List of Contributors
Philip H. Abbosh, MD, PhD Department of Surgical Oncology, Fox Chase Cancer Center-Temple Health, Philadelphia, PA, USA
Firas Abdollah, MD Vattikuti Urology Institute & VUI Center for Outcomes Research Analytics and Evaluation, Henry Ford Hospital, Detroit, MI, USA
Mohan P. Achary, PhD Department of Radiation Oncology and Radiology, Temple University School of Medicine, Philadelphia, PA, USA
Shaheen Alanee, MD, MPH Division of Urology, Department of Surgery, Southern Illinois University School of Medicine, Springfield, IL, USA
Peter C. Albertsen, MD, MS Department of Surgery, University of Connecticut Health Center, Farmington, CT, USA
Yousef Al-Shraideh, MD Department of Urology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
Gerald Andriole, MD Division of Urological Surgery, Washington University in St. Louis, St. Louis, MO, USA
Janet E. Baack Kukreja, MD Department of Urology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
Richard K. Babayan, MD Boston University School of Medicine, Boston, MA, USA
Brock R. Baker, BS Department of Radiation Oncology, University of North Carolina, Chapel Hill, NC, USA
Christopher E. Bayne, MD Department of Urology, The George Washington University, Washington, DC, USA
Marijo Bilusic, MD, PhD Department of Medical Oncology, Fox Chase Cancer Center/Temple University, Philadelphia, PA, USA
Leonard P. Bokhorst, MD Department of Urology, Erasmus University Medical Center, Rotterdam, The Netherlands
David B. Cahn, DO, MBS Department of Urology, Einstein Healthcare Network, Philadelphia, PA, USA
Daniel J. Canter, MD Department of Urology, Fox Chase Cancer Center and Einstein Healthcare Network, Philadelphia, PA, USA
David Y.T. Chen, MD, FACS Department of Surgical Oncology, Fox Chase Cancer Center-Temple Health, Philadelphia, PA, USA
Ronald C. Chen, MD, MPH Department of Radiation Oncology, University of North Carolina, Chapel Hill, NC, USA
Juan Chipollini, MD Department of Urology, University of Miami Miller School of Medicine, Miami, FL, USA
Peter L. Choyke, MD Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Matthew R. Cooperberg, MD, MPH Department of Urology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA
Anthony Costello, MD, FRACS, FRCSI Departments of Urology and Surgery, Royal Melbourne Hospital and University of Melbourne, Melbourne; Epworth Prostate Centre, Epworth Healthcare, Melbourne, Australia
E. David Crawford, MD University of Colorado Health Science Center, Aurora, CO, USA
Curtiland Deville, MD Johns Hopkins University, The Sidney Kimmel Comprehensive Cancer Center, Sibley Memorial Hospital, Washington, DC, USA
Essel Dulaimi, MD Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, USA
Danuta Dynda, MD Division of Urology, Department of Surgery, Southern Illinois University School of Medicine, Springfield, IL, USA
John B. Eifler, MD Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
Cesar E. Ercole, MD Center for Urologic Oncology, Glickman Urological & Kidney Institute, Cleveland Clinic, Cleveland, OH, USA
Daniel D. Eun, MD Department of Urology, Temple University Hospital, Philadelphia, PA, USA
Wouter Everaerts, MD, PhD Division of Cancer Surgery, Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne; Department of Urology, Royal Melbourne Hospital, Parkville; and Epworth Prostate Centre, Epworth Healthcare, Richmond, Victoria, Australia
Izak Faiena, MD Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey and Division of Urology, Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
Michael A. Ferragamo, MD, FACS Department of Urology, State University of New York, University Hospital, Stony Brook, NY, USA
Kristen R. Scarpato, MD, MPH Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
George R. Schade, MD Department of Urology, University of Washington School of Medicine, Seattle, WA, USA
Matthew S. Schaff, MD Department of Urology, Temple University Hospital, Philadelphia, PA, USA
Samir V. Sejpal, MD, MPH Department of Radiation Oncology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
Neal D. Shore, MD, FACS Carolina Urologic Research Center, Atlantic Urology Clinics, Myrtle Beach, SC, USA
Jay Simhan, MD Department of Urology, Fox Chase Cancer Center, Einstein Urologic Institute, Philadelphia, PA, USA
Susan F. Slovin, MD, PhD Genitourinary Oncology Service, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY; Department of Medicine, Weill-Cornell Medical College, USA
Marc C. Smaldone, MD Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
Joseph A. Smith, Jr, MD William L. Bray Professor of Urologic Surgery, Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
Andrew J. Stephenson, MD, FACS, FRCS(C) Center for Urologic Oncology, Glickman Urological & Kidney Institute, Cleveland Clinic, Cleveland; Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, USA
Ewout W. Steyerberg, PhD Department of Public Health, Erasmus University Medical Center, Rotterdam, The Netherlands
C.J. Stimson, MD, JD Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
Siobhan Sutcliffe, PhD Department of Surgery, Division of Public Health Sciences, Washington University School of Medicine, Siteman Cancer Center, St. Louis, MO, USA
Samir S. Taneja, MD Department of Urology and Radiology, New York University Langone Medical Center, New York, NY, USA
Vincent Tang, MBBS, MSc, DIC, FRCS Urol Department of Urology, Royal Melbourne Hospital, Melbourne, Australia; Division of Cancer Surgery, University of Melbourne, Peter MacCallum Cancer Centre, Melbourne, Australia
Timothy J. Tausch, MD Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA
James Brantley Thrasher, MD Department of Urology, University of Kansas Medical School, Kansas City, KS, USA
Taryn G. Torre, MD Division of Urology, Radiation Oncology Associates, a Division of Virginia Urology, Richmond, VA, USA
Edouard J. Trabulsi, MD, FACS Department of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
Baris Turkbey, MD Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Robert M. Turner II, MD Department of Urology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
Willie Underwood III, MD, MPH, MSci Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, USA
Goutham Vemana, MD Division of Urological Surgery, Washington University in St. Louis, St. Louis, MO, USA
Shilpa Venkatachalam, PhD, MA NYU Langone Medical Center, NYU School of Medicine, New York, NY, USA
Karen H. Ventii, PhD School of Medicine, Emory University, Atlanta, GA, USA
Alan Wein, MD, PhD(Hon) Department of Urology, Perelman Center for Advanced Medicine, Philadelphia, PA, USA
Jonathan L. Wright, MD, MS Department of Urology, University of Washington School of Medicine, Seattle; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Hadley Wyre, MD Department of Urology, University of Kansas Medical School, Kansas City, KS, USA
Isaac Yi Kim, MD, PhD Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey and Division of Urology, Department of Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
Melissa R. Young, MD, PhD Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, USA
James B. Yu, MD Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, USA
Nicholas G. Zaorsky, MD Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
1 Population Screening for Prostate Cancer and Early Detection
Judd W. Moul, MD, FACS
Department of Surgery and the Duke Cancer Institute, Division of Urology, Duke University School of Medicine, Durham, NC, USA
INTRODUCTION
Prostate cancer (PCa) is the most commonly diagnosed new solid cancer and the second most common cause of cancer-related deaths in men in the United States. The American Cancer Society (ACS) estimated that approximately 241,740 new cases and 28,170 PCarelated deaths would occur in the United States in 2014.1 PCa is now the second-leading cause of cancer death in men, exceeded only by lung cancer. It accounts for 29% of all male cancers and 9% of male cancer-related deaths. The prostate-specific antigen (PSA) concentration in the blood is a test approved by the US Food and Drug Administration as an aid to the early detection of PCa. Screening with PSA has been widely used to detect PCa for decades in the United States and many industrialized nations but it continues to be controversial.2–5 Until a few years ago, the ACS and the American Urological Association (AUA) recommended PCa screening for men at average risk who are 50 years or older and have a life expectancy of at least 10 years, after the patient and physician discuss the risks and benefits of screening and intervention.6–7 Screening was recommended for higher-risk groups, such as African-American (AA) men, beginning at age 40 years. There is much debate over the sensitivity of PSA tests and the ultimate effect on morbidity and mortality of detecting PCa at early, potentially clinically insignificant stages, so called “overdetection.”8–9
In May 2012, the US Preventive Services Task Force (USPSTF) issued a new guideline against PSA testing and gave the test a “D-rating” indicating that it resulted in more harm than good.10 Since this time, the debate has been heated and the AUA and other organizations have now come together to oppose population-based screening.2–9 In this chapter, I will further explore this contro-
Prostate Cancer. http://dx.doi.org/10.1016/B978-0-12-800077-9.00001-3
Copyright © 2016 Elsevier Ltd. All rights reserved.
versy and discuss the rationale and basis for using PSA in the early detection of PCa.
The USPSTF Firestorm
In May 2012, the USPSTF issued an opinion opposing PCa screening using the PSA test.10 The Task Force is an independent government-appointed panel of experts in prevention and evidence-based medicine composed of primary care providers (internists, pediatricians, family physicians, nurses, gynecologists/obstetricians, and health behavior specialists) who do not typically treat PCa patients. They receive funding from the US Government through the Department of Health and Human Services Agency for Health Care Research and Quality with the charge to conduct scientific evidence reviews of clinical preventive health care services and to develop recommendations for primary care clinicians and health systems.
The recommendations of the USPSTF ignited a firestorm of controversy. I was part of a group, composed of a number of recognized experts in the diagnosis and treatment of PCa, along with specialists in preventive medicine, oncology, and primary care, issued a brief commentary opposing their recommendations when they were initially published.11 We also have articulated a critical analysis of the USPSTF and AUA recommendations.12
SPECIFIC CRITICISMS OF THE USPSTF REPORT
In the initial presentation of their review and analysis, the USPSTF proposed to answer four main questions.13 The first question asked if PSA-based screening decreases PCa-specific or all-cause mortality.
The Task Force based their recommendations on a review of five studies of the potential benefits of PSA testing but gave significant weight to only two of these studies. The Prostate, lung, Colorectal, and ovarian (PlCo) Cancer Screening Trial was conducted in the United States from 1993 to 2001, randomly assigning 76,693 men aged 55–74 years at 10 US study centers to receive either screening, defined as annual PSA testing for 6 years and digital rectal examinations for 4 years or “usual care” as the control group.14 After 7 years of follow-up, there were 2820 PCas diagnosed in the screened group and 2322 in the control group (RR, 1.22; 95% CI, 1.16–1.29). The incidence of death per 10,000 person-years was 2.0 in the screened group and 1.7 in the control group (rate ratio, 1.13; 95% CI, 0.75–1.70).
The European Randomized Study of Screening for Prostate Cancer (ERSPC), with screening in all centers between 1994 and 2006, and ongoing continued followup and screening in several of the major centers, involved 162,000 men, aged 55–69 years, randomly assigned either to a group offered PSA screening once every 4 years or to a control group that did not receive screening.15 The cumulative incidence of PCa was 8.2% in the screened group and 4.8% in the control group, but the rate ratio for death from PCa in the screened group as compared with the control group was 0.80 (95% CI, 0.65–0.98; adjusted p = 0.04), resulting in decreased PCa-specific mortality. In the additional follow-up years 10 and 11, the rate ratio for death from PCa dropped to 0.62 (95% CI, 0.45–0.85; adjusted p = 0.003) for screened patients.16 The USPSTF maintained that the cancer-specific mortality advantages in the two studies did not justify the “harms” of screening. Since 2012, the ERSPC has updated results with 13 years of follow-up as well as additional analysis that further support a beneficial impact on mortality.17–22
The critique is that the USPSTF did not acknowledge known methodological flaws in these two major studies. The best documented objection being “contamination” of the control populations by PSA screening performed outside the study protocols by subject choice. In the PlCo study, fully 44% of the control subjects had PSA tests performed prior to randomization, and 83% had at least one PSA test outside the study protocol at some point during the 6-year screening period of the trial. out of these, the 17% had 1–2 tests, 42% had 3–4, and 24% had 5–6 PSA tests during the 6-year study period.23–25 This “contamination” of the control group invalidated the original comparison hypotheses of the study. There was also a significant protocol violation as 60–70% of the men with an abnormal PSA screening test failed to get a timely prostate biopsy, although 64% did eventually undergo a biopsy within 3 years.25,26 In the ERSPC trial, there was also nonprotocol screening, but far less than in the PlCo study. A reanalysis of the Rotterdam data set from the ERSPC trial, corrected for nonattendance and
contamination, showed that PSA screening reduced the risk of dying of PCa by up to 31% as compared to the prior estimate of 20%.27,28
A further and perhaps even more serious problem with the USPSTF analysis of mortality was the inadequate follow-up time, median of about 6 years in the PlCo trial and 9 years in the ERSPC study. The time for the clinical evolution of PCa is much longer; in a Swedish study of an unscreened population, the lead time from onset of elevated PSA level to PCa diagnosis reached 10.7 years.29 In a different Swedish study, a small cohort of 223 men with untreated localized PCa was followed for 32 years.30 There were 90 (41.4%) local progression events and 41 (18.4%) cases of progression to distant metastasis. In total, 38 (17%) men died of PCa, but the relative rate of PCa-specific death increased from 4.9 at 5–9 years to 23.5 at 15–20 years, suggesting that cancer death accounts for a greater proportional mortality with advancing duration of the disease.
Interim follow-up results from the Göteborg randomized population-based Prostate-Cancer Screening Trial with a median follow up of 14 years, heighten the concern that the Task Force recommendation was based on inadequate duration of follow-up.31 In this currently ongoing long-term study, 20,000 men aged 50–64 years were randomized either to a screening group to receive PSA testing every 2 years or to a nontested control group. There was a cumulative incidence of PCa of 12.7% in the screened group and 8.2% in the control group (hazard ratio, 1.64; 95% CI, 1.50–1.80; p < 0.0001). yet despite a significantly higher incidence of PCa, the rate ratio for death from PCa for the screened group was lower at 0.56 (95% CI, 0.39–0.82; p = 0.002), a reduction of 44%.31
The second question that the USPSTF addressed was regarding the harms of PSA-based screening for PCa. The USPSTF considered false positive results (an elevated PSA level not leading to cancer diagnosis) as harmful. In the PlCo trial, the cumulative risk for at least one falsepositive result was 13%, with a 5.5% risk for undergoing at least one unnecessary biopsy.32 In the ERSPC trial, 76% of the prostate biopsies did not show PCa.33 In a prior review in 2008, the USPSTF noted that false-positive PSA test results can cause adverse psychological effects.34 In addition, there were biopsy complications such as infection, bleeding, and urinary difficulties in both trials: 68 events per 10,000 evaluations in the PlCo study; while the Rotterdam center of the ERSPC trial reported that among 5,802 prostate biopsies, 200 men (3.5%) developed a fever, 20 (0.4%) experienced urinary retention, and 27 (0.5%) required hospitalization due to prostatitis or urosepsis.33
The error in the Task Force argument is one of incomplete comparison, assuming that the absence of PSA screening completely avoids all diagnostic procedures. In fact, diagnostic procedures for PCa were frequently
I. ETIoloGy, PATHoloGy, AnD TUMoR BIoloGy
weak on making special recommendations for high-risk groups.89 These guidelines do endorse PSA testing every other year between the ages of 55 and 69 and are patterned after the Göteborg arm of the ERSPC. However, this is to be considered only after shared decision/ informed consent. Critics have contended that the new guidelines are “soft” on high-risk groups, particularly AA men.12
IMPACT OF AGE ON PROSTATE SCREENING DECISIONS
The 2012 USPSTF guidelines was opposed to PSA testing irrespective of age.10 The expected lifespan in the United States for a male aged 75 is about 10 years.90 In 2008, the USPSTF recommended against PSA screening of men over the age of 75.34 It is plausible that the aging process in most 75-year-old men will progress to mortality prior to the advent of advanced PCa, but the current expected life span for men aged 45–50 years in the United States is about 30 years for whites and 27 years for blacks.90 The recent blanket USPSTF recommendation may result in delayed diagnosis of potentially curable PCas in young men who will otherwise suffer advanced disease and death, and some otherwise healthy older men with high-grade PCa will also unnecessarily suffer advanced disease and cancer death.
SCREENING/RISK ASSESSMENT IN YOUNG MEN
Whether PCa screening should include average-risk younger men is a subject of debate in the medical literature. The incidence of PCa in this age group is low, and the clinical significance of detected PCa in these men is unclear.91 Recent data suggest that a PSA value above 0.7 ng/ml in young men is associated with greater risk for development of PCa.92
In 2006, the national Comprehensive Cancer network (nCCn) adopted by “nonuniform consensus” a risk-stratification strategy for young men that includes a “baseline” PSA measurement at age 40 years and subsequent risk stratification based on the result of this initial test.93 The nCCn early-detection protocol is supported by evidence that young men with PSA levels above the age-specific median are at greater risk for future PCa. In the Baltimore longitudinal Study of Aging, the relative risk of PCa was 3.75 for men aged 40–49 years with a PSA level above the age-specific median of 0.6 ng/ml, whereas the risk was similar among men in their 50s with PSA levels above and below the age-specific median.94 Similarly, among men aged 40–49 years who were at greater risk (either because of positive family history
or AA race), a PSA level between the age-specific median (0.7 ng/ml) and 2.5 ng/ml was associated with a higher risk of PCa, with screening of 36 higher-risk men required to detect one additional case of cancer. The external validity of this finding is unclear; it is not known how many young men at average risk would need a PSA test to detect one additional case of cancer.92
overdiagnosis of PCa using current detection strategies is not insignificant and leads to potentially avoidable harms in the course of treatment.95–99 Etzioni et al. estimated an overdiagnosis rate of 29% among white patients aged <60 years, based on model comparisons to the national Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database.96 Similarly, using data from the ERSPC, Draisma et al. found an overdiagnosis rate of 27% for men aged 55 years.95 High overdiagnosis rates make the benefit of PCa screening unclear, but the adverse effects of treatment are clear and are similar for clinically detected and screening-related cancers.99 If all of the 2.1 million 40-year-old men in the United States underwent PSA testing, this could result in up to 48,000 additional biopsies for elevated PSA levels alone, with up to 12,000 men diagnosed with PCa.100–102 The incidence of treatment-related side effects (e.g., impotence and incontinence) are well known, and given current life expectancy among men at age 40 years, the effects of treatment could result in a significant decrement in quality-adjusted life-years. These costs should be balanced against the potential benefits of PCa screening in young men, which may include years of life saved and decreases in the costs of advanced disease management. Given the well-recognized limitations of retrospectively identified screening strategies and cost–benefit models, the issue of obtaining a baseline “risk-stratification” PSA remains controversial.97,103
The large majority of men in this age group who have a PSA test will not be diagnosed with PCa, although some may develop it later in life. Additional baseline testing of young men will likely have substantial costs, both direct and indirect.
Health care resource use associated with PSA testing could increase substantially under the nCCn protocol. Based on a prior study from my center, 22.5% of men aged 40–49 years have a PSA test annually.104–106 In the United States, there are approximately 22.4 million men aged 40–49 years.100 This translates into approximately 5 million annual PSA tests in this age group. If all men underwent PSA testing at age 40 years (current US population of 40-year-old men: 2.1 million), this would add up to 2 million annual tests.100 For men with PSA levels above the age-specific median, annual PSA testing with digital rectal examination is recommended (e.g., up to 1 million annual PSA tests). Under this protocol, the number of PSA tests in men aged 40–49 years would more than double.
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PROLIFERATIVE INFLAMMATORY ATROPHY
The lesion that links inflammation with PCa is called proliferative inflammatory atrophy or PIA. Whereas most areas of prostatic atrophy are quiescent, areas of atrophy next to inflammation have been found to proliferate. These areas, called PIA, have been suggested as precursors to PCa either directly or indirectly by progression to PI n 24,25 m orphologic studies have reported transition from PIA to PI n and from PIA to cancer. 26 Proliferation in PAH lesions is significantly greater than in BPH or SA, but less than in PI n and PCa. 27
There are biochemical changes in PIA lesions that are also found in PIn and PCa28:
• Glutathione-S-transferases (gST) is a cellular enzyme that neutralizes reactive oxygen species (RoS). methylation inactivates this enzyme, increasing the chance of oxidative damage. This is found in areas of PIA, PIn, and PCa, but not found in normal prostate cells.
• Amplification of chromosome 8, reported as a marker for poor prognosis in prostate adenocarcinoma.
• Protein products of three prostate tumor suppressor genes, nKX3.1, CDKn1B, which encodes p27 and PTEn (phosphatase and tensin homolog), are all downregulated in focal atrophy lesions – present in normal prostate, and frequently decreased or absent in PIn and cancer.
• There is decreased apoptosis attributed to increased Bcl-2 expression.29
PIA also appears to go along with prognosis. Davidsson et al.24 looked at TuRP specimens in which stage T1a-b PCa was diagnosed. They compared men who died of PCa with those who lived 10 years without metastasis. Chronic inflammation itself had no correlation with survival but when chronic inflammation was associated with areas of atrophy, there was a fivefold increase in risk of dying of PCa.
MECHANISMS OF INFLAMMATORY CARCINOGENESIS
one of the hypotheses linking inflammation to PCa is that chronic inflammation leads to release of inflammatory mediators and free radicals that damage the cells. The cells then attempt to regenerate in this environment to repair themselves. The mediators are also genotoxic and the end result is an increased risk of mutation and malignant transformation. Cytokines from macrophages, T lymphocytes or even tumor cells themselves may contribute to malignant progression.
Several cytokines and inflammatory mediators have been implicated in the development of PCa.
Tumor Necrosis Alpha (TNF-a)
TnF-a is produced by macrophage/monocytes after exposure to noxious stimuli. TnF-a induces other inflammatory responses. High levels of TnF are toxic to tumors by destruction of tumor vascularity and apoptosis, but in small doses chronically, may be a tumor promoter.1 It can lead to induction of Cox-2, matrix metalloproteases and chemokines, which are procarcinogenic.30 TnF-a also stimulates tumor cell proliferation directly by activation of nuclear factor kappa (nF-kB).31 This family of transcription factors key regulator of cell growth and inhibitors of apoptosis, thus inflammation can lead to decreased cell death.32 In prostate cells, TnF also suppresses androgen receptor expression and can lead to loss of androgen sensitivity.33
Reactive Species
RoS include the highly reactive molecules superoxide and hydrogen peroxide, which are produced by activated macrophages and by other cell types as by-products of oxidative metabolism. RoS are unstable and reactive as they contain unpaired electrons. They are neutralized by intracellular antioxidants such as vitamin E and beta carotenes and cellular enzymes like glutathione peroxides and gST.34 Reactive nitrogen species (RnS) include nitric oxide (no) and its reactive intermediates. no is a toxic gas with free radical properties produced by inflammatory cells and most other cell types by inoS following stimulation by inflammatory cytokines such as TnF-a and Il-1.35 RoS and RnS both damage cellular lipids, proteins, and DnA, which can ultimately lead to carcinogenesis. They also inactivate DnA repair enzymes, producing a net imbalance between rate of mutagenesis and ability to repair mutations without error, also contributing to carcinogenesis.31
Cyclo-oxygenase 2 (Cox-2)
Cox-2 is the inducible form of cyclo-oxygenase and catalyzes the conversion of arachidonic acid to prostaglandins. Cox-2 is expressed by inflammatory cells, such as macrophages, and can be induced by TnF and EgF.36 The prostaglandins and eicosanoids produced can have a major role in the development of human cancers but the role is not as firmly established in PCa.37 There is over-expression of Cox-2 in PCa and PIn compared to normal or hyperplastic prostate.38,39 In vitro Cox-2 inhibitors inhibit PCA growth and increase apoptosis in PCa cell lines.40 Cox-2 may play a role in more advanced T3 or T4 cancers.41
an inverse relationship between soy consumption and risk of PCa with an oR, 0.7; CI, 0.57–0.84.98
Tomatoes and lycopenes may have an ameliorating effect on the development of PCa. lycopene is a red carotenoid pigment in tomatoes, watermelon, and grapefruit. In vitro has antiproliferative effect by inhibiting cell cycle at g0/g1 phase.99 It also produces an increase in number of IgF-1 binding proteins, resulting in net decrease of insulin-like growth factor-1, IgF-1, which has been associated with increased risk of PCa.100 meta-analysis of 21 studies concluded that there was an RR of 0.89 with eating lots of raw tomato and cooked tomato products.101 However, a recent FDA panel concluded only limited evidence that lycopenes and tomato consumption reduces risk of PCa based on evaluation of 13 observational studies.102 Similar to lycopenes, there was an initial interest in vitamin E after an initial report from the ATBC study (a-tocopherol, b-carotene cancer prevention study) looked at vitamin A (b-carotene) or vitamin E (a-tocopherol) supplementation in lung cancer. After 6 years, there was 34% reduction in incidence of PCa in those randomized to vitamin E.94,103 However, large follow-up studies have not reproduced this benefit including in the SElECT trial.104 longer-term follow-up in the SElECT cohort showed that vitamin E supplementation actually increased the risk of PCa,104 while selenium had no effect.
Polyunsaturated fats omega 3 and 6 are essential fatty acids derived entirely from the diet, as the body is unable to synthesize these de novo In vitro and human studies have found w-6 and trans-fatty acids (TFAs) to be proinflammatory and w-3 to be anti-inflammatory.95 one would think that the anti-inflammatory lipids may protect against PCa. However, in the PCPT and the SElECT trial, blood levels of phospholipid fatty acids have reported increased risk of high-grade PCa with high levels of w-3 fatty acids.105,106 The risk of lethal PCa is increased with several SnPs of fatty acid synthase, and the risk is associated with BmI. In obese but not lean men, the polymorphism rs1127678 was associated with a risk of advanced PCa of 2.49 and a risk of mortality from PCa of 2.04.107
Eating large amounts of red meat and certain processed meats appears to increase the risk of PCa. In a review of a large study of men aged 50–71, red meat increased the risk of PCa by 12% and red processed meat increased the risk by 7%. grilling meat resulted in an 11% increased risk of total PCa and a 36% increased risk of advanced PCa. The risk was associated with levels of nitrites and nitrates in the meat.108 In a study of 7949 African-American men, there was no association with red, white, or processed meat but there was a 20% greater risk for nonadvanced PCa in those consuming red meats cooked at high temperature.109
obesity itself may be a risk for PCa. Adipose cells are a source of inflammation as well as macrophages in adipose, which release inflammatory mediators.110 In the
PCPT, there was a protective effect of 18% for men with a BmI >30 for low-grade cancer (gleason < 7), but these same men had a 29% increased risk of high-grade PCa (gleason ≥ 7).111 other studies have also reported a significantly positive association between PCa aggressiveness and obesity.112 one of the difficulties in interpreting results for obese men is that they have greater circulating plasma volume and therefore a “hemodilution” of PSA.113 However, the clinical impact of this finding on predicting tumor volume and stage is not certain, as some studies have found no need to adjust for BmI.114
BIOMARKERS FOR INFLAMMATION AND PROSTATE CANCER
C reactive protein (CRP) was initially reported to be positively associated with PCa in small studies, but a more recent meta-analysis of five studies did not show an association of CRP and PCa with a risk estimate of 1.115,116 A study of over 17,000 men showed no association of neither CRP nor other available markers thought to indicate inflammation – albumin, haptoglobin, hemoglobin, and leukocytes – with risk of PCa.117 A recent study however did show a correlation between CRP and albumin, called the modified glasgow predictive score (mgPS). In almost 900 patients with PCa, the mgPS predicted poorer overall 5-year survival and relative survival independent of age and disease grade.118 Il-6 is elevated in men with untreated metastatic or castration-resistant PCa, and is associated with an aggressive phenotype of cancer.119 Il-6 may play a role in the development of castration-resistant PCa by activation of the androgen receptor.120 A polymorphism for Il-6 gene is also reported to be associated with more aggressive PCa.121
CHEMOPREVENTION WITH ASA OR NSAIDs
Animal studies have suggested that using aspirin or nonsteroidal anti-inflammatory drugs (nSAIDs) can reduce the growth of PCa.56,122 large studies in humans have had mixed results. Recent large studies include a meta-analysis of 24,000 patients, which showed that aspirin use reduced the risk of overall PCa by 17%, and 19% for advanced cancer. nonaspirin nSAIDs were less consistent in effect but still suggestive of a benefit.123 using the Saskatchewan database and examining over 9000 men with PCa, there was a class effect seen. Propionates (Ibuprofen and naprosyn) were most effective with the most risk reduction and oR 0.90, while other types of nSAIDs were not associated with a PCa risk reduction, nor was aspirin. The anti-inflammatories were most effective if started 11–15 years prior to the study date.124
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