniel E Spratt Edward M Schaeffer Felix Y Feng Brandon Mahal Paul L Nguyen Robert B Den Mark D Greenberger Randy Bradley Justin M Watson Matthew Beamer Lambros Stamatakis Darrell J Carmen Shivanshu Awasthi Jonathan Hwang Rachel Weil Harri Merisaari Nihal Mohamed Leslie A Deane Dimple Chakravarty Kamlesh K Yadav Kosj Yamoah

Commun Biol 2021 06 3;4(1):670. Epub 2021 Jun 3.

Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL, USA.

Racial disparities in prostate cancer have not been well characterized on a genomic level. Here we show the results of a multi-institutional retrospective analysis of 1,152 patients (596 African-American men (AAM) and 556 European-American men (EAM)) who underwent radical prostatectomy. Comparative analyses between the race groups were conducted at the clinical, genomic, pathway, molecular subtype, and prognostic levels. The EAM group had increased ERG (P < 0.001) and ETS (P = 0.02) expression, decreased SPINK1 expression (P < 0.001), and basal-like (P < 0.001) molecular subtypes. After adjusting for confounders, the AAM group was associated with higher expression of CRYBB2, GSTM3, and inflammation genes (IL33, IFNG, CCL4, CD3, ICOSLG), and lower expression of mismatch repair genes (MSH2, MSH6) (p < 0.001 for all). At the pathway level, the AAM group had higher expression of genes sets related to the immune response, apoptosis, hypoxia, and reactive oxygen species. EAM group was associated with higher levels of fatty acid metabolism, DNA repair, and WNT/beta-catenin signaling. Based on cell lines data, AAM were predicted to have higher potential response to DNA damage. In conclusion, biological characteristics of prostate tumor were substantially different in AAM when compared to EAM.
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http://dx.doi.org/10.1038/s42003-021-02140-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175556PMC
June 2021

Association of Medicaid expansion and insurance status, cancer stage, treatment and mortality among patients with cervical cancer.

Authors:
Grace Lee Edward Christopher Dee E John Orav Daniel W Kim Paul L Nguyen Alexi A Wright Miranda B Lam

Cancer Rep (Hoboken) 2021 12 2;4(6):e1407. Epub 2021 May 2.

Harvard Medical School, Boston, Massachusetts, USA.

Background: Currently, little is known about the effect of the Patient Protection and Affordable Care Act's Medicaid expansion on care delivery and outcomes in cervical cancer.

Aim: We evaluated whether Medicaid expansion was associated with changes in insurance status, stage at diagnosis, timely treatment, and survival outcomes in cervical cancer.

Methods And Results: Using the National Cancer Database, we performed a difference-in-differences (DID) cross-sectional analysis to compare insurance status, stage at diagnosis, timely treatment, and survival outcomes among cervical cancer patients residing in Medicaid expansion and nonexpansion states before (2011-2013) and after (2014-2015) Medicaid expansion. January 1, 2014 was used as the timepoint for Medicaid expansion. The primary outcomes of interest were insurance status, stage at diagnosis, treatment within 30 and 90 days of diagnosis, and overall survival. Fifteen thousand two hundred sixty-five patients (median age 50) were included: 42% from Medicaid expansion and 58% from nonexpansion states. Medicaid expansion was significantly associated with increased Medicaid coverage (adjusted DID = 11.0%, 95%CI = 8.2, 13.8, p < .01) and decreased rates of uninsured (adjusted DID = -3.0%, 95%CI = -5.2, -0.8, p < .01) among patients in expansion states compared with non-expansion states. However, Medicaid expansion was not associated with any significant changes in cancer stage at diagnosis or timely treatment. There was no significant change in survival from the pre- to post-expansion period in either expansion or nonexpansion states, and no significant differences between the two (DID-HR = 0.95, 95%CI = 0.83, 1.09, p = .48).

Conclusion: Although Medicaid expansion was associated with an increase in Medicaid coverage and decrease in uninsured among patients with cervical cancer, the effects of increased coverage on diagnosis and treatment outcomes may have yet to unfold. Future studies, including longer follow-up are necessary to understand the effects of Medicaid expansion.
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http://dx.doi.org/10.1002/cnr2.1407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8714536PMC
December 2021

Risk of cardiovascular mortality with androgen deprivation therapy in prostate cancer: A secondary analysis of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Randomized Controlled Trial.

Authors:
Santino S Butler Brandon A Mahal Javid J Moslehi Anju Nohria Edward C Dee Rishi Makkar Amanda Whitbeck Janet Wangoe Kent W Mouw Paul L Nguyen Vinayak Muralidhar

Cancer 2021 Jul 27;127(13):2213-2221. Epub 2021 Apr 27.

Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts.

Background: For men with radiation-managed prostate cancer, there is conflicting evidence regarding the association between androgen deprivation therapy (ADT) and cardiovascular mortality (CVM), particularly among those who have with preexisting comorbidities. The objective of this study was to analyze the association between ADT and CVM across patient comorbidity status using prospectively collected data from a large clinical trial.

Methods: In total, 1463 men were identified who were diagnosed with clinically localized, intermediate-risk/high-risk prostate cancer (T2b-T4, Gleason 7-10, or prostate-specific antigen >10 ng/mL) from 1993 to 2001 and managed with either radiation therapy (RT) alone or RT plus ADT during the randomized Prostate, Lung, Colon, and Ovarian (PLCO) Cancer Screening Trial. Adjusted hazard ratios (aHRs) for cause-specific mortality (prostate cancer-specific mortality vs other-cause mortality-including the primary end point of CVM [death from ischemic heart disease, cerebrovascular accident, or other circulatory disease]) were determined using Fine and Gray competing-risk regression analysis and stratified by comorbidity history.

Results: There was no difference in the risk of 5-year CVM between ADT plus RT and RT alone (2.3% vs 3.3%, respectively; aHR, 0.69; 95% CI, 0.38-1.24; P = .21) overall or on subgroup analysis among men with a history of ≥1 preexisting comorbidities (3.2% vs 5.3%, respectively; aHR, 0.83; 95% CI, 0.43-1.60; P = .58), ≥2 preexisting comorbidities (6.9% vs 8.3%, respectively; aHR, 0.95; 95% CI, 0.40-2.25; P = .90), or cardiovascular disease/risk factors (3.6% vs 4.3%, respectively; aHR, 0.85; 95% CI, 0.44-1.65; P = .63). These results were all similar when each component of CVM was analyzed separately-either cardiac, stroke, or other vascular mortality (P > .05).

Conclusions: This study provides prospectively collected evidence that the use of ADT plus RT, compared with RT alone, is not associated with an increased risk of CVM, even among subgroups of men who have preexisting comorbidities and cardiovascular disease.
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http://dx.doi.org/10.1002/cncr.33486DOI Listing
July 2021

Clinical characterization of radiation-associated muscle-invasive bladder cancer.

Authors:
Sybil T Sha Edward Christopher Dee Matthew Mossanen Brandon A Mahal Cierra Zaslowe-Dude Trevor J Royce Michelle S Hirsch Guru Sonpavde Mark A Preston Paul L Nguyen Kent W Mouw Vinayak Muralidhar

Urology 2021 Aug 20;154:208-214. Epub 2021 Apr 20.

Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Objective: To characterize the presentation, patterns of care, and outcomes of radiation-associated muscle-invasive bladder cancer (RA-MIBC) compared to primary (non-radiation associated) MIBC. RA-MIBC has been suggested to represent a more aggressive disease variant and be more difficult to treat compared to primary (non-radiation associated) MIBC.

Methods: We identified 60,090 patients diagnosed with MIBC between 1988-2015 using the Surveillance, Epidemiology, and End Results database and stratified patients based on whether radiation had been administered to a prior pelvic primary cancer. We used Fine-Gray competing risks regression to compare adjusted bladder cancer-specific mortality (BCSM) for RA-MIBC compared to primary MIBC.

Results: There were 1,093 patients with RA-MIBC and 58,997 patients with primary MIBC. RA-MIBCs were more likely to be T4 at diagnosis (21.0% vs 17.3%, P < .001), and less likely to be node-positive (10.3% vs 17.1%, P < .001). The rate of 5-year BCSM was significantly higher for patients with RA-MIBC vs primary MIBC (56.1% vs 35.3%, AHR 1.24, P < .001), even after stratification by other tumor, treatment and patient-specific factors.

Conclusion: RA-MIBCs tended to present with higher grade and T stage disease and were less likely to receive curative treatment. Even when accounting for stage, grade, and receipt of treatment, patients with RA-MIBC had worse survival compared to those with primary MIBC. These findings suggest that RA-MIBC present unique clinical challenges and may also represent a biologically more aggressive disease compared to primary MIBC. Future research is needed to better understand the biology of RA-MIBC and develop improved treatment approaches.
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http://dx.doi.org/10.1016/j.urology.2021.03.033DOI Listing
August 2021

Assessment of Simulated SARS-CoV-2 Infection and Mortality Risk Associated With Radiation Therapy Among Patients in 8 Randomized Clinical Trials.

Authors:
Shervin Tabrizi Lorenzo Trippa Daniel Cagney Ayal A Aizer Shyam Tanguturi Steffen Ventz Geoffrey Fell Jennifer R Bellon Harvey Mamon Paul L Nguyen Anthony V D'Amico Daphne Haas-Kogan Brian M Alexander Rifaquat Rahman

JAMA Netw Open 2021 03 1;4(3):e213304. Epub 2021 Mar 1.

Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts.

Importance: During the COVID-19 pandemic, cancer therapy may put patients at risk of SARS-CoV-2 infection and mortality. The impacts of proposed alternatives on reducing infection risk are unknown.

Objective: To investigate how the COVID-19 pandemic is associated with the risks and benefits of standard radiation therapy (RT).

Design, Setting, And Participants: This comparative effectiveness study used estimated individual patient-level data extracted from published Kaplan-Meier survival figures from 8 randomized clinical trials across oncology from 1993 to 2014 that evaluated the inclusion of RT or compared different RT fractionation regimens. Included trials were Dutch TME and TROG 01.04 examining rectal cancer; CALGB 9343, OCOG hypofractionation trial, FAST-Forward, and NSABP B-39 examining early stage breast cancer, and CHHiP and HYPO-RT-PC examining prostate cancer. Risk of SARS-CoV-2 infection and mortality associated with receipt of RT in the treatment arms were simulated and trials were reanalyzed. Data were analyzed between April 1, 2020, and June 30, 2020.

Exposures: COVID-19 risk associated with treatment was simulated across different pandemic scenarios, varying infection risk per fractions (IRFs) and case fatality rates (CFRs).

Main Outcomes And Measures: Overall survival was evaluated using Cox proportional hazards modeling under different pandemic scenarios.

Results: Estimated IPLD from a total of 14 170 patients were included in the simulations. In scenarios with low COVID-19-associated risks (IRF, 0.5%; CFR, 5%), fractionation was not significantly associated with outcomes. In locally advanced rectal cancer, short-course RT was associated with better outcomes than long-course chemoradiation (TROG 01.04) and was associated with similar outcomes as RT omission (Dutch TME) in most settings (eg, TROG 01.04 median HR, 0.66 [95% CI, 0.46-0.96]; Dutch TME median HR, 0.91 [95% CI, 0.80-1.03] in a scenario with IRF 5% and CFR 20%). Moderate hypofractionation in early stage breast cancer (OCOG hypofractionation trial) and prostate cancer (CHHiP) was not associated with survival benefits in the setting of COVID-19 (eg, OCOG hypofractionation trial median HR, 0.89 [95% CI, 0.74-1.06]; CHHiP median HR, 0.87 [95% CI, 0.75-1.01] under high-risk scenario with IRF 10% and CFR 30%). More aggressive hypofractionation (FAST-Forward, HYPO-RT-PC) and accelerated partial breast irradiation (NSABP B-39) were associated with improved survival in higher risk scenarios (eg, FAST-Forward median HR, 0.58 [95% CI, 0.49-0.68]; HYPO-RT-PC median HR, 0.60 [95% CI, 0.48-0.75] under scenario with IRF 10% and CFR 30%).

Conclusions And Relevance: In this comparative effectiveness study of data from 8 clinical trials of patients receiving radiation therapy to simulate COVID-19 risk and mortality rates, treatment modification was not associated with altered risk from COVID-19 in lower-risk scenarios and was only associated with decreased mortality in very high COVID-19-risk scenarios. This model, which can be adapted to dynamic changes in COVID-19 risk, provides a flexible, quantitative approach to assess the potential impact of treatment modifications and supports the continued delivery of standard evidence-based care with appropriate precautions against COVID-19.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.3304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008289PMC
March 2021

Correlative analysis between two commercially available post-prostatectomy genomic tests.

Authors:
Mohammed Shahait Mohammed Alshalalfa Paul L Nguyen Ayah Al-Fahmawi Ryan W Dobbs Priti Lal David I Lee

Prostate Cancer Prostatic Dis 2021 06 9;24(2):575-577. Epub 2021 Mar 9.

Division of Urology, University of Pennsylvania, Philadelphia, PA, USA.

Background: Multiple genomic tests are available following radical prostatectomy (RP), however, there is a lack of head-to-head evidence for these tests. We sought to compare the performance of two genomic tests in predicting post-RP oncological outcomes.

Methods: A cohort of 16 post-RP patients with adverse pathological features who had obtained both Decipher (D) and Prolaris (P) testing. The Pearson correlation was used to compare scores from D and cell cycle progression (CCP) from P. Then, we derived a microarray CCP (mCCP) from D and correlated with P-CCP. The associations of D and mCCP with biochemical recurrence (BCR) and metastasis (M) was evaluated in multivariable survival analysis (MVA) in a large cohort of RP patients treated at Johns Hopkins University (1992-2010). In addition, we characterized the expression of the 31 P-CCP genes and mCCP scores in a cohort of 17,967 RP samples from Decipher platform.

Results: There was significant correlation between the D score and P-CCP (r = 0.67, p = 0.004), and between the 10-year probability of BCR reported by P and 5-year probability of M reported by D (r = 0.69, p = 0.003). In this cohort, mCCP derived from the D platform was highly correlated to the reported P-CCP scores from the P platform (r = 0.88, p = 6.7e-6). In a comparative retrospective RP cohort, both mCCP and D were significantly associated with M outcome (p < 0.01 for both). On MVA, D was a predictor of M (HR 1.3, 95% CI [1.12-1.52], p = 0.0005), while mCCP was not a predictor of M (p = 0.62). In the D platform cohort, the 31 P-CCP genes were correlated to each other, and TOP2A was the most correlated to mCCP (r = 0.7).

Conclusions: We found that P and D scores post-RP were correlated and help in identifying patients who at high risk of BCR in this cohort. In a larger cohort with longer follow-up, D was predictor of M, whereas mCCP was not.
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http://dx.doi.org/10.1038/s41391-020-00305-0DOI Listing
June 2021

Financial worry and psychological distress among cancer survivors in the United States, 2013-2018.

Authors:
Edward Christopher Dee Ryan D Nipp Vinayak Muralidhar Zizi Yu Santino S Butler Brandon A Mahal Paul L Nguyen Nina N Sanford

Support Care Cancer 2021 Sep 16;29(9):5523-5535. Epub 2021 Mar 16.

Department of Radiation Oncology, University of Texas Southwestern, Dallas, TX, USA.

Background: A growing proportion of cancer survivors experience financial toxicity. However, the psychological burden of cancer costs and associated mental health outcomes require further investigation. We assessed prevalence and predictors of self-reported financial worry and mental health outcomes among cancer survivors.

Patients And Methods: Data from the 2013-2018 National Health Interview Survey (NHIS) for adults reporting a cancer diagnosis were used. Multivariable ordinal logistic regressions defined adjusted odds ratios (AORs) of reporting financial worry by relevant sociodemographic variables, and sample weight-adjusted prevalence of financial worry was estimated. The association between financial worry and psychological distress, as defined by the six-item Kessler Psychological Distress Scale was also assessed.

Results: Among 13,361 survey participants (median age 67; 60.0% female), 9567 (71.6%) self-reported financial worry, including worries regarding costs of paying for children's college education (62.7%), maintaining one's standard of living (59.7%), and medical costs due to illness or accident (58.3%). Female sex, younger age, and Asian American race were associated with increased odds of financial worry (P < 0.05 for all). Of 13,218 participants with complete responses to K6 questions, 701 (5.3%) met the threshold for severe psychological distress. Participants endorsing financial worry were more likely to have psychological distress (6.6 vs. 1.2%, AOR 2.89, 95% CI 2.03-4.13, P< 0.001) with each additional worry conferring 23.9% increased likelihood of psychological distress.

Conclusions: A majority of cancer survivors reported financial worry, which was associated with greater odds of reporting psychological distress. Policies and guidelines are needed to identify and mitigate financial worries and psychologic distress among patients with cancer, with the goal of improving psychological well-being and overall cancer survivorship care.
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http://dx.doi.org/10.1007/s00520-021-06084-1DOI Listing
September 2021

The Case for Brachytherapy: Why It Deserves a Renaissance.

Authors:
Vonetta M Williams Jenna M Kahn Nikhil G Thaker Sushil Beriwal Paul L Nguyen Douglas Arthur Daniel Petereit Brandon A Dyer

Adv Radiat Oncol 2021 Mar-Apr;6(2):100605. Epub 2020 Nov 6.

Department of Radiation Oncology, University of Washington, Seattle, Washington.

The recent global events related to the coronavirus disease of 2019 pandemic have significantly changed the medical landscape and led to a shift in oncologic treatment perspectives. There is a renewed focus on preserving treatment outcomes while maintaining medical accessibility and decreasing medical resource utilization. Brachytherapy, which is a vital part of the treatment course of many cancers (particularly prostate and gynecologic cancers), has the ability to deliver hypofractionated radiation and thus shorten treatment time. Studies in the early 2000s demonstrated a decline in brachytherapy usage despite data showing equivalent or even superior treatment outcomes for brachytherapy in disease sites, such as the prostate and cervix. However, newer data suggest that this trend may be reversing. The renewed call for shorter radiation courses based on data showing equivalent outcomes will likely establish hypofractionated radiation as the standard of care across multiple disease sites. With shifting reimbursement, brachytherapy represents the pinnacle in hypofractionated, conformal radiation therapy, and with extensive long-term data in support of the treatment modality brachytherapy is primed for a renaissance.
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http://dx.doi.org/10.1016/j.adro.2020.10.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940781PMC
November 2020

Intermediate clinical endpoints for surrogacy in localised prostate cancer: an aggregate meta-analysis.

Authors:
Laila A Gharzai Ralph Jiang David Wallington Gavin Jones Samuel Birer Neil Jairath Elizabeth M Jaworski Matthew R McFarlane Brandon A Mahal Paul L Nguyen Howard Sandler Todd M Morgan Zachery R Reichert Joshi J Alumkal Rohit Mehra Amar U Kishan Karim Fizazi Susan Halabi Edward M Schaeffer Felix Y Feng David Elliott Robert T Dess William C Jackson Matthew J Schipper Daniel E Spratt

Lancet Oncol 2021 03;22(3):402-410

Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA. Electronic address:

Background: The international Intermediate Clinical Endpoints in Cancer of the Prostate working group has established metastasis-free survival as a surrogate for overall survival in localised prostate cancer based on the findings of 19 predominantly radiotherapy-based trials. We sought to comprehensively assess aggregate trial-level performance of commonly reported intermediate clinical endpoints across all randomised trials in localised prostate cancer.

Methods: For this meta-analysis, we searched PubMed for all trials in localised or biochemically recurrent prostate cancer published between Jan 1, 1970, and Jan 15, 2020. Eligible trials had to be randomised, therapeutic, reporting overall survival and at least one intermediate clinical endpoint, and with a sample size of at least 70 participants. Trials of metastatic disease were excluded. Intermediate clinical endpoints included biochemical failure, local failure, distant metastases, biochemical failure-free survival, progression-free survival, and metastasis-free survival. Candidacy for surrogacy was assessed using the second condition of the meta-analytical approach (ie, correlation of the treatment effect of the intermediate clinical endpoint and overall survival), using R weighted by the inverse variance of the log intermediate clinical endpoint hazard ratio. The intermediate clinical endpoint was deemed to be a surrogate for overall survival if R was 0·7 or greater.

Findings: 75 trials (53 631 patients) were included in our analysis. Median follow-up was 9·1 years (IQR 5·7-10·6). Biochemical failure (R 0·38 [95% CI 0·11-0·64]), biochemical failure-free survival (R 0·12 [0·0030-0·33]), biochemical failure and clinical failure (R 0·28 [0·0045-0·65]), and local failure (R 0·085 [0·00-0·37]) correlated poorly with overall survival. Progression-free survival (R 0·46 [95% CI 0·22-0·67]) showed moderate correlation with overall survival, and metastasis-free survival (R 0·78 [0·59-0·89]) correlated strongly.

Interpretation: Intermediate clinical endpoints based on biochemical and local failure did not meet the second condition of the meta-analytical approach and are not surrogate endpoints for overall survival in localised prostate cancer. Our findings validate metastasis-free survival as the only identified surrogate endpoint for overall survival to date.

Funding: Prostate Cancer Foundation and National Institutes of Health.
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http://dx.doi.org/10.1016/S1470-2045(20)30730-0DOI Listing
March 2021

Disparities in Refusal of Locoregional Treatment for Prostate Adenocarcinoma.

Authors:
Edward Christopher Dee Melaku A Arega David D Yang Santino S Butler Brandon A Mahal Nina N Sanford Paul L Nguyen Vinayak Muralidhar

JCO Oncol Pract 2021 10 25;17(10):e1489-e1501. Epub 2021 Feb 25.

Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Purpose: We assessed sociodemographic factors associated with and survival implications of refusal of potentially survival-prolonging locoregional treatment (LT, including radiotherapy and surgery) despite provider recommendation among men with localized prostate adenocarcinoma.

Methods: The National Cancer Database (2004-2015) identified men with TxN0M0 prostate cancer who either received or refused LT despite provider recommendation. Multivariable logistic regression defined adjusted odds ratios (AORs) with 95% CI of refusing LT, with sociodemographic and clinical covariates. Models were stratified by low-risk and intermediate- or high-risk (IR or HR) disease, with a separate interaction analysis between race and risk group. Multivariable Cox proportional hazard ratios compared overall survival (OS) among men who received versus refused LT.

Results: Of 887,839 men (median age 64 years, median follow-up 6.14 years), 2,487 (0.28%) refused LT. Among men with IR or HR disease (n = 651,345), Black and Asian patients were more likely to refuse LT than White patients (0.35% 0.29% 0.17%; Black White AOR, 1.75; 95% CI, 1.52 to 2.01; < .001; Asian White AOR, 1.47; 95% CI, 1.05 to 2.06; = .027, race * risk group interaction < .001). Later year of diagnosis, community facility type, noninsurance or Medicaid, and older age were also associated with increased odds of LT refusal, overall and when stratifying by risk group. For men with IR or HR disease, LT refusal was associated with worse OS (5-year OS 80.1% 91.5%, HR, 1.65, < .001).

Conclusion: LT refusal has increased over time; racial disparities were greater in higher-risk disease. Refusal despite provider recommendation highlights populations that may benefit from efforts to assess and reduce barriers to care.
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http://dx.doi.org/10.1200/OP.20.00839DOI Listing
October 2021

Validation of a 22-Gene Genomic Classifier in Patients With Recurrent Prostate Cancer: An Ancillary Study of the NRG/RTOG 9601 Randomized Clinical Trial.

Authors:
Felix Y Feng Huei-Chung Huang Daniel E Spratt Shuang George Zhao Howard M Sandler Jeffry P Simko Elai Davicioni Paul L Nguyen Alan Pollack Jason A Efstathiou Adam P Dicker Tamara Todorovic Jennifer Margrave Yang Seagle Liu Bashar Dabbas Darby J S Thompson Rajdeep Das James J Dignam Christopher Sweeney Gerhardt Attard Jean-Paul Bahary Himanshu R Lukka William A Hall Thomas M Pisansky Amit B Shah Stephanie L Pugh William U Shipley Phuoc T Tran

JAMA Oncol 2021 04;7(4):544-552

Department of Radiation Oncology, Johns Hopkins University, Baltimore, Maryland.

Importance: Decipher (Decipher Biosciences Inc) is a genomic classifier (GC) developed to estimate the risk of distant metastasis (DM) after radical prostatectomy (RP) in patients with prostate cancer.

Objective: To validate the GC in the context of a randomized phase 3 trial.

Design, Setting, And Participants: This ancillary study used RP specimens from the phase 3 placebo-controlled NRG/RTOG 9601 randomized clinical trial conducted from March 1998 to March 2003. The specimens were centrally reviewed, and RNA was extracted from the highest-grade tumor available in 2019 with a median follow-up of 13 years. Clinical-grade whole transcriptomes from samples passing quality control were assigned GC scores (scale, 0-1). A National Clinical Trials Network-approved prespecified statistical plan included the primary objective of validating the independent prognostic ability of GC for DM, with secondary end points of prostate cancer-specific mortality (PCSM) and overall survival (OS). Data were analyzed from September 2019 to December 2019.

Intervention: Salvage radiotherapy (sRT) with or without 2 years of bicalutamide.

Main Outcomes And Measures: The preplanned primary end point of this study was the independent association of the GC with the development of DM.

Results: In this ancillary study of specimens from a phase 3 randomized clinical trial, GC scores were generated from 486 of 760 randomized patients with a median follow-up of 13 years; samples from a total of 352 men (median [interquartile range] age, 64.5 (60-70) years; 314 White [89.2%] participants) passed microarray quality control and comprised the final cohort for analysis. On multivariable analysis, the GC (continuous variable, per 0.1 unit) was independently associated with DM (hazard ratio [HR], 1.17; 95% CI, 1.05-1.32; P = .006), PCSM (HR, 1.39; 95% CI, 1.20-1.63; P < .001), and OS (HR, 1.17; 95% CI, 1.06-1.29; P = .002) after adjusting for age, race/ethnicity, Gleason score, T stage, margin status, entry prostate-specific antigen, and treatment arm. Although the original planned analysis was not powered to detect a treatment effect interaction by GC score, the estimated absolute effect of bicalutamide on 12-year OS was less when comparing patients with lower vs higher GC scores (2.4% vs 8.9%), which was further demonstrated in men receiving early sRT at a prostate-specific antigen level lower than 0.7 ng/mL (-7.8% vs 4.6%).

Conclusions And Relevance: This ancillary validation study of the Decipher GC in a randomized trial cohort demonstrated association of the GC with DM, PCSM, and OS independent of standard clinicopathologic variables. These results suggest that not all men with biochemically recurrent prostate cancer after surgery benefit equally from the addition of hormone therapy to sRT.

Trial Registration: ClinicalTrials.gov identifier: NCT00002874.
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http://dx.doi.org/10.1001/jamaoncol.2020.7671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879385PMC
April 2021

Initial Management of Noncastrate Advanced, Recurrent, or Metastatic Prostate Cancer: ASCO Guideline Update.

Authors:
Katherine S Virgo R Bryan Rumble Ronald de Wit David S Mendelson Thomas J Smith Mary-Ellen Taplin James L Wade Charles L Bennett Howard I Scher Paul L Nguyen Martin Gleave Scott C Morgan Andrew Loblaw Sean Sachdev David L Graham Neha Vapiwala Amy M Sion Virgil H Simons James Talcott

J Clin Oncol 2021 04 26;39(11):1274-1305. Epub 2021 Jan 26.

Nanhealth, Inc, Culver City, CA.

Purpose: Update all preceding ASCO guidelines on initial hormonal management of noncastrate advanced, recurrent, or metastatic prostate cancer.

Methods: The Expert Panel based recommendations on a systematic literature review. Recommendations were approved by the Expert Panel and the ASCO Clinical Practice Guidelines Committee.

Results: Four clinical practice guidelines, one clinical practice guidelines endorsement, 19 systematic reviews with or without meta-analyses, 47 phase III randomized controlled trials, nine cohort studies, and two review papers informed the guideline update.

Recommendations: Docetaxel, abiraterone, enzalutamide, or apalutamide, each when administered with androgen deprivation therapy (ADT), represent four separate standards of care for noncastrate metastatic prostate cancer. Currently, the use of any of these agents in any particular combination or series cannot be recommended. ADT plus docetaxel, abiraterone, enzalutamide, or apalutamide should be offered to men with metastatic noncastrate prostate cancer, including those who received prior therapies, but have not yet progressed. The combination of ADT plus abiraterone and prednisolone should be considered for men with noncastrate locally advanced nonmetastatic prostate cancer who have undergone radiotherapy, rather than castration monotherapy. Immediate ADT may be offered to men who initially present with noncastrate locally advanced nonmetastatic disease who have not undergone previous local treatment and are unwilling or unable to undergo radiotherapy. Intermittent ADT may be offered to men with high-risk biochemically recurrent nonmetastatic prostate cancer. Active surveillance may be offered to men with low-risk biochemically recurrent nonmetastatic prostate cancer. The panel does not support use of either micronized abiraterone acetate or the 250 mg dose of abiraterone with a low-fat breakfast in the noncastrate setting at this time.Additional information is available at www.asco.org/genitourinary-cancer-guidelines.
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http://dx.doi.org/10.1200/JCO.20.03256DOI Listing
April 2021

Association Between Travel Distance and Use of Postoperative Radiation Therapy Among Men With Organ-Confined Prostate Cancer: Does Geography Influence Treatment Decisions?

Authors:
Melaku A Arega David D Yang Trevor J Royce Brandon A Mahal Edward Christopher Dee Santino S Butler Sybil Sha Kent W Mouw Paul L Nguyen Vinayak Muralidhar

Pract Radiat Oncol 2021 Jul-Aug;11(4):e426-e433. Epub 2021 Feb 6.

Dana-Farber Cancer Institute/Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address:

Purpose: After radical prostatectomy, men with adverse pathologic features or a persistent postoperative detectable prostate-specific antigen (PSA) are candidates for postoperative radiation therapy (PORT). Previous data have suggested disparities in receipt of adjuvant radiation therapy for adverse pathologic features according to travel distance. Among patients without adverse pathologic features (pT2 disease and negative margins), the main indication for PORT is a persistent postoperative detectable PSA. However, it remains unknown whether the rate of receipt of PORT in this cohort of men with persistently detectable PSA is related to travel distance from the treating facility.

Methods And Materials: Using the National Cancer Database, we identified 170,379 men with prostate cancer diagnosed from 2004 to 2015 managed with upfront surgery who were found to have pT2 disease with negative surgical margins. Multivariable logistic regression defined adjusted odds ratios (AORs) with 95% confidence intervals (CIs) of receiving PORT as the primary dependent variable and distance (<5, 5-10, 10-20, ≥20 miles from the treatment facility) as the primary independent variable.

Results: Within our cohort, progressively farther distance from the treatment facility was associated with lower rates of PORT. In patients living <5 miles, 5 to 10 miles, 10 to 20 miles, and >20 miles from the treating facility, rates of PORT of were 1.37% (referent), 1.16% (AOR, 0.90; 95% CI, 0.79-1.04; P = .158), 0.98% (AOR, 0.80; 95% CI, 0.70-0.93; P = .003), and 0.64% (AOR, 0.47; 95% CI, 0.41-0.54; P < .001), respectively.

Conclusions: For men with localized prostate cancer without adverse pathologic features managed with surgery, increasing distance from treatment facility was associated with lower receipt of PORT. Given that the rate of a persistent postoperative detectable PSA is unlikely to depend on the distance to the treatment facility, these findings raise the possibility that the geographic availability of radiation treatment facilities influences the decision to undergo PORT for patients with persistent postoperative detectable PSA.
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http://dx.doi.org/10.1016/j.prro.2020.12.002DOI Listing
September 2021

Health care spending in prostate cancer: An assessment of characteristics and health care utilization of high resource-patients.

Authors:
Maxine Sun Maya Marchese David F Friedlander David-Dan Nguyen Alexander P Cole Sean A Fletcher Brandon A Mahal Paul L Nguyen Toni K Choueiri Adam S Kibel Quoc-Dien Trinh

Urol Oncol 2021 02 9;39(2):130.e17-130.e24. Epub 2020 Dec 9.

Department of Urology, Brigham and Women's Hospital, Boston, MA; Center for Surgery and Public Health, Brigham and Women's Hospital, Boston, MA; Genitourinary Lank Center, Dana-Farber Cancer Institute, Boston, MA. Electronic address:

Background: Prostate cancer ranks among the top 5 cancers in contribution to national expenditures. Previous reports have identified that 5% of the population accounts for 50% of the nation's annual health care spending. To date, the assessment of the top 5% resource-patients among men diagnosed with prostate cancer (PCa) has never been performed. We investigate the determinants and health care utilization of high resource-patients diagnosed with PCa using a population-based cohort using the Surveillance, Epidemiology, and End Results Medicare-linked database.

Methods: Men aged ≥66-year-old with a primary diagnosis of PCa in 2009 were identified. High resource spenders were defined as the top 5% of the sum of the total cost incurred for all services rendered per beneficiary. The spending in each group and predictors of being a high resource-patient were assessed.

Results: The top 5% resource-patients consisted of 646 men who spent a total of $62,474,504, comprising 26% of the total cost incurred for all 12,875 men who were diagnosed with PCa in 2009. Of the top 5% resource-patients, the average amount spent per patient was $96,710 vs. $14,664 among the bottom 95% resource-patients. In adjusted analyses, older (odds ratio [OR]: 1.02, 95% confidence interval [CI]: 1.00-1.03), Charlson Comorbidity Index ≥2 (OR: 3.78, 95% CI: 3.10-4.60) men, and advanced disease (metastasis OR: 2.29, 95% CI: 1.68-3.11) were predictors of being a top 5% resource-patient. Of these patients, 210 men died within 1 year of PCa diagnosis (32.5%) vs. 606 men of the bottom 95% resource-patients (5.0%, P < 0.001).

Conclusion: Five percent of men diagnosed with PCa bore 26% of the total cost incurred for all men diagnosed with the disease in 2009. Multimorbidity and advanced disease stage represent the primary drivers of being a high-resource PCa patient. Multidisciplinary care and shared decision-making is encouraged for such patients to better manage cost and quality of care.
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http://dx.doi.org/10.1016/j.urolonc.2020.09.033DOI Listing
February 2021

A Systematic Review and Meta-analysis of Local Salvage Therapies After Radiotherapy for Prostate Cancer (MASTER).

Authors:
Luca F Valle Eric J Lehrer Daniela Markovic David Elashoff Rebecca Levin-Epstein R Jeffery Karnes Robert E Reiter Matthew Rettig Jeremie Calais Nicholas G Nickols Robert T Dess Daniel E Spratt Michael L Steinberg Paul L Nguyen Brian J Davis Nicholas G Zaorsky Amar U Kishan

Eur Urol 2021 09 11;80(3):280-292. Epub 2020 Dec 11.

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

Context: Management of locally recurrent prostate cancer after definitive radiotherapy remains controversial due to the perceived high rates of severe genitourinary (GU) and gastrointestinal (GI) toxicity associated with any local salvage modality.

Objective: To quantitatively compare the efficacy and toxicity of salvage radical prostatectomy (RP), high-intensity focused ultrasound (HIFU), cryotherapy, stereotactic body radiotherapy (SBRT), low-dose-rate (LDR) brachytherapy, and high-dose-rate (HDR) brachytherapy.

Evidence Acquisition: We performed a systematic review of PubMed, EMBASE, and MEDLINE. Two- and 5-yr recurrence-free survival (RFS) rates and crude incidences of severe GU and GI toxicity were extracted as endpoints of interest. Random-effect meta-analyses were conducted to characterize summary effect sizes and quantify heterogeneity. Estimates for each modality were then compared with RP after adjusting for individual study-level covariates using mixed-effect regression models, while allowing for differences in between-study variance across treatment modalities.

Evidence Synthesis: A total of 150 studies were included for analysis. There was significant heterogeneity between studies within each modality, and covariates differed between modalities, necessitating adjustment. Adjusted 5-yr RFS ranged from 50% after cryotherapy to 60% after HDR brachytherapy and SBRT, with no significant differences between any modality and RP. Severe GU toxicity was significantly lower with all three forms of radiotherapeutic salvage than with RP (adjusted rates of 20% after RP vs 5.6%, 9.6%, and 9.1% after SBRT, HDR brachytherapy, and LDR brachytherapy, respectively; p ≤ 0.001 for all). Severe GI toxicity was significantly lower with HDR salvage than with RP (adjusted rates 1.8% vs 0.0%, p < 0.01), with no other differences identified.

Conclusions: Large differences in 5-yr outcomes were not uncovered when comparing all salvage treatment modalities against RP. Reirradiation with SBRT, HDR brachytherapy, or LDR brachytherapy appears to result in less severe GU toxicity than RP, and reirradiation with HDR brachytherapy yields less severe GI toxicity than RP. Prospective studies of local salvage for radiorecurrent disease are warranted.

Patient Summary: In a large study-level meta-analysis, we looked at treatment outcomes and toxicity for men treated with a number of salvage treatments for radiorecurrent prostate cancer. We conclude that relapse-free survival at 5 years is equivalent among salvage modalities, but reirradiation may lead to lower toxicity.
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http://dx.doi.org/10.1016/j.eururo.2020.11.010DOI Listing
September 2021

A Systematic Review of the Evidence for the Decipher Genomic Classifier in Prostate Cancer.

Authors:
Neil K Jairath Alan Dal Pra Randy Vince Robert T Dess William C Jackson Jeffrey J Tosoian Sean M McBride Shuang G Zhao Alejandro Berlin Brandon A Mahal Amar U Kishan Robert B Den Stephen J Freedland Simpa S Salami Samuel D Kaffenberger Alan Pollack Phuoc Tran Rohit Mehra Todd M Morgan Adam B Weiner Osama Mohamad Peter R Carroll Matthew R Cooperberg R Jeffrey Karnes Paul L Nguyen Jeff M Michalski Jonathan D Tward Felix Y Feng Edward M Schaeffer Daniel E Spratt

Eur Urol 2021 03 5;79(3):374-383. Epub 2020 Dec 5.

Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA. Electronic address:

Context: Molecular biomarkers aim to address the established limitations of clinicopathologic factors to accurately risk stratify patients with prostate cancer (PCa). Questions remain as to whether sufficient evidence supports adoption of these biomarkers for clinical use.

Objective: To perform a systematic review of the available evidence supporting the clinical utility of the Decipher genomic classifier (GC).

Evidence Acquisition: The review was performed as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines by searching PubMed and conference abstracts from January 2010 to June 2020. Evidence was then graded using the criteria of Simon et al (Simon RM, Paik S, Hayes DF. Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst 2009;101:1446-52) and American Urology Association (AUA) criteria.

Evidence Synthesis: In total, 42 studies and 30407 patients were included. GC performance data were available for localized, postprostatectomy, nonmetastatic castration-resistant, and metastatic hormone-sensitive PCa as part of retrospective studies (n=12141), prospective registries (n=17053), and prospective and post hoc randomized trial analyses (n=1213). In 32 studies (n=12600), the GC was independently prognostic for all study endpoints (adverse pathology, biochemical failure, metastasis, and cancer-specific and overall survival) on multivariable analysis and improved the discrimination over standard of care in 24 studies (n=8543). GC use changed the management in active surveillance (number needed to test [NNT]=9) and postprostatectomy (NNT=1.5-4) settings in five studies (n=4331). Evidence strength was levels 1 and 2 by the Simon criteria for all disease states other than high-risk PCa, and grades A and B by AUA criteria depending on disease state.

Conclusions: Consistent data are now present from diverse levels of evidence, which when viewed together, have demonstrated clinical utility of the GC in PCa. The utility of the GC is strongest for intermediate-risk PCa and postprostatectomy decision-making.

Patient Summary: In this paper, we review the evidence of the Decipher genomic classification tool for men with prostate cancer. We found consistent evidence that the test helps identify which cancers are more or less aggressive, which in turn aids in personalized treatment decision-making.
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http://dx.doi.org/10.1016/j.eururo.2020.11.021DOI Listing
March 2021

Factors Influencing Noncompletion of Radiation Therapy Among Men With Localized Prostate Cancer.

Authors:
Edward Christopher Dee Vinayak Muralidhar Melaku A Arega Amar U Kishan Daniel E Spratt Robert T Dess Martin T King Sybil T Sha Patricia Mae G Santos Santino S Butler Nina N Sanford Paul L Nguyen Brandon A Mahal

Int J Radiat Oncol Biol Phys 2021 04 1;109(5):1279-1285. Epub 2020 Dec 1.

Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida; Office of Community Outreach and Engagement, Sylvester Comprehensive Cancer Center, Miami, Florida. Electronic address:

Purpose: Treatment noncompletion may occur with radiation therapy (RT), especially with protracted treatment courses such as RT for prostate cancer, and may affect the efficacy of RT. For men with localized prostate cancer managed with primary RT, we evaluated associations between rates of treatment noncompletion and RT fractionation schedules.

Methods And Materials: The National Cancer Database identified men diagnosed from 2004 to 2014 treated with primary RT. Patients receiving 180 cGy/fraction or 200 cGy/fraction were defined as having completed radiation therapy if they received ≥41 fractions of 180 cGy/fraction or ≥37 fractions of 200 cGy/fraction. Stereotactic body radiation therapy (SBRT) was defined as 5 to 8 fractions of 600 to 800 cGy/fraction. Odds ratios compared rates of treatment noncompletion, adjusting for sociodemographic covariates. A propensity-adjusted multivariable Cox regression assessed the association between treatment completion and overall survival.

Results: Of 157,657 patients, 95.7% (n = 150,847) received conventional fractionation and 4.3% (n = 6810) received SBRT. Rates of noncompletion were 12.5% (n = 18,803) among patients who received conventional fractionation and 1.9% (n = 131) among patients who received SBRT (odds ratio [OR] versus conventional, 0.21; 95% confidence interval [CI], 0.18-0.26; P < .001). The rate of noncompletion among 25,727 African American patients was 12.8%, compared with 11.8% among 126,199 white patients (OR, 1.14; 95% CI, 1.09-1.19; P < .001). In a subgroup analysis, the disparity in noncompletion persisted for conventional fractionation (13.2% vs 12.3%, respectively; OR, 1.09; 95% CI, 1.05-1.13; P < .001), but not for SBRT (2.2% vs 1.8%, respectively; OR, 1.26; 95% CI, 0.79-2.00; P = .34). Noncompletion was associated with worse survival in a propensity-adjusted multivariable analysis (hazard ratio, 1.25; 95% CI, 1.22-1.29; P < .001).

Conclusions: SBRT was associated with lower rates of RT noncompletion among men with localized prostate cancer. African American race was associated with greater rates of treatment noncompletion, although the disparity may be decreased among men receiving SBRT.
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http://dx.doi.org/10.1016/j.ijrobp.2020.11.064DOI Listing
April 2021

Cognition and depression effects of androgen receptor axis-targeted drugs in men with prostate cancer: A systematic review.

Authors:
Anupam Batra Michele Marchioni Ardeshir Z Hashmi Peter E Lonergan Alicia K Morgans Kevin T Nead Paul L Nguyen Eric Winquist Joseph L Chin

J Geriatr Oncol 2021 06 22;12(5):687-695. Epub 2020 Nov 22.

Departments of Surgery (Urology) and Oncology, Western University and London Health Sciences Centre, London, Ontario, Canada. Electronic address:

Context: Novel androgen receptor axis-targeting drugs (ARATs) have been shown to improve outcomes in men with prostate cancer. Central nervous system androgen blockade may be harmful for older adults who may be at increased risk of adverse cognitive and psychologic effects.

Objective: To systematically evaluate the effect of ARATs on cognition and depression in men with metastatic prostate cancer.

Evidence Acquisition: We searched PubMed and EMBASE for articles published in English between September 2012 and September 2019 reporting cognition and depression outcomes in men receiving ARATs for metastatic prostate cancer using validated psychometric tools. The level of evidence and risk of bias were assessed using the GRADE approach for randomized clinical trials and observational studies.

Results: 15 reports studying 8954 men with metastatic castration-sensitive and -resistant, or non-metastatic castration-resistant prostate cancer were identified. Data were available for abiraterone, enzalutamide and apalutamide but not darolutamide. The mean (and 95% confidence interval) and median (and min-max) of the absolute scores and changes from baseline were included, when available. There was heterogeneity in the psychometric tools used which obviated statistical pooling of results. Very limited data assessing cognition suggested that abiraterone was associated with improved cognitive functioning or perhaps less cognitive harm versus enzalutamide. Fourteen reports assessed emotional wellbeing. ARATs reduced depressive symptoms when compared to prednisone alone or placebo but not compared to bicalutamide. Abiraterone may improve short-term emotional functioning relative to enzalutamide. The quality of evidence was low when examining ARAT effect on cognitive function and moderate when examining ARAT effect on depression.

Conclusions: Depression was assessed more frequently than cognition in men receiving ARATs. Self-reported depression measures favored abiraterone over enzalutamide and both abiraterone and enzalutamide over placebo. Data evaluating apalutamide and darolutamide are lacking. Further studies of ARATs using validated clinician-based psycho-cognition tools along with self-reported measures in men with metastatic prostate cancer are needed.
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http://dx.doi.org/10.1016/j.jgo.2020.11.002DOI Listing
June 2021
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