PSAPC (FHCRC)

A joint model of prostate-specific antigen (PSA) growth and prostate cancer (PC) progression

Basic Model Attributes
Cancer site	Prostate
Host institution	Fred Hutch Cancer Research Center
Purpose	The original objective behind modeling prostate cancer trends was to disentangle the roles of PSA screening and changes in primary treatment patterns in US prostate cancer incidence and mortality trends. While both prostate cancer incidence and mortality rates have continued to fall since the early 1990s, the relative contributions of screening and treatment to the observed declines in mortality remain intensely debated. Additional applications of the model, supporting by its continued development and extensions, include studying disease natural history and heterogeneity; investigating roles of different natural history and treatment efficacies in racial disparities; evaluating comparative and cost-effectiveness of alternative PSA screening strategies; improving methods to quantify individual risks of overdiagnosis and overtreatment; quantifying the effects of timing of treatment for low-risk prostate cancers; and reconciling seemingly conflicting results of two randomized clinical trials of PSA screening--Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial in the US and the European Randomized Study of Screening for Prostate Cancer (ERSPC).
Contact	Roman Gulati (rgulati@fredhutch.org)
Profile	cisnet_prostate_fhcrc_psapc.pdf
Website	http://research.fhcrc.org/etzioni

The PSAPC model is a microsimulation model that links a man's prostate-specific antigen (PSA) levels and prostate cancer (PC) progression. PSA levels grow exponentially with rates before and after disease onset (Figure A) estimated using data from the control arm of the Prostate Cancer Prevention Trial¹, which screened 9,000 men annually for up to 7 years with an exit biopsy regardless of PSA test results. PSA growth rates are greater for high-grade disease. Risks of onset and of high-grade disease at onset increase age, while risks of clinical diagnosis (i.e., diagnosis that would occur in the absence of PSA screening) and of metastasis (Figure B) increase with PSA levels.

Figure A. Underlying PSA growth accelerates at onset of a preclinical tumor, with faster post-onset growth for tumors with higher Gleason score

Figure B. The risk of onset increases with age, and risks of progression across preclinical stages and diagnosis increase with underlying PSA

The model allows two stages (local-regional or distant) and two grades (Gleason 2–7 or 8–10). Stage progression is permitted, but grade is fixed at the time of disease onset. To calibrate the model, we superimpose PSA screening² and biopsy frequencies³ according to observed US screening patterns and obtain model-projected disease incidence. We use a simulated maximum likelihood algorithm based on a Poisson-type likelihood function to identify rates of onset, metastasis, and clinical diagnosis so that model-projected incidence matches incidence observed in the Surveillance, Epidemiology, and End Results (SEER) program by age, year, stage, and grade. The calibrated model closely replicates observed age-adjusted incidence rates by age, year, stage, and grade.⁴

The survival component of the model consists of disease-specific and other-cause survival. Disease-specific survival depends on age, stage (local-regional or distant), and grade (Gleason 2–7 or 8–10) at diagnosis. For local-regional cases, disease-specific survival also depends on primary treatment (radiation or surgery). In the absence of screening and treatment, disease-specific survival is based on data from cases diagnosed in SEER between 1983 and 1986, just prior to the PSA era. Treatment impacts survival after clinical diagnosis via a proportional hazards model with relative risks based on treatment trials^5-7 and comparative effectiveness studies.^8-10

Screening benefit arises from the detection of earlier stage tumors than might be identified without screening. For cases that are detected at an earlier stage by screening, their original survival from the time of clinical diagnosis is replaced by a survival time that corresponds to the earlier stage, leading to a reduction in the risk of prostate cancer death. We refer to this as a “stage-shift model” for the impact of screening on prostate cancer mortality.

Recently, the model was extended to accommodate dependence of the distribution of disease grade on age at onset. Additionally, the number of stages has been expanded to three (early localized, advanced localized, and distant) and the number of grades has been expanded to three (Gleason 2–6, 7, and 8–10). We also added several variations on the survival benefit model. In addition to a stage-shift model, we implemented a cure model, in which the benefit of screening is to cure a fraction of those cases who would have died of disease in the absence of screening, with the cure fraction constant, lead time-dependent, or PSA-dependent. We have also developed a flexible stage-shift model, in which the full improvement in survival that would be expected from a stage shift is downweighted using a parameter that is proportional to an individual’s lead time.¹¹

References

Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N. Engl. J. Med. 2003;349(3):215-224. [Abstract]
Mariotto A, Etzioni R, Krapcho M, Feuer EJ. Reconstructing prostate-specific antigen (PSA) testing patterns among black and white men in the US from Medicare claims and the National Health Interview Survey. Cancer. 2007;109(9):1877-1886. [Abstract]
Pinsky PF, Andriole GL, Kramer BS, Hayes RB, Prorok PC, Gohagan JK. Prostate biopsy following a positive screen in the Prostate, Lung, Colorectal and Ovarian cancer screening trial. J. Urol. 2005;173(3):746-750; discussion 750-751. [Abstract]
Gulati R, Inoue L, Katcher J, Hazelton W, Etzioni R. Calibrating disease progression models using population data: a critical precursor to policy development in cancer control. Biostatistics. 2010;11(4):707-719. [Abstract]
Bill-Axelson A, Holmberg L, Ruutu M, et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N. Engl. J. Med. 2011;364(18):1708-1717. [Abstract]
Wilt T, Brawer MK, Jones K, Barry M. Radical Prostatectomy versus Observation for Localized Prostate Cancer. N. Engl. J. Med. 2012;367(3):203-213. [Abstract]
Bolla M, Gonzalez D, Warde P, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N. Engl. J. Med. 1997;337(5):295-300. [Abstract]
Hadley J, Yabroff KR, Barrett MJ, Penson DF, Saigal CS, Potosky AL. Comparative effectiveness of prostate cancer treatments: evaluating statistical adjustments for confounding in observational data. J. Natl. Cancer Inst. 2010;102(23):1780-1793. [Abstract]
Cooperberg MR, Vickers AJ, Broering JM, Carroll PR. Comparative risk-adjusted mortality outcomes after primary surgery, radiotherapy, or androgen-deprivation therapy for localized prostate cancer. Cancer. 2010;116(22):5226-5234. [Abstract]
Boorjian SA, Karnes RJ, Viterbo R, et al. Long-term survival after radical prostatectomy versus external-beam radiotherapy for patients with high-risk prostate cancer. Cancer. 2011;117(13):2883-2891. [Abstract]
Gulati R, Tsodikov A, Etzioni R, et al. Expected population impacts of discontinued prostate-specific antigen screening. Cancer. 2014;120(22):3519-3526. [Abstract]

Tip: Hover your cursor over the dashed attribute links below for more information. View the details of this model in a grid with other prostate models.

Detailed Package Attributes
Attribute Category	Attribute
Approach
Primary Purpose	Screening evaluation, Epidemiological analysis, Policy evaluation, Population trends,
Features
Intervention	Prevention, Screening, Treatment,
Natural History	Metastases, Biomarker,
Construction
Approach	Micro Simulation,
Methods	Likelihood optimization, Stochastic process, Time to Event,
Unit of Analysis	Person,
Data Source
Census
Cancer Registry	SEER,
Linked	SEER-Medicare,
Clinical Trial	ERSPC, PCPT, PLCO, SPCG-4,
Survey	NHIS,
Meta Analysis
Assumptions
Benefit Factors
Screening	Stage Shift, Temporal Trends (Age), Cure Rate, Lead Time,
Treatment	Temporal Trends (Calendar year, Age), Modality,
Vaccination
Inputs	Incidence, Disease, Grade Distribution, Stage Distribution,
Screening	Attendance, Dissemination, Effect, Risk Adaptive Factors,
Diagnosis
Precancer
Treatment	Dissemination, Efficacy,
Precancer
Survival	Observed, Relative,
Mortality	Other cause, Tumor Attributes,
Risk Factor	Age,
Vaccination
Outputs	Cost, Incidence,
Disease	Stage Distribution, Grade Distribution, Other Conditions,
Prevalence
Treatment	Effect,
Precancer
Screening	Effect, Test Performance, Tumor Attributes,
Risk Factor	Natural History,
Outcomes	Survival, Life years, QALY, Cause-specific Mortality, All-cause Mortality,
Screening	False Positives, True Positives, False Negatives, True Negatives, Biopsies performed, Unnecessary biopsies, Overdiagnoses, History,
Treatment	Overtreatment,
Implementation
Development
Tested Platforms	Linux and Unix,
Language	C or C++, R, Python,

2022

Keeney E, Sanghera S, Martin RM, Gulati R, Wiklund F, Walsh EI, Donovan JL, Hamdy F, Neal DE, Lane JA, et al., Cost-Effectiveness Analysis of Prostate Cancer Screening in the UK: A Decision Model Analysis Based on the CAP Trial., Pharmacoeconomics, Dec. 1, 2022 [Abstract]
Basourakos SP, Gulati R, Vince RA Jr, Spratt DE, Lewicki PJ, Hill A, Nyame YA, Cullen J, Markt SC, Barbieri CE, et al., Harm-to-Benefit of Three Decades of Prostate Cancer Screening in Black Men., NEJM Evid, June 1, 2022 [Abstract]
Heijnsdijk EAM, Gulati R, Lange JM, Tsodikov A, Roberts R, Etzioni R, Evaluation of Prostate Cancer Screening Strategies in a Low-Resource, High-risk Population in the Bahamas., JAMA Health Forum, May 20, 2022 [Abstract]

2021

Jiao B, Gulati R, Hendrix N, Gore JL, Rais-Bahrami S, Morgan TM, Etzioni R, Economic Evaluation of Urine-Based or Magnetic Resonance Imaging Reflex Tests in Men With Intermediate Prostate-Specific Antigen Levels in the United States., Value Health, Aug. 1, 2021 [Abstract]
Hendrix N, Gulati R, Jiao B, Kader AK, Ryan ST, Etzioni R, Clarifying the Trade-Offs of Risk-Stratified Screening for Prostate Cancer: A Cost-Effectiveness Study., Am J Epidemiol, May 22, 2021 [Abstract]
Nyame YA, Gulati R, Heijnsdijk EAM, Tsodikov A, Mariotto AB, Gore JL, Etzioni R, The Impact of Intensifying Prostate Cancer Screening in Black Men: A Model-Based Analysis., J Natl Cancer Inst, May 8, 2021 [Abstract]
Lange J, Remmers S, Gulati R, Bill-Axelson A, Johansson JE, Kwiatkowski M, Auvinen A, Hugosson J, Hu JC, Roobol MJ, et al., Impact of cancer screening on metastasis: A prostate cancer case study., J Med Screen, Feb. 9, 2021 [Abstract]

2020

Heijnsdijk EAM, Gulati R, Tsodikov A, Lange JM, Mariotto AB, Vickers AJ, Carlsson SV, Etzioni R, Lifetime benefits and harms of PSA-based risk screening for prostate cancer., J Natl Cancer Inst, Jan. 9, 2020 [Abstract]

2019

Gulati R, Morgan TM, A'mar T, Psutka SP, Tosoian JJ, Etzioni R, Overdiagnosis and lives saved due to reflex testing men with intermediate prostate-specific antigen levels, J Natl Cancer Inst, June 21, 2019 [Abstract]
Gulati R, Psutka SP, Etzioni R, Personalized risks of overdiagnosis for screen-detected prostate cancer incorporating patient comorbidities: Estimation and communication, J Urol, May 21, 2019 [Abstract]
Karlsson A, Jauhiainen A, Gulati R, Eklund M, Grönberg H, Etzioni R, Clements M, A natural history model for planning prostate cancer testing: Calibration and validation using Swedish registry data, PLoS One, Jan. 1, 2019 [Abstract]

2018

Tsodikov A, Gulati R, Etzioni R, Reconciling the Effects of Screening on Prostate Cancer Mortality in the ERSPC and PLCO Trials, Ann Intern Med, April 17, 2018 [Abstract]
de Koning HJ, Gulati R, Moss SM, Hugosson J, Pinsky PF, Berg CD, Auvinen A, Andriole GL, Roobol MJ, Crawford ED, Nelen V, et al., The efficacy of prostate-specific antigen screening: Impact of key components in the ERSPC and PLCO trials, Cancer, March 15, 2018 [Abstract]
Etzioni R, Gulati R, When Clinical Trials Disagree, J Urol, March 1, 2018 [Abstract]
Kaur D, Ulloa-Pérez E, Gulati R, Etzioni R, Racial disparities in prostate cancer survival in a screened population: Reality versus artifact, Cancer, Jan. 25, 2018 [Abstract]

2017

Tsodikov A, Gulati R, Heijnsdijk EAM, Pinsky PF, Moss SM, Qiu S, de Carvalho TM, Hugosson J, Berg CD, Auvinen A, Andriole GL, et al., Reconciling the Effects of Screening on Prostate Cancer Mortality in the ERSPC and PLCO Trials, Ann Intern Med, Oct. 3, 2017 [Abstract]
Tsodikov A, Gulati R, de Carvalho TM, Heijnsdijk EAM, Hunter-Merrill RA, Mariotto AB, de Koning HJ, Etzioni R, Is prostate cancer different in black men? Answers from 3 natural history models, Cancer, June 15, 2017 [Abstract]
Gulati R, Cheng HH, Lange PH, Nelson PS, Etzioni R, Screening Men at Increased Risk for Prostate Cancer Diagnosis: Model Estimates of Benefits and Harms, Cancer Epidemiol Biomarkers Prev, Feb. 1, 2017 [Abstract]

2016

Roth JA, Gulati R, Gore JL, Cooperberg MR, Etzioni R, Economic Analysis of Prostate-Specific Antigen Screening and Selective Treatment Strategies, JAMA Oncol, July 1, 2016 [Abstract]

2015

Birnbaum JK, Feng Z, Gulati R, Fan J, Lotan Y, Wei JT, Etzioni R, Projecting Benefits and Harms of Novel Cancer Screening Biomarkers: A Study of PCA3 and Prostate Cancer, Cancer Epidemiol Biomarkers Prev, April 1, 2015 [Abstract]

2014

Gulati R, Tsodikov A, Etzioni R, Hunter-Merrill RA, Gore JL, Mariotto AB, Cooperberg MR, Expected population impacts of discontinued prostate-specific antigen screening, Cancer, Nov. 15, 2014 [Abstract]
Etzioni R, Gulati R, Oversimplifying overdiagnosis, J Gen Intern Med, Sept. 1, 2014 [Abstract]
Pataky R, Gulati R, Etzioni R, Black P, Chi KN, Coldman AJ, Pickles T, Tyldesley S, Peacock S, Is prostate cancer screening cost-effective? A microsimulation model of prostate-specific antigen-based screening for British Columbia, Canada, Int J Cancer, Aug. 15, 2014 [Abstract]
Lansdorp-Vogelaar I, Gulati R, Mariotto AB, Schechter CB, de Carvalho TM, Knudsen AB, van Ravesteyn NT, Heijnsdijk EA, Pabiniak C, van Ballegooijen M, Rutter CM, et al., Personalizing age of cancer screening cessation based on comorbid conditions: model estimates of harms and benefits, Ann Intern Med, July 15, 2014 [Abstract]
Etzioni RD, Thompson IM, What do the screening trials really tell us and where do we go from here?, Urol Clin North Am, May 1, 2014 [Abstract]
Etzioni R, Gulati R, RE: A model too far, J Natl Cancer Inst, April 1, 2014 [Abstract]
Gulati R, Inoue LY, Gore JL, Katcher J, Etzioni R, Individualized estimates of overdiagnosis in screen-detected prostate cancer, J Natl Cancer Inst, Feb. 1, 2014 [Abstract]

2013

Etzioni R, Gulati R, Mallinger L, Mandelblatt J, Influence of study features and methods on overdiagnosis estimates in breast and prostate cancer screening, Ann Intern Med, June 4, 2013 [Abstract]
Etzioni RD, Review of evidence concerning PSA screening for prostate cancer has limitations as basis for policy development, Evid Based Med, April 1, 2013 [Abstract]
Etzioni R, Gulati R, Cooperberg MR, Penson DM, Weiss NS, Thompson IM, Limitations of basing screening policies on screening trials: The US Preventive Services Task Force and Prostate Cancer Screening, Med Care, April 1, 2013 [Abstract]
Etzioni R, Gulati R, Response: Reading between the lines of cancer screening trials: using modeling to understand the evidence, Med Care, April 1, 2013 [Abstract]
Gulati R, Gore JL, Etzioni R, Comparative effectiveness of alternative prostate-specific antigen--based prostate cancer screening strategies: model estimates of potential benefits and harms, Ann Intern Med, Feb. 5, 2013 [Abstract]
Etzioni R, Durand-Zaleski I, Lansdorp-Vogelaar I, Evaluation of new technologies for cancer control based on population trends in disease incidence and mortality, J Natl Cancer Inst Monogr, Jan. 1, 2013 [Abstract]

2012

Etzioni R, Gulati R, Tsodikov A, Wever EM, Penson DF, Heijnsdijk EA, Katcher J, Draisma G, Feuer EJ, de Koning HJ, Mariotto AB, et al., The prostate cancer conundrum revisited: treatment changes and prostate cancer mortality declines, Cancer, Dec. 1, 2012 [Abstract]
Gulati R, Tsodikov A, Wever EM, Mariotto AB, Heijnsdijk EA, Katcher J, de Koning HJ, Etzioni R, The impact of PLCO control arm contamination on perceived PSA screening efficacy, Cancer Causes Control, June 1, 2012 [Abstract]

2011

Gulati R, Mariotto AB, Chen S, Gore JL, Etzioni R, Long-term projections of the harm-benefit trade-off in prostate cancer screening are more favorable than previous short-term estimates, J Clin Epidemiol, Dec. 1, 2011 [Abstract]
Gulati R, Wever EM, Tsodikov A, Penson DF, Inoue LY, Katcher J, Lee SY, Heijnsdijk EA, Draisma G, de Koning HJ, Etzioni R, et al., What if I don't treat my PSA-detected prostate cancer? Answers from three natural history models, Cancer Epidemiol Biomarkers Prev, May 1, 2011 [Abstract]

2010

Gulati R, Inoue L, Katcher J, Hazelton W, Etzioni R, Calibrating disease progression models using population data: a critical precursor to policy development in cancer control, Biostatistics, Oct. 1, 2010 [Abstract]

2009

Draisma G, Etzioni R, Tsodikov A, Mariotto A, Wever E, Gulati R, Feuer E, de Koning H, Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context, J Natl Cancer Inst, March 18, 2009 [Abstract]
Fesinmeyer MD, Gulati R, Zeliadt S, Weiss N, Kristal AR, Etzioni R, Effect of population trends in body mass index on prostate cancer incidence and mortality in the United States, Cancer Epidemiol Biomarkers Prev, March 1, 2009 [Abstract]

2008

Etzioni R, Gulati R, Falcon S, Penson DF, Impact of PSA screening on the incidence of advanced stage prostate cancer in the United States: a surveillance modeling approach, Med Decis Making, May 1, 2008 [Abstract]
Etzioni R, Feuer E, Studies of prostate-cancer mortality: caution advised, Lancet Oncol, May 1, 2008 [Abstract]
Telesca D, Etzioni R, Gulati R, Estimating lead time and overdiagnosis associated with PSA screening from prostate cancer incidence trends, Biometrics, March 1, 2008 [Abstract]
Etzioni R, Tsodikov A, Mariotto A, Szabo A, Falcon S, Wegelin J, DiTommaso D, Karnofski K, Gulati R, Penson DF, Feuer E, et al., Quantifying the role of PSA screening in the US prostate cancer mortality decline, Cancer Causes Control, March 1, 2008 [Abstract]
Inoue LY, Etzioni R, Morrell C, Müller P, Modeling Disease Progression with Longitudinal Markers., J Am Stat Assoc, Jan. 1, 2008 [Abstract]

2007

Mariotto AB, Etzioni R, Krapcho M, Feuer EJ, Reconstructing PSA testing patterns between black and white men in the US from Medicare claims and the National Health Interview Survey, Cancer, May 1, 2007 [Abstract]
Zeliadt SB, Etzioni R, Ramsey SD, Penson DF, Potosky AL, Trends in treatment costs for localized prostate cancer: the healthy screenee effect, Med Care, Feb. 1, 2007 [Abstract]

2006

Zeliadt SB, Potosky AL, Penson DF, Etzioni R, Survival benefit associated with adjuvant androgen deprivation therapy combined with radiotherapy for high- and low-risk patients with nonmetastatic prostate cancer, Int J Radiat Oncol Biol Phys, Oct. 1, 2006 [Abstract]

2004

Shaw PA, Etzioni R, Zeliadt SB, Mariotto A, Karnofski K, Penson DF, Weiss NS, Feuer EJ, An ecologic study of prostate-specific antigen screening and prostate cancer mortality in nine geographic areas of the United States, Am J Epidemiol, Dec. 1, 2004 [Abstract]
Feuer EJ, Etzioni R, Cronin KA, Mariotto A, The use of modeling to understand the impact of screening on U.S. mortality: examples from mammography and PSA testing, Stat Methods Med Res, Dec. 1, 2004 [Abstract]
Zeliadt SB, Potosky AL, Etzioni R, Ramsey SD, Penson DF, Racial disparity in primary and adjuvant treatment for nonmetastatic prostate cancer: SEER-Medicare trends 1991 to 1999, Urology, Dec. 1, 2004 [Abstract]
Inoue LY, Etzioni R, Slate EH, Morrell C, Penson DF, Combining longitudinal studies of PSA, Biostatistics, July 1, 2004 [Abstract]

2003

Zeliadt SB, Penson DF, Albertsen PC, Concato J, Etzioni RD, Race independently predicts prostate specific antigen testing frequency following a prostate carcinoma diagnosis, Cancer, Aug. 1, 2003 [Abstract]

2002

Etzioni R, Penson DF, Legler JM, di Tommaso D, Boer R, Gann PH, Feuer EJ, Overdiagnosis due to prostate-specific antigen screening: lessons from U.S. prostate cancer incidence trends, J Natl Cancer Inst, July 3, 2002 [Abstract]
Etzioni R, Berry KM, Legler JM, Shaw P, Prostate-specific antigen testing in black and white men: an analysis of medicare claims from 1991-1998, Urology, Feb. 1, 2002 [Abstract]