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Risk and Prognostics of Second Primary Cancer After Prostate Radiation Therapy

Liu, Elisa K; Daniels, Thomas B; Lischalk, Jonathan W; Oh, Cheongeun; Haas, Jonathan A; Evans, Andrew J; Byun, David J
INTRODUCTION/UNASSIGNED:As overall survival in prostate cancer increases due to advances in early detection and management, there is a growing need to understand the long-term morbidity associated with treatment, including secondary tumors. The significance of developing radiation-associated secondary cancers in an elderly population remains unknown. METHODS/UNASSIGNED:Patients diagnosed with prostate cancer between 1975 and 2016 in one of 9 Surveillance, Epidemiology, and End Results registries were included in this study. Risk of second primary pelvic malignancies (SPPMs) were assessed with death as a competing risk using the Fine-Gray model. Time-varying Cox proportional hazard models were employed to analyze risk to overall mortality based on secondary tumor status. RESULTS/UNASSIGNED:A total of 569,167 primary prostate cancers were included in analysis with an average follow-up of 89 months. Among all prostate cancer patients, 4956 SPPMs were identified. After controlling for differences in age, year of diagnosis, and surgery at time of prostate cancer treatment, radiation receipt was associated with a significantly higher incidence of SPPMs (1.1% vs 1.8% at 25 years). Among those who received radiation during initial prostate cancer treatment (n = 195,415), developing an SPPM is significantly associated with worse survival (adjusted hazard ratio = 1.76), especially among younger patients (under age 63, adjusted hazard ratio = 2.36). CONCLUSIONS/UNASSIGNED:While developing a secondary malignancy carries a detrimental effect on overall survival, the absolute risk of developing such tumors is exceedingly low regardless of radiation treatment.
PMID: 37917577
ISSN: 2352-0787
CID: 5612762

Late Toxicity of Moderately Hypofractionated Intensity Modulated Proton Therapy Treating the Prostate and Pelvic Lymph Nodes for High-Risk Prostate Cancer

Choo, Richard; Hillman, David W; Mitchell, Cecilia; Daniels, Thomas; Vargas, Carlos; Rwigema, Jean Claude; Corbin, Kimberly; Keole, Sameer; Vora, Sujay; Merrell, Kenneth; Stish, Bradley; Pisansky, Thomas; Davis, Brian J; Amundson, Adam; Wong, William
PURPOSE/OBJECTIVE:To evaluate late gastrointestinal (GI) and genitourinary (GU) toxicity of moderately hypofractionated intensity modulated proton therapy (IMPT) targeting the prostate and pelvic lymph nodes. METHODS AND MATERIALS/METHODS:A target accrual of 56 patients with high-risk or unfavorable intermediate risk prostate cancer were enrolled into a prospective study (ClinicalTrials.gov: NCT02874014) of moderately hypofractionated IMPT. IMPT with pencil beam scanning was used to deliver 6750 and 4500 cGy relative biological effectiveness in 25 daily fractions simultaneously to the prostate and pelvic lymph nodes, respectively. All received androgen deprivation therapy. Late GI and GU toxicity was prospectively assessed using Common Terminology Criteria for Adverse Events version 4.0, at baseline, weekly during radiation therapy, 3-month postradiation therapy, and then every 6 months. Actuarial rates of late GI and GU toxicity were estimated using Kaplan-Meier method. RESULTS:Median age was 75.5 years. Fifty-four patients were available for late toxicity evaluation. Median follow-up was 43.9 months (range, 16-66). The actuarial rate of late grade ≥2 GI toxicity at both 2 and 3 years was 7.4% (95% confidence interval [CI], 0.2%-14.2%). The actuarial rate of late grade 3 GI toxicity at both 2 and 3 years was 1.9% (95% CI, 0%-5.4%). One patient experienced grade 3 GI toxicity with proctitis. The actuarial rate of late grade ≥2 GU toxicity was 20.5% (95% CI, 8.9%-30.6%) at 2 years, and 29.2 % (95% CI, 15.5%-40.7%) at 3 years. None had grade 3 GU toxicity. The presence of baseline GU symptoms was associated with a higher likelihood of experiencing late grade 2 GU toxicity. CONCLUSIONS:A moderately hypofractionated IMPT targeting the prostate and regional pelvic lymph nodes was generally well tolerated. Patients with pre-existing GU symptoms had a higher rate of late grade 2 GU toxicity. A phase 3 study is needed to assess any therapeutic gain of IMPT, in comparison with photon-based radiation therapy.
PMID: 36427645
ISSN: 1879-355x
CID: 5384472

Preliminary Analysis of a Phase II Trial of Stereotactic Body Radiation Therapy for Prostate Cancer With High-Risk Features After Radical Prostatectomy

Laughlin, Brady S.; Voss, Molly M.; Toesca, Diego A.S.; Daniels, Thomas; Golafshar, Michael A.; Keole, Sameer R.; Wong, William W.; Rwigema, Jean Claude; Davis, Brian; Schild, Steven E.; Stish, Brad J.; Choo, Richard; Lester, Scott; DeWees, Todd A.; Vargas, Carlos E.
Purpose: There are limited data regarding using stereotactic body radiation therapy (SBRT) in the postprostatectomy setting. Here, we present a preliminary analysis of a prospective phase II trial that aimed to evaluate the safety and efficacy of postprostatectomy SBRT for adjuvant or early salvage therapy. Materials and methods: Between May 2018 and May 2020, 41 patients fulfilled inclusion criteria and were stratified into 3 groups: group I (adjuvant), prostate-specific antigen (PSA) < 0.2 ng/mL with high-risk features including positive surgical margins, seminal vesicle invasion, or extracapsular extension; group II (salvage), with PSA ≥ 0.2 ng/mL but < 2 ng/mL; or group III (oligometastatic), with PSA ≥ 0.2 ng/mL but < 2 ng/mL and up to 3 sites of nodal or bone metastases. Androgen deprivation therapy was not offered to group I. Androgen deprivation therapy was offered for 6 months for group II and 18 months for group III patients. SBRT dose to the prostate bed was 30 to 32 Gy in 5 fractions. Baseline-adjusted physician reported toxicities (Common Terminology Criteria for Adverse Events), patient reported quality-of-life (Expanded Prostate Index Composite, Patient-Reported Outcome Measurement Information System), and American Urologic Association scores were evaluated for all patients. Results: The median follow-up was 23 months (range, 10-37). SBRT was adjuvant in 8 (20%) patients, salvage in 28 (68%), and salvage with the presence of oligometastases in 5 (12%) patients. Urinary, bowel, and sexual quality of life domains remained high after SBRT. Patients tolerated SBRT with no grade 3 or higher (3+) gastrointestinal or genitourinary toxicities. The baseline adjusted acute and late toxicity grade 2 genitourinary (urinary incontinence) rate was 2.4% (1/41) and 12.2% (5/41). At 2 years, clinical disease control was 95%, and biochemical control was 73%. Among the 2 clinical failures, 1 was a regional node and the other a bone metastasis. Oligometastatic sites were salvaged successfully with SBRT. There were no in-target failures. Conclusions: Postprostatectomy SBRT was very well tolerated in this prospective cohort, with no significant effect on quality of life metrics postirradiation, while providing excellent clinical disease control.
SCOPUS:85145322812
ISSN: 2452-1094
CID: 5407872

Cardiopulmonary Toxicity Following Intensity-Modulated Proton Therapy (IMPT) Versus Intensity-Modulated Radiation Therapy (IMRT) for Stage III Non-Small Cell Lung Cancer

Yu, Nathan Y; DeWees, Todd A; Voss, Molly M; Breen, William G; Chiang, Jennifer S; Ding, Julia X; Daniels, Thomas B; Owen, Dawn; Olivier, Kenneth R; Garces, Yolanda I; Park, Sean S; Sarkaria, Jann N; Yang, Ping; Savvides, Panayiotis S; Ernani, Vinicius; Liu, Wei; Schild, Steven E; Merrell, Kenneth W; Sio, Terence T
INTRODUCTION/BACKGROUND:Intensity-modulated proton therapy (IMPT) has the potential to reduce radiation dose to normal organs when compared to intensity-modulated radiation therapy (IMRT). We hypothesized that IMPT is associated with a reduced rate of cardiopulmonary toxicities in patients with Stage III NSCLC when compared with IMRT. METHODS:We analyzed 163 consecutively treated patients with biopsy-proven, stage III NSCLC who received IMPT (n = 35, 21%) or IMRT (n = 128, 79%). Patient, tumor, and treatment characteristics were analyzed. Overall survival (OS), freedom-from distant metastasis (FFDM), freedom-from locoregional relapse (FFLR), and cardiopulmonary toxicities (CTCAE v5.0) were calculated using the Kaplan-Meier estimate. Univariate cox regressions were conducted for the final model. RESULTS:Median follow-up of surviving patients was 25.5 (range, 4.6-58.1) months. Median RT dose was 60 (range, 45-72) Gy [RBE]. OS, FFDM, and FFLR were not different based on RT modality. IMPT provided significant dosimetric pulmonary and cardiac sparing when compared to IMRT. IMPT was associated with a reduced rate of grade more than or equal to 3 pneumonitis (HR 0.25, P = .04) and grade more than or equal to 3 cardiac events (HR 0.33, P = .08). Pre-treatment predicted diffusing capacity for carbon monoxide less than equal to 57% (HR 2.8, P = .04) and forced expiratory volume in the first second less than equal to 61% (HR 3.1, P = .03) were associated with an increased rate of grade more than or equal to 3 pneumonitis. CONCLUSIONS:IMPT is associated with a reduced risk of clinically significant pneumonitis and cardiac events when compared with IMRT without compromising tumor control in stage III NSCLC. IMPT may provide a safer treatment option, particularly for high-risk patients with poor pretreatment pulmonary function.
PMID: 36104272
ISSN: 1938-0690
CID: 5336282

Late Gastrointestinal and Genitourinary Toxicities of a Moderately Hypofractionated Regimen of Intensity-Modulated Proton Therapy Targeting the Prostate/Seminal Vesicles and Pelvic Lymph Nodes for High Risk or Unfavorable Intermediate Risk Prostate Cancer [Meeting Abstract]

Choo, C R; Hillman, D; Mitchell, C; Daniels, T B; Vargas, C; Rwigema, J C; Corbin, K S; Keole, S R; Vora, S A; Merrell, K W; Stish, B J; Pisansky, T M; Davis, B J; Wong, W W
Purpose/Objective(s): To assess late gastrointestinal (GI) and genitourinary (GU) toxicities of intensity-modulated proton therapy (IMPT) targeting the prostate/seminal vesicles and regional pelvic lymph nodes for high risk (HR) or unfavorable intermediate risk (UIR) prostate cancer (Pca). Materials/Methods: A prospective study (ClinicalTrials.gov: NCTXXX) to evaluate a moderately hypofractionated regimen of IMPT for HR-Pca or UIR-Pca accrued a target sample size of 55 patients. The prostate/seminal vesicles and pelvic lymph nodes were treated simultaneously with 67.5 Gy (2.7 Gy/fraction) and 45 Gy (1.8 Gy/fraction), respectively, in 25 fractions over 5 weeks. IMPT plan was prepared with pre-defined dose-volume histogram objectives for target volumes and organs at risk. All received androgen deprivation therapy (ADT). GI and GU toxicities were prospectively assessed, using the CTCAEv.4, at baseline (before IMPT); 3-, 6-, and 12-month post-RT and then every 6 months thereafter. Late toxicity was defined as toxicity persisting for > 3 months, or developing > 3 months post-RT. Late GI and GU toxicity rates were computed using Kaplan-Meier estimates, and log-rank tests were utilized for comparisons of time-to-event distributions.
Result(s): Median age was 75 years (range: 55-87). Median PSA was 10.5 ng/mL (range: 0.65 -97.3). Fifty-three patients had HR-Pca; 2 had UIR-Pca. Median duration of ADT was 18 months. Fifty-four patients were available for late toxicity assessment. Median follow-up was 46 months (range: 16-66). 29% and 6% experienced late grade 1 and 2 GI toxicity, respectively. One patient (2%) had late grade 3 GI toxicity (proctitis). The actuarial rate of late grade >= 2 GI toxicity was 7% (95% CI: 0.2-14%) at both 2 and 3 years. The actuarial rate of late grade 3 GI toxicity was 2% (95% CI: 0-5%) at both 2 and 3 years. 76% and 24% experienced late grade 1 and 2 GU toxicity, respectively. None had late grade >= 3 GU toxicity. The actuarial rate of late grade 2 GU toxicity was 21% (95% CI: 9-31%) at 2 years, and 29% (95% CI: 15-40%) at 3 years. None had late grade >= 4 GI or GU toxicity. The presence of baseline GU symptom was associated with a greater likelihood of experiencing late grade 2 GU toxicity. Of 44 patients with baseline GU symptoms, late grade 2 GU toxicity rate at 3 years was 36% (95%: 19-49%), compared to 0% among 10 patients with no baseline GU symptoms (p=0.02).
Conclusion(s): A moderately hypofractionated regimen of IMPT targeting prostate/seminal vesicles and pelvic lymph nodes for HR-Pca or UIR-Pca yielded very acceptable late GI and GU toxicity.
Copyright
EMBASE:2020264295
ISSN: 1879-355x
CID: 5366282

Comparison of Patient-Reported Quality-of-Life between Spot Scanned Proton Stereotactic Body Radiation Therapy and Conventional Proton Therapy after Radiotherapy for Intermediate-Risk Prostate Cancer: A Single-Center Prospective Registry Experience [Meeting Abstract]

Gawu, P; DeWees, T A; Voss, M M; Thorpe, C S; Wong, W W; Rwigema, J C; Daniels, T B; Keole, S R; Schild, S E; Vargas, C E
Purpose/Objective(s): Proton stereotactic body proton therapy (SBPT) for prostate cancer takes advantage of biologic advantages with hypofractionation and the technical advances of spot scanning. We report toxicities and quality-of-life (QOL) in patients treated with SBPT versus conventional proton therapy (CPT) in a single-institution prospective registry. Materials/Methods: Patients (Pt) with localized intermediate-risk prostate cancer (PC) were treated with proton radiation (RT) from 2016 to 2018 on an IRB approved prospective registry. Treatment included SBPT (>=6 Gy/fx) or CPT (<2 Gy/fx) per physician choice. Expanded Prostate Cancer Index Composite (EPIC), AUASI, SF-12, Promis10, FACIT-COST, and PRO-CTCAE QOL were administered pre-RT, end-of-treatment, 3, 6, 12 months post RT, and then annually. Toxicities were recorded according to CTCAE v5. Fisher's Exact and Kruskal-Wallis tests were utilized to compare pt characteristics between groups. Effect of treatment were analyzed using logistic regression (toxicity), Kaplan-Meier statistics, and repeated measure mixed models (QOL) with all events were baseline adjusted.
Result(s): 191 pts were included with a median follow-up of 43.2 months (SBPT:39.9, CPT: 44.9). SBPT (38 Gy/5 fxs) was used in 47 pts (24.6%) while CPT used in 144 pts (75.6%) ranged from 75.6-79.2 Gy in 39-44 fx. At baseline, SBPT pts, tended to be younger, higher BMI, lower Gleason score, lower T stage, less likely to have had prior or treatment concurrent ADT, and less likely to have had concurrent urinary medications. There was no significant difference between arms in terms of survival (p=0.22) and development of new primary cancers (p=0.63). At last follow-up, there were 1x failures for SBPT and 4x failure for CPT (p=0.92). Grade 2+ AE were experienced by 12.8% SBPT versus 11.1% CPT (p=0.76). When adjusted for baseline toxicity, neither acute (<=3 months) grade 2+ (p=0.3) nor chronic grade 2+ (p=0.24) AEs were significantly different between the arms. No significant differences occurred between the arms for Promis10 overall (p=0.76), Physical (p=0.75), or Social (p=0.79) domains, PRO-CTCAE (p>0.73), or FACIT-COST (p=0.92). In regard to EPIC domains, SBPT pts fared significantly (all p<0.05) better in: urinary, bowel, urinary function, urinary bother, urinary irritative/obstructive, bowel bother, and Mental SF12. All other domains did not approach statistical significance (all p>0.1).
Conclusion(s): There was no significant difference in PC patients treated with SBPT versus CPT except for an improvement in prostate specific QOL in SBPT patients. SBPT appears safe and effective, while providing improved QOL over CPT.
Copyright
EMBASE:2020263872
ISSN: 1879-355x
CID: 5366312

A Phase II prospective study of hypofractionated proton therapy of prostate and pelvic lymph nodes: Acute effects on patient-reported quality of life

Wong, William W; Hillman, David W; Daniels, Thomas B; Vargas, Carlos E; Rwigema, Jean Claude; Corbin, Kimberly S; Keole, Sameer R; Merrell, Kenneth W; Stish, Bradley J; Pisansky, Thomas M; Davis, Brian J; Mitchell, Cecilia M; Choo, Richard
BACKGROUND:The objective of this study was to report acute changes in patient-reported quality of life (PRQOL) using the 26-item Expanded Prostate Index Composite (EPIC-26) questionnaire in a prospective study using hypofractionated intensity-modulated proton beam therapy (H-IMPT) targeting the prostate and the pelvic lymph nodes for high-risk or unfavorable intermediate-risk prostate cancer. METHODS:Fifty-five patients were enrolled. H-IMPT consisted of 45 GyE to the pelvic lymph nodes and 67.5 GyE to the prostate and seminal vesicles in 25 fractions. PRQOL was assessed with the urinary incontinence (UI), urinary irritative/obstructive symptoms (UO), and bowel function (BF) domains of EPIC-26 questionnaire. Mean changes in domain scores were analyzed from pretreatment to the end of treatment and 3 months posttreatment. A clinically meaningful change (or minimum important change) was defined as a score change > 50% of the baseline standard deviation. RESULTS:The mean scores of UO, UI, and BF at baseline were 84.6, 91.1, and 95.3, respectively. At the end of treatment, there were statistically significant and clinically meaningful declines in UO and BF scores (-13.5 and -2.3, respectively), while the decline in UI score was statistically significant but not clinically meaningful (-13.7). A clinically meaningful decline in UO, UI, and BF scores occurred in 53.5%, 22.7%, and 73.2% of the patients, respectively. At 3 months posttreatment, all three mean scores showed an improvement, with fewer patients having a clinically meaningful decline in UO, UI, and BF scores (18.4%, 20.5%, and 45.0%, respectively). There was no significant reduction in the mean UO and UI scores compared to baseline, although the mean BF score remained lower than baseline and the difference was clinically meaningful. CONCLUSIONS:UO, UI, and BF scores of PRQOL declined at the end of H-IMPT. UO and UI scores showed improvement at 3 months posttreatment and were similar to the baseline scores. However, BF score remained lower at 3 months posttreatment with a clinically meaningful decline.
PMID: 35789497
ISSN: 1097-0045
CID: 5318862

Assessing concordance between patient-reported and investigator-reported CTCAE after proton beam therapy for prostate cancer

Kowalchuk, Roman O; Hillman, David; Daniels, Thomas B; Vargas, Carlos E; Rwigema, Jean-Claude M; Wong, William W; Stish, Bradley J; Dueck, Amylou C; Choo, Richard
Purpose/UNASSIGNED:We report acute patient-reported outcomes using CTCAE (PRO-CTCAE) of proton beam radiotherapy for high-risk or unfavorable intermediate-risk prostate cancer in a prospective clinical trial. PRO-CTCAE were correlated with investigator reported-CTCAE (IR-CTCAE) to assess the degree of concordance. Methods and materials/UNASSIGNED:11 PRO-CTCAE questions assessed gastrointestinal (GI), genitourinary (GU), or erectile function side effects. The correlation scheme between PRO-CTCAE and IR-CTCAE was independently developed by two physicians. Analyses of PRO-CTCAE and IR-CTCAE were conducted using both descriptive terms and the converted grade scores. The Kappa statistic described the degree of concordance. Results/UNASSIGNED:55 patients were included. IR-CTCAE underestimated diarrhea compared to PRO-CTCAE at the end of treatment (EOT), with a 28% rate of underestimation (11% by ≥ 2 toxicity grades). Similarly, urinary tract pain was underestimated in 45% of cases (17% by ≥ 2 grades) at EOT. Differences were less pronounced at baseline or 3 months after radiotherapy. The incidence of urinary urgency and frequency tended to be overestimated prior to treatment (36% and 24%, respectively) but underestimated at EOT (35% and 31%, respectively). The degree of interference with daily activities was consistently overestimated by investigators (45%-85%). Finally, erectile dysfunction showed a 36-56% rate of discordance by ≥ 2 toxicity grades. Conclusions/UNASSIGNED:Our study shows a low agreement between IR-CTCAE and PRO-CTCAE in the setting of proton therapy for prostate cancer. Compared to patient-reported outcomes, physicians underestimated the frequency and severity of urinary symptoms and diarrhea at the end of treatment. Continued use of PROs should be strongly encouraged.
PMCID:8463742
PMID: 34604551
ISSN: 2405-6308
CID: 5138442

Intensity-modulated proton therapy (IMPT) interplay effect evaluation of asymmetric breathing with simultaneous uncertainty considerations in patients with non-small cell lung cancer

Shan, Jie; Yang, Yunze; Schild, Steven E; Daniels, Thomas B; Wong, William W; Fatyga, Mirek; Bues, Martin; Sio, Terence T; Liu, Wei
PURPOSE/OBJECTIVE:Intensity-modulated proton therapy (IMPT) is sensitive to uncertainties from patient setup and proton beam range, as well as interplay effect. In addition, respiratory motion may vary from cycle to cycle, and also from day to day. These uncertainties can severely degrade the original plan quality and potentially affect patient's outcome. In this work, we developed a new tool to comprehensively consider the impact of all these uncertainties and provide plan robustness evaluation under them. METHODS:We developed a comprehensive plan robustness evaluation tool that considered both uncertainties from patient setup and proton beam range, as well as respiratory motion simultaneously. To mimic patients' respiratory motion, the time spent in each phase was randomly sampled based on patient-specific breathing pattern parameters as acquired during the four-dimensional (4D)-computed tomography (CT) simulation. Spots were then assigned to one specific phase according to the temporal relationship between spot delivery sequence and patients' respiratory motion. Dose in each phase was calculated by summing contributions from all the spots delivered in that phase. The final 4D dynamic dose was obtained by deforming all doses in each phase to the maximum exhalation phase. Three hundred (300) scenarios (10 different breathing patterns with 30 different setup and range uncertainty scenario combinations) were calculated for each plan. The dose-volume histograms (DVHs) band method was used to assess plan robustness. Benchmarking the tool as an application's example, we compared plan robustness under both three-dimensional (3D) and 4D robustly optimized IMPT plans for 10 nonrandomly selected patients with non-small cell lung cancer. RESULTS:, P = 0.020) favoring 4D plans and comparable normal tissue sparing including esophagus, heart, and spinal cord for both 3D and 4D plans were observed. The calculation time for all patients included in this study was 11.4 ± 2.6 min. CONCLUSION/CONCLUSIONS:A comprehensive plan robustness evaluation tool was successfully developed and benchmarked for plan robustness evaluation in the presence of interplay effect, setup and range uncertainties. The very high efficiency of this tool marks its clinical adaptation, highly practical and versatile nature, including possible real-time intra-fractional interplay effect evaluation as a potential application for future use.
PMID: 32964474
ISSN: 2473-4209
CID: 4631192

Early Outcomes of Patients With Locally Advanced Non-small Cell Lung Cancer Treated With Intensity-Modulated Proton Therapy Versus Intensity-Modulated Radiation Therapy: The Mayo Clinic Experience

Yu, Nathan Y; DeWees, Todd A; Liu, Chenbin; Daniels, Thomas B; Ashman, Jonathan B; Beamer, Staci E; Jaroszewski, Dawn E; Ross, Helen J; Paripati, Harshita R; Rwigema, Jean-Claude M; Ding, Julia X; Shan, Jie; Liu, Wei; Schild, Steven E; Sio, Terence T
Purpose/UNASSIGNED:There are very little data available comparing outcomes of intensity-modulated proton therapy (IMPT) to intensity-modulated radiation therapy (IMRT) in patients with locally advanced NSCLC (LA-NSCLC). Methods/UNASSIGNED: = 46 [58%]) from 2016 to 2018 at our institution. Survival rates were calculated using the Kaplan-Meier method and compared with the log-rank test. Acute and subacute toxicities were graded based on Common Terminology Criteria for Adverse Events, version 4.03. Results/UNASSIGNED: = .47). There was 1 treatment-related death from radiation pneumonitis 6 months after IMRT in a patient with idiopathic pulmonary fibrosis. Conclusions/UNASSIGNED:Compared with IMRT, our early experience suggests that IMPT resulted in similar outcomes in a frailer population of LA-NSCLC who were more often being reirradiated. The role of IMPT remains to be defined prospectively.
PMCID:7276663
PMID: 32529140
ISSN: 2452-1094
CID: 4631182