Publications by authors named "Daniel E Spratt"

321 Publications

Association Between Physician and Patient Reported Symptoms in Patients Treated with Definitive Radiotherapy for Locally Advanced Lung Cancer in a Statewide Consortium.

Int J Radiat Oncol Biol Phys 2021 Nov 25. Epub 2021 Nov 25.

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

Introduction: Little data have been reported about the patient experience during curative radiotherapy for lung cancer in routine clinical practice, or how this relates to treatment toxicity reported by clinicians. The purpose of this study was to compare clinician-reported adverse events (AEs) with patient-reported outcomes (PROs) including both specific symptoms/side effects as well as overall quality of life (QOL) during and after definitive radiotherapy (RT) for locally advanced lung cancer (LALC) in a large statewide cohort.

Methods And Materials: Patient-reported outcomes (PROs) were prospectively collected from patients treated with definitive radiotherapy for LALC at 24 institutions within the XXXX Radiation Oncology Quality Consortium between 2012-2018 using the Functional Assessment of Cancer Therapy Trial Outcome Index (FACT-TOI). Physicians prospectively recorded adverse events (AEs) using CTCAE version 4.0. Patient-reported quality of life (QOL) changes from baseline were assessed during and after radiotherapy using the FACT-TOI. Spearman correlation coefficients were calculated for AEs and similar PROs, and multivariable analysis was used to assess associations with QOL.

Results: 1361 patients were included and 53% of respondents reported clinically meaningful declines in QOL at the end of RT. Correlation between clinician-reported esophagitis and patient-reported trouble swallowing was moderate (R=0.67) while correlations between clinician-reported pneumonitis and patient-reported shortness of breath (R=0.13) and cough (R=0.09) were weak. Clinician-reported AEs were significantly associated with clinically meaningful declines inpatient-reported QOL, with R=-0.46 for a summary AE-score. QOL was more strongly associated with fatigue (R=-0.41) than lung-specific AEs.

Conclusions: AEs are associated with clinically meaningful declines in QOL during and after RT for LALC, but associations between AEs and QOL are only modest. This highlights the importance of PRO data, and future research should assess whether earlier detection of PRO changes could allow for interventions that reduce the frequency of treatment-related clinically meaningful declines in QOL.
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http://dx.doi.org/10.1016/j.ijrobp.2021.11.024DOI Listing
November 2021

MRI-Targeted Biopsy in Prostate Cancer Screening.

N Engl J Med 2021 Nov;385(22):2109-2110

University Hospitals Cleveland Medical Center, Cleveland, OH

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http://dx.doi.org/10.1056/NEJMc2115775DOI Listing
November 2021

Association of Short-term Patient-reported Outcomes with Long-term Oncologic Outcomes in Localized Prostate Cancer Patients Treated with Radiotherapy and ADT in a Randomized Controlled Trial.

Int J Radiat Oncol Biol Phys 2021 Nov 14. Epub 2021 Nov 14.

The Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa, ON, Canada. Electronic address:

Background: Both oncologic outcomes and patient-reported outcomes are pivotal in prostate cancer (PCa). However, it remains unknown if there is any association between these two outcomes. In this secondary analysis of a randomized controlled trial, we investigated the association of short-term changes in patient-reported outcome with long-term event-free survival (EFS) and metastasis-free survival (MFS) in localized PCa.

Methodology: Localized PCa patients with Gleason score ≤7, clinical stage T1b-T3a, and PSA <30 ng/mL were randomized to neoadjuvant and concurrent ADT for 6 months starting 4 months before prostate radiotherapy or concurrent and adjuvant ADT for 6 months starting simultaneously with radiotherapy. Patient-reported symptom burden was evaluated using EORTC QoL questionnaire PR.25. Clinically meaningful deterioration (CMD) was defined as a ≥10-point worsening at any time within 10 months post-randomization regardless of subsequent improvement. Landmark analyses were performed to determine the association of CMD of urinary and bowel symptoms separately with EFS and MFS in patients who responded to baseline questionnaire, were alive and event-free at 10 months.

Results: Overall, 393 patients had responded to baseline QoL questionnaire. One patient died and one patient had failure within 10 months. Therefore, 391 patients were eligible for the landmark analyses. After adjusting for age, Gleason score, PSA, performance status, and treatment group, CMD of urinary symptoms was associated with worse EFS (HR: 1.79, 95%CI: 1.21-2.65) and MFS (HR: 1.69, 95%CI: 1.11-2.57). Considering deaths as competing events, CMD of urinary symptoms was associated with a significant increase in the relative incidence of progression (subdistribution HR: 2.42, 95%CI: 1.12-5.20). However, no association was found between CMD of bowel symptoms and EFS or MFS.

Conclusions: In this study, short-term CMD of urinary symptoms was associated with significantly inferior EFS, MFS and increase in the relative incidence of progression. Further investigations are needed to explore the biological rationale of such association in the context of ADT and radiotherapy.
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http://dx.doi.org/10.1016/j.ijrobp.2021.11.010DOI Listing
November 2021

Race and Genetic Alterations in Prostate Cancer.

JCO Precis Oncol 2021 27;5. Epub 2021 Oct 27.

Fredrick R. Schumacher, PhD, Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH; Spyridon P. Basourakos, MD, and Patrick J. Lewicki, MD, Department of Urology, NewYork-Presbyterian Hospital, Weill Cornell Medicine, New York, NY; Randy Vince, MD, Department of Urology, University of Michigan, Ann Arbor, MI; Daniel E. Spratt, MD, Department of Radiation Oncology, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH; Christopher E. Barbieri, MD, PhD, Department of Urology, NewYork-Presbyterian Hospital, Weill Cornell Medicine, New York, NY; and Jonathan E. Shoag, MD, Department of Urology, NewYork-Presbyterian Hospital, Weill Cornell Medicine, New York, NY, Department of Urology, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH.

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http://dx.doi.org/10.1200/PO.21.00324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8563071PMC
October 2021

Reporting of Racial Health Disparities Research: Are We Making Progress?

J Clin Oncol 2021 Oct 25:JCO2101780. Epub 2021 Oct 25.

Department of Radiation Oncology, University Hospitals, Seidman Cancer Center, Case Western Reserve University, Cleveland, OH.

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http://dx.doi.org/10.1200/JCO.21.01780DOI Listing
October 2021

Development and Validation of an Improved Pathological Nodal Staging System in Men With Prostate Cancer.

J Urol 2021 Oct 25:101097JU0000000000002256. Epub 2021 Oct 25.

Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.

Background: Prostate cancer pathological nodal staging uses a single category for all node-positive patients. We sought to improve risk stratification by creating and validating a novel pathological nodal staging system incorporating number of metastatic lymph nodes (+LNs).

Methods: 118,450 men who underwent radical prostatectomy (RP) for nonmetastatic prostate cancer in the National Cancer Database comprised our development cohort. Multivariable Cox proportional hazards analysis with restricted cubic splines was used to assess the non-linear association between number of +LNs and overall mortality (OM). A novel staging system based on number of +LNs was derived by recursive partitioning analysis (RPA). The staging system was validated for prediction of overall and prostate-specific mortality (PCSM) in 105,568 men with nonmetastatic prostate cancer undergoing RP from the Surveillance, Epidemiology, and End Results database. Discrimination was assessed via Harrell's c-index.

Results: In multivariable Cox analysis, OM risk increased with higher number of +LNs up to four (HR1.30 per each LN+, 95%CI 1.23-1.38), with a non-statistically significant increase in risk (HR 1.05, 95%CI 0.99-1.11) beyond four +LN. In the development cohort, RPA identified optimal cutoffs at 0 (N0:Ref), 1 (N1:HR1.40, 95%CI 1.25-1.58), 2 (N2:HR1.67, 95%CI 1.40-1.99), 3-5 (N3a: HR2.18, 95%CI 0.84-2.60), and ≥6 (N3b:HR3.00, 95%CI 2.37-3.79) +LNs. In the validation cohort, these groups had markedly different 10-year OM (0+LNs (N0:15%), 1+LN (N1:35%), 2+LNs (N2:43%), 3-5+LNs (N3a:52%), and ≥6+LNs(N3b:59%) (p <0.05)) and PCSM. The novel staging system improved survival classification over current staging for node-positive patients (optimism-corrected c-index 0.669 (95%CI 0.668-0.671) vs 0.649 (95%CI 0.648-0.651)).

Conclusions: Pathological nodal staging in prostate cancer is improved with stratification by number of +LNs.
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http://dx.doi.org/10.1097/JU.0000000000002256DOI Listing
October 2021

Elective Nodal Radiotherapy for Prostate Cancer: For None, Some, or all?

Int J Radiat Oncol Biol Phys 2021 11;111(4):965-967

Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH.

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http://dx.doi.org/10.1016/j.ijrobp.2021.07.1699DOI Listing
November 2021

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

Int J Radiat Oncol Biol Phys 2021 Sep 18. Epub 2021 Sep 18.

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
September 2021

An international Delphi consensus for pelvic stereotactic ablative radiotherapy re-irradiation.

Radiother Oncol 2021 Sep 21;164:104-114. Epub 2021 Sep 21.

Leeds Teaching Hospitals NHS Trust, UK; University of Leeds, UK. Electronic address:

Introduction: Stereotactic Ablative Radiotherapy (SABR) is increasingly used to treat metastatic oligorecurrence and locoregional recurrences but limited evidence/guidance exists in the setting of pelvic re-irradiation. An international Delphi study was performed to develop statements to guide practice regarding patient selection, pre-treatment investigations, treatment planning, delivery and cumulative organs at risk (OARs) constraints.

Materials And Methods: Forty-one radiation oncologists were invited to participate in three online surveys. In Round 1, information and opinion was sought regarding participants' practice. Guidance statements were developed using this information and in Round 2 participants were asked to indicate their level of agreement with each statement. Consensus was defined as ≥75% agreement. In Round 3, any statements without consensus were re-presented unmodified, alongside a summary of comments from Round 2.

Results: Twenty-three radiation oncologists participated in Round 1 and, of these, 21 (91%) and 22 (96%) completed Rounds 2 and 3 respectively. Twenty-nine of 44 statements (66%) achieved consensus in Round 2. The remaining 15 statements (34%) did not achieve further consensus in Round 3. Consensus was achieved for 10 of 17 statements (59%) regarding patient selection/pre-treatment investigations; 12 of 13 statements (92%) concerning treatment planning and delivery; and 7 of 14 statements (50%) relating to OARs. Lack of agreement remained regarding the minimum time interval between irradiation courses, the number/size of pelvic lesions that can be treated and the most appropriate cumulative OAR constraints.

Conclusions: This study has established consensus, where possible, in areas of patient selection, pre-treatment investigations, treatment planning and delivery for pelvic SABR re-irradiation for metastatic oligorecurrence and locoregional recurrences. Further research into this technique is required, especially regarding aspects of practice where consensus was not achieved.
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http://dx.doi.org/10.1016/j.radonc.2021.09.010DOI Listing
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).

Cancer Genet 2021 Nov 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

Racial disparities in prostate cancer among black men: epidemiology and outcomes.

Prostate Cancer Prostatic Dis 2021 Sep 2. Epub 2021 Sep 2.

Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA.

Prostate cancer has the widest racial disparities of any cancer, and these disparities appear at every stage of the cancer continuum. This review focuses on the disparities in prostate cancer between Black and White men, spanning from prevention and screening to clinical outcomes. We conduct an expansive review of the literature on racial disparities in prostate cancer, interpret the findings, and discuss areas of unmet need in research. We provide an overview of epidemiologic concepts necessary to understanding the current state of prostate cancer disparities, discuss the complexities of studying race, and review potential drivers of disparities in incidence and mortality. We argue that the cause of this disparity is multifactorial and due to a combination of social and environmental factors. The path forward needs to focus on enrolling and retaining Black men in prostate cancer clinical trials and observational studies and identifying potential interventions to improve prevention and clinical outcomes in Black men.
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http://dx.doi.org/10.1038/s41391-021-00451-zDOI Listing
September 2021

Prospective Multicenter Comparison of Open and Robotic Radical Prostatectomy: The PROST-QA/RP2 Consortium.

J Urol 2021 Aug 26:101097JU0000000000002176. Epub 2021 Aug 26.

Department of Urology, Emory University School of Medicine, Atlanta, Georgia.

Purpose: To evaluate the comparative effectiveness of robot-assisted laparoscopic prostatectomy (RALP) and open radical prostatectomy (ORP) in a multicenter study.

Materials And Methods: We evaluated men with localized prostate cancer at 11 high-volume academic medical centers in the United States from the PROST-QA (2003-2006) and the PROST-QA/RP2 cohorts (2010-2013) with a pre-specified goal of comparing RALP (549) and ORP (545). We measured longitudinal patient-reported health-related quality of life (HRQOL) at pre-treatment and at 2, 6, 12, and 24 months, and pathological and perioperative outcomes/complications.

Results: Demographics, cancer characteristics, and margin status were similar between surgical approaches. ORP subjects were more likely to undergo lymphadenectomy (89% vs 47%; p <0.01) and nerve sparing (94% vs 89%; p <0.01). RALP vs ORP subjects experienced less mean intraoperative blood loss (192 vs 805 mL; p <0.01), shorter mean hospital stay (1.6 vs 2.1 days; p <0.01), and fewer blood transfusions (1% vs 4%; p <0.01), wound infections (2% vs 4%; p=0.02), other infections (1% vs 4%; p <0.01), deep vein thromboses (0.5% vs 2%; p=0.04), and bladder neck contractures requiring dilation (1.6% vs 8.3%; p <0.01). RALP subjects reported less pain (p=0.04), less activity interference (p <0.01) and higher incision satisfaction (p <0.01). Surgical approach (RALP vs ORP) was not a significant predictor of longitudinal HRQOL change in any HRQOL domain.

Conclusions: In high-volume academic centers, RALP and ORP patients may expect similar long-term HRQOL outcomes. Overall, RALP patients have less pain, shorter hospital stays, and fewer post-surgical complications such as blood transfusions, infections, deep venous thromboses, and bladder neck contractures.
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http://dx.doi.org/10.1097/JU.0000000000002176DOI Listing
August 2021

Radiation therapy dose and androgen deprivation therapy in localized prostate cancer: a meta-regression of 5-year outcomes in phase III randomized controlled trials.

Prostate Cancer Prostatic Dis 2021 Aug 16. Epub 2021 Aug 16.

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

Background: While multiple randomized trials have evaluated the benefit of radiation therapy (RT) dose escalation and the use and prolongation of androgen deprivation therapy (ADT) in the treatment of prostate cancer, few studies have evaluated the relative benefit of either form of treatment intensification with each other. Many trials have included treatment strategies that incorporate either high or low dose RT, or short-term or long-term ADT (STADT or LTADT), in one or more trial arms. We sought to compare different forms of treatment intensification of RT in the context of localized prostate cancer.

Methods: Using preferred reporting items for systemic reviews and meta-analyses (PRISMA) guidelines, we collected over 40 phases III clinical trials comparing different forms of RT for localized prostate cancer. We performed a meta-regression of 40 individual trials with 21,429 total patients to allow a comparison of the rates and cumulative proportions of 5-year overall survival (OS), prostate cancer-specific mortality (PCSM), and distant metastasis (DM) for each treatment arm of every trial.

Results: Dose-escalation either in the absence or presence of STADT failed to significantly improve any 5-year outcome. In contrast, adding LTADT to low dose RT significantly improved 5-year PCSM (Odds ratio [OR] 0.34, 95% confidence interval [CI] 0.22-0.54, p < 0.001) and DM (OR 0.35, 95% CI 0.20-0.63. p < 0.001) over low dose RT alone. Adding STADT also significantly improved 5-year PCSM over low dose RT alone (OR 0.55, 95% CI 0.41-0.75, p < 0.001).

Conclusion: While limited by between-study heterogeneity and a lack of individual patient data, this meta-analysis suggests that adding ADT, versus increasing RT dose alone, offers a more consistent improvement in clinical endpoints.
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http://dx.doi.org/10.1038/s41391-021-00432-2DOI Listing
August 2021

Salvage therapy for prostate cancer after radical prostatectomy.

Nat Rev Urol 2021 Nov 6;18(11):643-668. Epub 2021 Aug 6.

Department of Radiation Oncology, UCLA, Los Angeles, CA, USA.

More than 40% of men with intermediate-risk or high-risk prostate cancer will experience a biochemical recurrence after radical prostatectomy. Clinical guidelines for the management of these patients largely focus on the use of salvage radiotherapy with or without systemic therapy. However, not all patients with biochemical recurrence will go on to develop metastases or die from their disease. The optimal pre-salvage therapy investigational workup for patients who experience biochemical recurrence should, therefore, include novel techniques such as PET imaging and genomic analysis of radical prostatectomy specimen tissue, as well as consideration of more traditional clinical variables such as PSA value, PSA kinetics, Gleason score and pathological stage of disease. In patients without metastatic disease, the only known curative intervention is salvage radiotherapy but, given the therapeutic burden of this treatment, importance must be placed on accurate timing of treatment, radiation dose, fractionation and field size. Systemic therapy also has a role in the salvage setting, both concurrently with radiotherapy and as salvage monotherapy.
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http://dx.doi.org/10.1038/s41585-021-00497-7DOI Listing
November 2021

Prostate SBRT Dose Escalation (9 Gy × 5, 13.3 Gy × 3, 24 Gy × 1): Are We Making Progress?

Int J Radiat Oncol Biol Phys 2021 09;111(1):110-112

Department of Radiation Oncology, University Hospitals, Case Western Reserve, Cleveland, Ohio.

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http://dx.doi.org/10.1016/j.ijrobp.2021.05.013DOI Listing
September 2021

A comprehensive assessment of Ga-PSMA-11 PET in biochemically recurrent prostate cancer: Results from a prospective multi-center study in 2005 patients.

J Nucl Med 2021 Jul 29. Epub 2021 Jul 29.

Radiology Department, University of Michigan, United States.

We prospectively investigated the performance of the prostate-specific membrane antigen (PSMA) ligand Ga-PSMA-11 for detecting prostate adenocarcinoma in patients with elevated prostate-specific-antigen (PSA) after initial therapy. Ga-PSMA-11 hybrid positron emission tomography (PET) was performed in 2005 patients at the time of biochemical recurrent prostate cancer (BCR) following either radical prostatectomy (RP) (50.8 %), definitive radiation therapy (RT) (19.7 %), or RP with post-operative RT (PORT) (29.6 %). Presence of prostate cancer was assessed qualitatively (detection rate = positivity rate) and quantitatively on a per-patient and per-region basis creating a disease burden estimate from presence or absence of local (prostate/prostate bed), nodal (N1: pelvis) and distant metastatic (M1: distant soft tissue and bone) disease. The primary study endpoint was the positive predictive value (PPV) of Ga-PSMA-11 PET/CT confirmed by histopathology. Following prostatectomy, the scan detection rate increased significantly with rising PSA levels (44.8 % at PSA < 0.25 to 96.2 % at PSA > 10 ng/mL; < 0.001). The detection rate significantly increased with rising PSA levels in each individual region, overall disease burden, prior androgen deprivation, clinical T-stage, and Gleason grading from prostatectomy specimen ( < 0.001). Following RT, the detection rate for in-gland prostate recurrence was 64.0 % compared to 20.6 % prostate bed recurrences after RP and 13.3 % following PORT. PSMA-positive pelvic nodal disease was detected in 42.7 % following RP, in 40.8 % after PORT and 38.8 % after RT. In patients with histopathologic validation the PPV per-patient was 0.82 (146/179). The SUV of histologically proven true positive lesions was significantly higher than false positive lesions (median 11.0 (IQR 6.3 - 22.2) vs 5.1 (IQR 2.2 - 7.4) < 0.001). We confirmed a high PPV of Ga-PSMA-11 PET in BCR and the PSA level as the main predictor of scan positivity.
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http://dx.doi.org/10.2967/jnumed.121.262412DOI Listing
July 2021

Predictors of Pneumonitis After Conventionally Fractionated Radiotherapy for Locally Advanced Lung Cancer.

Int J Radiat Oncol Biol Phys 2021 12 24;111(5):1176-1185. Epub 2021 Jul 24.

Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan; Department of Biostatistics, University of Michigan, Ann Arbor, Michigan.

Purpose: Multiple factors influence the risk of developing pneumonitis after radiation therapy (RT) for lung cancer, but few resources exist to guide clinicians in predicting risk in an individual patient treated with modern techniques. We analyzed toxicity data from a state-wide consortium to develop an integrated pneumonitis risk model.

Methods And Materials: All patients (N = 1302) received conventionally fractionated RT for stage II-III non-small cell lung cancer between April 2012 and July 2019. Pneumonitis occurring within 6 months of treatment was graded by local practitioners and collected prospectively from 27 academic and community clinics participating in a state-wide quality consortium. Pneumonitis was modeled as either grade ≥2 (G2+) or grade ≥3 (G3+). Logistic regression models were fit to quantify univariable associations with dose and clinical factors, and stepwise Akaike information criterion-based modeling was used to build multivariable prediction models.

Results: The overall rate of pneumonitis of any grade in the 6 months following RT was 16% (208 cases). Seven percent of cases (n = 94) were G2+ and <1% (n = 11) were G3+. Adjusting for incomplete follow-up, estimated rates for G2+ and G3+ were 14% and 2%, respectively. In univariate analyses, gEUD, V5, V10, V20, V30, and mean lung dose (MLD) were positively associated with G2+ pneumonitis risk, whereas current smoking status was associated with lower odds of pneumonitis. G2+ pneumonitis risk of ≥22% was independently predicted by MLD of ≥20 Gy, V20 of ≥35%, and V5 of ≥75%. In multivariate analyses, the lung V5 metric remained a significant predictor of G2+ pneumonitis, even when controlling for MLD, despite their close correlation. For G3+ pneumonitis, MLD and V20 were statistically significant predictors. Number of patient comorbidities was an independent predictor of G3+, but not G2+ pneumonitis.

Conclusions: We present an analysis of pneumonitis risk after definitive RT for lung cancer using a large, prospective dataset. We incorporate comorbidity burden, smoking status, and dosimetric parameters in an integrated risk model. These data may guide clinicians in assessing pneumonitis risk in individual patients.
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http://dx.doi.org/10.1016/j.ijrobp.2021.07.1691DOI Listing
December 2021

Cancer Misinformation and Harmful Information on Facebook and Other Social Media: A Brief Report.

J Natl Cancer Inst 2021 Jul 22. Epub 2021 Jul 22.

Department of Population Sciences, University of Utah, Salt Lake City, UT, USA.

There are little data on the quality of cancer treatment information available on social media. Here, we quantify the accuracy of cancer treatment information on social media and its potential for harm. Two cancer experts reviewed 50 of the most popular social media articles on each of the 4 most common cancers. The proportion of misinformation and potential for harm were reported for all 200 articles, and their association with the number of social media engagements using a 2-sample Wilcoxon rank-sum test. All statistical tests were 2-sided. Of 200 total articles, 32.5% (n = 65) contained misinformation and 30.5% (n = 61) contained harmful information. Among articles containing misinformation, 76.9% (50 of 65) contained harmful information. The median number of engagements for articles with misinformation was greater than factual articles (median [IQR] = 2300 [1200-4700] vs 1600 [819-4700], P = .05). The median number of engagements for articles with harmful information was statistically significantly greater than safe articles (median [IQR] = 2300 [1400-4700] vs 1500 [810-4700], P = .007).
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http://dx.doi.org/10.1093/jnci/djab141DOI Listing
July 2021

Pan-cancer analysis of prognostic metastatic phenotypes.

Int J Cancer 2022 Jan 27;150(1):132-141. Epub 2021 Aug 27.

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

Although cancer is highly heterogeneous, all metastatic cancer is considered American Joint Committee on Cancer (AJCC) Stage IV disease. The purpose of this project was to redefine staging of metastatic cancer. Internal validation of nationally representative patient data from the National Cancer Database (n = 461 357; 2010-2013), and external validation using the Surveillance, Epidemiology and End Results database (n = 106 595; 2014-2015) were assessed using the concordance index for evaluation of survival prediction. A Cox proportional hazards model was used for overall survival by considering identified phenotypes (latent classes) and other confounding variables. Latent class analysis was performed for phenotype identification, where Bayesian information criterion (BIC) and sample-size-adjusted BIC were used to select the optimal number of distinct clusters. Kappa coefficients assessed external cluster validation. Latent class analysis identified five metastatic phenotypes with differences in overall survival (P < .0001): (Stage IVA) nearly exclusive bone-only metastases (n = 59 049, 12.8%; median survival 12.7 months; common in lung, breast and prostate cancers); (IVB) predominant lung metastases (n = 62 491, 13.5%; 11.4 months; common in breast, stomach, kidney, ovary, uterus, thyroid, cervix and soft tissue cancers); (IVC) predominant liver/lung metastases (n = 130 014, 28.2%; 7.0 months; common in colorectum, pancreatic, lung, esophagus and stomach cancers); (IVD) bone/liver/lung metastases predominant over brain (n = 61 004, 13.2%; 5.9 months; common in lung and breast cancers); and (IVE) brain/lung metastases predominant over bone/liver (n = 148 799, 32.3%; 5.7 months; lung cancer and melanoma). Long-term survivors were identified, particularly in Stages IVA-B. A pan-cancer nomogram model to predict survival (STARS: site, tumor, age, race, sex) was created, validated and provides 13% better prognostication than AJCC: 1-month concordance index of 0.67 (95% confidence interval [CI]: 0.66-0.67) vs 0.61 (95% CI: 0.60-0.61). STARS is simple, uses easily accessible variables, better prognosticates survival outcomes and provides a platform to develop novel metastasis-directed clinical trials.
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http://dx.doi.org/10.1002/ijc.33744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8595638PMC
January 2022

Impact of Decipher Biopsy testing on clinical outcomes in localized prostate cancer in a prospective statewide collaborative.

Prostate Cancer Prostatic Dis 2021 Jul 20. Epub 2021 Jul 20.

Department of Urology, University of Michigan, Ann Arbor, MI, USA.

Background: Decipher Biopsy is a commercially available gene expression classifier used in risk stratification of newly diagnosed prostate cancer (PCa). Currently, there are no prospective data evaluating its clinical utility. We seek to assess the clinical utility of Decipher Biopsy in localized PCa patients.

Methods: A multi-institutional study of 855 men who underwent Decipher Biopsy testing between February 2015 and October 2019. All patients were tracked through the prospective Michigan Urological Surgery Improvement Collaborative and linked to the Decipher Genomics Resource Information Database (GRID; NCT02609269). Patient matching was performed by an independent third-party (ArborMetrix Inc.) using two or more unique identifiers. Cumulative incidence curves for time to treatment (TTT) and time to failure (TTF) were constructed using Kaplan-Meier estimates. Multivariable Cox proportional hazard models were used to evaluate the independent association of high-risk Decipher scores with the conversion from AS to radical therapy and treatment failure (biochemical failure or receipt of salvage therapy).

Results And Limitations: Eight hundred fifty-five patients underwent Decipher Biopsy testing during the study period. Of the 855 men, 264 proceeded to AS (31%), and 454 (53%) received radical therapy. In men electing AS, after adjusting for NCCN risk group, age, PSA, prostate volume, body mass index, and percent positive cores, a high-risk Decipher score was independently associated with shorter TTT (HR 2.51, 95% CI 1.52-4.13 p < 0.001). Similarly, in patients that underwent radical therapy, a high-risk Decipher score was independently associated with TTF (HR 2.98, 95% CI 1.22-7.29, p = 0.01) on multivariable analysis. Follow-up time was a limitation.

Conclusion: In a prospective statewide registry, high-risk Decipher Biopsy score was strongly and independently associated with conversion from AS to definitive treatment and treatment failure. These real-world data support the clinical utility of Decipher Biopsy. An ongoing phase 3 randomized trial (NCT04396808) will provide level 1 evidence of the clinical impact of Decipher biopsy testing.
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http://dx.doi.org/10.1038/s41391-021-00428-yDOI Listing
July 2021

Drivers of racial disparities in prostate cancer trial enrollment.

Prostate Cancer Prostatic Dis 2021 Dec 12;24(4):946-947. Epub 2021 Jul 12.

Department of Radiation Oncology, University Hospitals, Case Western Reserve University, Cleveland, OH, USA.

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http://dx.doi.org/10.1038/s41391-021-00427-zDOI Listing
December 2021

A transcriptomic model for homologous recombination deficiency in prostate cancer.

Prostate Cancer Prostatic Dis 2021 Jul 5. Epub 2021 Jul 5.

Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Background: Tumors with mutations associated with homologous recombination deficiency (HRD) are uncommon in prostate cancer (PCa) and variably responsive to PARP inhibition. To better identify tumors with HRD, we developed a transcriptomic signature for HRD in PCa (HRD-P).

Methods: By using an established mutational signature, we created and validated HRD-P in six independent PCa cohorts (primary PCa, n = 8224; metastatic castration-resistant PCa [mCRPC], n = 328). Molecular and clinical features were compared between HRD-P+ tumors and those with single HR-gene mutations.

Results: HRD-P+ tumors were more common than tumors with single HR-gene mutations in primary (201/491, 41% vs 32/491 6.5%) and mCRPC (126/328, 38% vs 82/328, 25%) cases, and HRD-P+ was more predictive of genomic instability suggestive of HRD. HRD-P+ was associated with a shorter time to recurrence following surgery and shorter overall survival in men with mCRPC. In a prospective trial of mCRPC treated with olaparib (n = 10), all three men with HRD-P+ experienced prolonged (>330 days) PSA progression-free survival.

Conclusion: These results suggest transcriptomics can identify more patients that harbor phenotypic HRD than single HR-gene mutations and support further exploration of transcriptionally defined HRD tumors perhaps in conjunction with genomic markers for therapeutic application.
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http://dx.doi.org/10.1038/s41391-021-00416-2DOI Listing
July 2021

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

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

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

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

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

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

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

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

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

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

Protons Versus Photons for Prostate Cancer: An Answer That Is Long Overdue and Coming.

Int J Radiat Oncol Biol Phys 2021 07;110(4):1098-1100

University Hospitals, Seidman Cancer Center, Case Western Reserve University, Cleveland Ohio; University of Michigan, Ann Arbor, Michigan. Electronic address:

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http://dx.doi.org/10.1016/j.ijrobp.2021.03.037DOI Listing
July 2021

BET Bromodomain Inhibition Blocks an AR-Repressed, E2F1-Activated Treatment-Emergent Neuroendocrine Prostate Cancer Lineage Plasticity Program.

Clin Cancer Res 2021 Sep 18;27(17):4923-4936. Epub 2021 Jun 18.

Zenith Epigenetics Ltd, Calgary, Alberta, Canada.

Purpose: Lineage plasticity in prostate cancer-most commonly exemplified by loss of androgen receptor (AR) signaling and a switch from a luminal to alternate differentiation program-is now recognized as a treatment resistance mechanism. Lineage plasticity is a spectrum, but neuroendocrine prostate cancer (NEPC) is the most virulent example. Currently, there are limited treatments for NEPC. Moreover, the incidence of treatment-emergent NEPC (t-NEPC) is increasing in the era of novel AR inhibitors. In contradistinction to NEPC, t-NEPC tumors often express the AR, but AR's functional role in t-NEPC is unknown. Furthermore, targetable factors that promote t-NEPC lineage plasticity are also unclear.

Experimental Design: Using an integrative systems biology approach, we investigated enzalutamide-resistant t-NEPC cell lines and their parental, enzalutamide-sensitive adenocarcinoma cell lines. The AR is still expressed in these t-NEPC cells, enabling us to determine the role of the AR and other key factors in regulating t-NEPC lineage plasticity.

Results: AR inhibition accentuates lineage plasticity in t-NEPC cells-an effect not observed in parental, enzalutamide-sensitive adenocarcinoma cells. Induction of an AR-repressed, lineage plasticity program is dependent on activation of the transcription factor E2F1 in concert with the BET bromodomain chromatin reader BRD4. BET inhibition (BETi) blocks this E2F1/BRD4-regulated program and decreases growth of t-NEPC tumor models and a subset of t-NEPC patient tumors with high activity of this program in a BETi clinical trial.

Conclusions: E2F1 and BRD4 are critical for activating an AR-repressed, t-NEPC lineage plasticity program. BETi is a promising approach to block this program.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416959PMC
September 2021

Dose Escalation for Oligometastatic Disease: Is More Better?

Int J Radiat Oncol Biol Phys 2021 07;110(3):680-681

Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.

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http://dx.doi.org/10.1016/j.ijrobp.2021.02.031DOI Listing
July 2021

End Point Definitions and Surrogacy in Prostate Cancer: Will Metastasis-Free Survival Become Event-Free Survival With Advances in Molecular Imaging?

J Clin Oncol 2021 09 4;39(25):2844-2845. Epub 2021 Jun 4.

Robert T. Dess, MD, and William C. Jackson, MD, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI; and Daniel E. Spratt, MD, Department of Radiation Oncology, University Hospitals, Cleveland, OH, Department of Radiation Oncology, Case Western Reserve University School of Medicine, Cleveland, OH.

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http://dx.doi.org/10.1200/JCO.21.00376DOI Listing
September 2021

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

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

Contemporary Practice Patterns for Palliative Radiation Therapy of Bone Metastases: Impact of a Quality Improvement Project on Extended Fractionation.

Pract Radiat Oncol 2021 Nov-Dec;11(6):e498-e505. Epub 2021 May 26.

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

Purpose: Radiation therapy effectively palliates bone metastases, although variability exists in practice patterns. National recommendations advocate against using extended fractionation (EF) with courses greater than 10 fractions. We previously reported EF use of 14.8%. We analyzed practice patterns within a statewide quality consortium to assess EF use in a larger patient population after implementation of a quality measure focused on reducing EF.

Methods And Materials: Patients treated for bone metastases within a statewide radiation oncology quality consortium were prospectively enrolled from March 2018 through October 2020. The EF quality metric was implemented March 1, 2018. Data on patient, physician, and facility characteristics; fractionation schedules; and treatment planning and delivery techniques were collected. Multivariable binary logistic regression was used to assess EF.

Results: Twenty-eight facilities enrolled 1445 consecutive patients treated with 1934 plans. The median number of treatment plans per facility was 52 (range, 7-307). Sixty different fractionation schedules were used. EF was delivered in 3.4% of plans. Initially, EF use was lower than expected and remained low over time. Significant predictors for EF use included complicated metastasis (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.04-4.02; P = .04), lack of associated central nervous system or visceral disease (OR, 2.27; 95% CI, 1.2-4.2; P = .01), nonteaching versus teaching facilities (OR, 8.97; 95% CI, 2.1-38.5; P < .01), and treating physicians with more years in practice (OR, 12.82; 95% CI, 3.9-42.4; P < .01).

Conclusions: Within a large, prospective population-based data set, fractionation schedules for palliative radiation therapy of bone metastases remain highly variable. Resource-intensive treatments including EF persist, although EF use was low after implementation of a quality measure. Complicated metastases, lack of central nervous system or visceral disease, and treatment at nonteaching facilities or by physicians with more years in practice significantly predict use of EF. These results support ongoing efforts to more clearly understand and address barriers to high-value radiation approaches in the palliative setting.
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http://dx.doi.org/10.1016/j.prro.2021.05.002DOI Listing
November 2021
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