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prostate cancer

Etiology: 1) cause unknown 2) risk factors: a) family history, prostate cancer in a 1st degree relative b) age > 50 c) black race d) vasectomy (no association) [142,143] - no associations between vasectomy & incident high-grade, advanced, or fatal prostate cancer [151] e) dietary fat f) cow's milk consumption, especially aggressive or fatal forms g) occupational exposure to cadmium or rubber h) colon cancer i) obesity in black men [18,116] j) low levels of vitamin D [18] k) excessive use of multivitamin [31] - folic acid 1 mg QD associated with 3-fold risk [45] - vitamin E 400 IU QD increases risk 17% [66] l) omega-3 fatty acids increase risk [89,96] (RR-1.4-1.7) m) bisphenol A (BPA) exposure increases risk n) circumcision lowers risk (HR=0.85) [69] o) frequent ejaculation may diminish risk [13,117] 3) generally slow growing, androgen sensitive - serum levels of testosterone & estradiol NOT related to risk of prostate cancer in healthy men [39] 4) 5-alpha-reductase inhibitors not a risk for high-grade prostate cancer. 5) finasteride reduces risk of prostate cancer, but not cancer mortality [2] Epidemiology: 1) most common malignancy in men, excluding skin cancers 2) one in six men will develop prostate cancer; one in 35 men will die of it [42] 3) incidence 240,000 cases/year - increased incidence of metastatic prostate cancer in the United States (2004-2013) [137] - 92% increase in men 55-69 years of age - for men 45-74, 17 cases of metastatic prostate cancer/100,000 [209] - for men > 75, 89 cases of metastatic prostate cancer/100,000 [209] 4) 2nd most common cause of cancer mortality in men 40,000/year 5) 23% of men > 50, 35% of men > 60, 46% of men > 70 years with autopsy-confirmed prostate cancer [40] 6) prevalence 45%-59% for men in > 60 years, increasing with age [95] 7) prevalence is 7% with serum PSA < 0.5 ug/L, 27% with serum PSA 3.1-4.9 ug/L [15] 8) mean age at diagnosis: 72 years 9) 10 year disease-specific survival for localized disease: 80-90% 10) racial predilection: blacks > whites > Japanese - uncommon in Asian countries [6] 11) fish consumption (omega-3 fatty acids?) may reduce risk [5] - increased serum DHA associated with high-grade prostate cancer [58] 12) red wine* consumption may reduce risk [17] *(see prophylaxis) 13) incidence increases in populations further from the equator (sunlight, vitamin D may play role) 14) diagnosis of early stage prostate cancer has declined since USPSTF recommendation against screening for prostate cancer [140] 15) transgender women retain prostate after gender-affirmation surgery & remain at risk of prostate cancer, regardless of estrogen use [214] Pathology: 1) most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts (95%) 2) other rare histopathologic types of prostate cancer include: a) small cell carcinoma b) mucinous carcinoma c) prostatic ductal carcinoma d) transitional cell carcinoma e) squamous cell carcinoma f) basal cell carcinoma g) adenoid cystic carcinoma h) signet-ring cell carcinoma i) neuroendocrine carcinoma [72] 2) most prostate cancers arise primarily from the peripheral zone of the prostate 3) surgical pathology a) 20-30% with capsular invasion or seminal vesicle involvement b) 40% of cases with positive margins 4) Gleason scoring system 5) metastases a) lymph nodes (68%) b) liver (36%) c) lung (49%) d) bone* (67%) e) brain (2%) f) skin (3%) g) adrenal (17%) h) kidney (11%) 6) histone-arginine methyltransferase CARM1 overexpressed 7) increased levels of IL11RA 8) PSMA is overexpressed in prostate cancer [184] - PSMA negative in tumor cells (stains vessels) 9) microvessel density associated with mortality (HR=3.0, highest vs lowest quartile) [46] 10) immunocytochemistry: - PSA positive (prostate origin) - NJX3.1 positive (prostate origin) - AMACR positive (prostate origin) - CK8/18 positive (carcinoma) - EpCAM (MOC31) positive (carcinoma) - CD45 negative (lymphoma, hematopoietic neoplasm) - pancytokeratin negative - CD7 & CD20 negative - TTF1 & napsin negative (lung origin) - P63 & HMWCK negative (squamous differentiation) - synaptophysin & chromogranin negative (neuroendocrine differentiation) - D2140, c-kit, & CD30 negative (germ cell tumor) - Sall4 negative (germ cell tumor) - mucicarmine negative (intracelluar mucin) - 0HMB45, MART, S100 & Sox10 negative (melanoma) - Pax8 negative (renal) - HepAr1 & Arginase negative (hepatocellular origin) * bone is most frequent site of distant metastases Genetics: 1) 5% of cases may be familial - 12% of men with metastatic prostate cancer have at least one germline mutation in a gene involved in DNA-repair [134] - mutations identified in 16 different genes, including BRCA2 (5.3%), ATM (1.6%), CHEK2 (1.9%), BRCA1 (0.9%), RAD51D (0.4%), & PALB2 (0.4%) [134] - susceptibility to prostate cancer - defects in RNASEL (type 1) - defects in ELAC2 - defects in MSMB (type 13) 2) metastatic castration-resistant prostate cancer - defects in androgen receptor (AR) - the mutated receptor stimulates prostate growth & metastases despite androgen ablation [118] - TP53 [118,178] - less frequently BRAF, BRCA2, & BRCA1 [118] 3) defects in bcl-2 (HR=1.6) & p53 (HR=1.5) associated with increased risk of mortality [46] 4) associated with defects in KLF6 5) some genes found to be hypermethylated include: - cyclin dependent kinase inhibitor 2A (CDKN2A) - glutathione S transferase protein 1 (GSTP1) - estrogen receptor (ER) - CH1, INTS6, CD44, endothelin receptor (EDNRB) 6) EZH2 gene [10] a) increased expression in BPH & prostate cancer b) expression better clinical predictor than Gleason score 7) single nucleotide polymorphisms in 5 chromosomal regions, 3 at 8q24, 1 at 17q12, 1 at 17q24.3 confer higher risk [36] 8) androgen receptor splice variant 7 in circulating tumor cells associated with resistance to enzalutamide & abiraterone [111] 9) loss of NCOR2 expression may accelerate resistance to androgen deprivation therapy in prostate cancer [206] 10) other implicated genes - STAT3, NKX3.1, KLK3 [178] - REPS2, PBOV1, STEAP1, GPR148, UBIAD1, AGK, CSAG2, TAK1L, FAM48A, BCL9L, AFAP1, SRD5A3, XRRA1, GREB1, CTNNB1, CCNDBP1, DERPC, PEG10, NOX5, PCOTH, SLC5A8, MXI1, SLC43A1, OR51E1, OR51E2, EPHB2, PKN3, FOLH1, CDKN3, LGALS8, ECAC2, BIRC5, IRX5, PSCA, USP7, TNK2,, COL18A1, CD164, TBC1D3 Clinical manifestations: 1) generally asymptomatic 2) urinary obstruction a) may be rapid in onset b) urgency, frequency, hesitancy, nocturia c) more commonly associated with BPH 3) regional signs/symptoms: a) hematuria b) lower extremity edema 4) systemic signs/symptoms: a) bone pain or back pain secondary to spinal metastases b) weight loss c) weakness d) lymphadenopathy 5) digital rectal exam: a) prostate nodule b) induration c) enlargement d) may be normal e) abnormal digital rectal examination should prompt referral to urology for transrectal prostate biopsy even if serum PSA is normal [2] 6) unusual presentations a) hydronephrosis b) adenocarcinoma, primary unknown Laboratory: 1) prostate-specific antigen (PSA) a) abnormal is > 4 ng/mL b) may be abnormal in benign prostatic hypertrophy (BPH) & prostatitis c) normal in 40% of patients with prostate cancer d) > 10 ng/mL suggests prostate cancer vs prostatitis e) any increase in serum PSA after prostatectomy indicates active prostate cancer [2] f) a progressive increase in serum PSA after radiation therapy is needed for diagnosis of recurrence [2] g) urinary obstruction increases serum PSA regardless of cause [2] 2) prostatic acid phosphatase (PAP) - evaluation of non-localized disease 3) liver function tests (liver metastases) 4) transrectal biopsy or fine-needle aspiration (FNA) 5) prostate cancer pathology panel 6) Multigene Panels [75] a) microarray technology has identified 2 proteins which may play an important role; hepsin & pim-1 kinase [7] b) prostate cancer genotyping c) BRCA1/BRCA2 genotyping [2] - high risk disease, positive lymph nodes, or metastatic disease [2] d) Oncotype Dx for prostate cancer e) prostate cancer promoter methylation profiling f) 18-gene prostate cancer urine panel may reduce additional testing for high-grade cancer in patients undergoing PSA screening [221] 7) other markers: a) PI16 b) prostate cancer antigen 3 in feces c) P504S Ag in tissue d) HMW cytokeratin Ag in tissue 8) pathology reports - other nodules > 10 mm in prostate cancer - other nodule quadrant in prostate cancer - other nodule plane in prostate cancer 9) autoantibodies: KIAA1524 10) see ARUP consult [74] Special laboratory: - transrectal ultrasound a) evaluation of hypoechoic areas of prostate for biopsy b) not routinely indicated for diagnosis; biopsy still needed [2] c) ultrasound guided biopsy d) Gleason score determined from prostate biopsy Radiology: 1) in low risk prostate cancer, imaging studies not necessary* 2) bone scan - indications: - serum PSA >= 10 ng/mL; Gleason score >= 8; stage T3 or T4* - bone pain & diagnosis of prostate cancer has been established - NOT routinely indicated for follow-up [2] 3) magnetic resonance imaging (MRI) - multiparametric MRI with greater sensitivity than transrectal ultrasound guided biopsy (93% vs 48%) but lower specificity (41% vs. 96%) [114,144,166] - MRI prior to biopsy could avoid 27-30% of biopsies [144,166] - integrating MRI in prostate cancer screening can reduce unnecessary biopsies & overdiagnosis of insignificant prostate cancer [219] - in men with elevated serum PSA, MRI in combination with prostate biopsy diagnosed more cancers than either alone [183] 4) dexa-scan for bone mineral density with androgen deprivation therapy 5) PET-CT scan - PSMA is overexpressed on prostate cancer cells - PET-CT using PSMA allows tumor-specific imaging of the entire body [184] * imaging studies to assess regional lymph node involvement or metastases indicated only for men at high risk [2,126] Differential diagnosis: 1) prostatitis 2) benign prostatic hypertrophy (BPH) Complications: - disseminated intravascular coagulation - bony metastases, osteoblastic rather than osteolytic [37] - external beam radiotherapy or radium-223 - complications of androgen deprivation therapy (osteoporotic fracture) [213] - iron-deficiency anemia due to radiation proctitis from radiation therapy - metastases to brain - obesity associated with increased all-cause mortality, cardiovascular mortality, & possibly prostate cancer-specific mortality [188] - weight gain after prostate cancer diagnosis associated with increased prostate cancer-specific mortality [188] - 78% of men with metastatic prostate cancer die from it [202] - treatment-related complications: - at 12 years, risk of urinary or sexual complications is 7-fold greater after prostatectomy & nearly 3-fold greater after radiotherapy vs men without prostate cancer [227] Management: === localized disease (stages T1, T2, A2, B) === 1) observation (watchful waiting) vs active surveillance [52,55,115,129,135,175] a) low risk & life expectancy < 10 years b) low risk & life expectancy > 10 years 1] active surveillance with serum PSA every 3-6 months [133], digital rectal exam yearly & repeat prostate biopsy at 6-12 months & every 2-5 years thereafter [2,129,133,154,156] 2] compliance with active surveillance is low a] 31% guideline-concordant b] 31% concordant for PSA testing but not biopsy c] 16% concordant for biopsy but not PSA testing d] 22% discordant for both PSA testing & biopsy [146] 3] effect of compliance on clinical outcomes is unclear [146] 4] anxiety with active surveillance in ~1/3 of men after 1 year [173] c) outcomes of active surveillance as favorable in men older & older than 60 years of age [177] - active surveillance for low-risk prostate cancer appears similarly safe in Black & white men [195] - survival is no different in men with low-risk localized prostate cancer regardless of treatment (prostatectomy, radiation or active surveillance) [2] - 1/2 of patients managed with active surveillance maintained low-grade classification after 7 years, with prostate cancer mortality of 0.1% [222] d) Gleason score of 7 (3+4) or less [130,133,148,153] e) serum PSA < 10 ng/mL [148] - free PSA plays no role in active surveillance: prostate biopsy per protocol [2] f) if risk of mortality from prostate cancer is < risk of mortality from other causes, observation would seem appropriate g) patients in multidisciplinary clinics are more likely to opt for active surveillance [78] h) employ shared decision making i) low-risk prostate cancer has a favorable prognosis without treatment [163] j) high vegetable diet of no benefit for slowing progression in low-risk prostate cancer [164] k) Mediterranean diet may help slow or prevent progression of prostate cancer in men on active surveillance [198] 2) surgery for localized disease a) transurethral resection/incision of the prostate (TURP, TUIP) prostatectomy> b) urethral stents c) radical prostatectomy - slightly better outcomes than observation [22] - reduces bone metastases but not all cause or prostate cancer-specific mortality [76] d) reserved for patients with life-expectancy > 10 years e) survival in early prostate cancer favors prostatectomy over watchful waiting [60] - diminishes risk of death from prostate cancer [60] a] 15% vs 21% mortality after 15 years b] 18% vs 29% after 18 years f) surgery is not associated with diminished mortality vs observation in patients with localized prostate cancer [150] - surgery is associated with more adverse effects, but less treatment for disease progression, mostly asymptomatic, local, or biochemical progression [150] g) benefit of prostatectomy vs active surveillance highly dependent on baseline risk, NNT=8 for localized prostate cancer [172] h) radical prostatectomy holds a cancer-specific mortality advantage over external beam radiation therapy in high-risk localized prostate cancer [207] i) prostatectomy associated with urinary incontinence & erectile dysfunction [2] 3) radiation therapy / brachytherapy a) poor surgical candidates b) high-grade malignancy c) best results when used in combination with androgen antagonist [47] starting 2 months prior to radiation, 4 months duration [64] - 6-12 monnths of androgen deprivation therapy after radiation [224] d) hormonal therapy not recommended for low-risk patients (localized disease with Gleason score < 8) [2] e) intensity-modulated radiation therapy provides some benefits versus conformal radiation therapy or proton therapy [71] f) proton beam radiotherapy not recommended [2] g) radiation therapy associated with short-term risk for enteritis radiation proctitis & cystitis & long-term risk of erectile dysfunction [2] h) low-dose brachytherapy associated with increase risk of secondary pelvic cancer (bladder cancer, rectal cancer) 6.4% at 15 years 7 9.8% at 20 years vs 3.2% & 4.2% after prostatectomy [220] - overall risk of any secondary cancer not higher for brachytherapy 4) stereotactic ablative radiotherapy may benefit limited metastatic (oligometastatic) prostate cancer [185] 5) focal ablative therapy may benefit elderly who wish to avoid complications from radical intervention [215] a) high-intensity focal ultrasound [70,161,189] b) cryotherapy/cryoablation: new therapy, long term result? [14,197] c) 5-year failure-free survival higher with radical intervention ((96% vs 82%) but 5-year survival for focal ablative therapy is 96% [215] 6) surgery &/or radiation may benefit elderly (> 75) [28] 7) see prostate cancer outcomes 8) dutasteride lowers risk for disease progression [67] 9) specialist visits strongly influence prostate cancer treatment choices [56] a) specialists tend to recommend treatment that they deliver b) men seen by primary care providers were more likely to be observed rather than treated [56] 10) men age >= 60 years with 3 or more comorbidities may not benefit from treatment [85] 11) individualize therapy for older men [103] 12) androgen deprivation therapy for stage T1-T2 prostate cancer does not confer 15 year survival benefit [109,110] 13) androgen deprivation therapy for localized prostate cancer in men with multiple comorbidities is associated with increased mortality [121] 14) apalutamide (Erleada) FDA-approved for non-metastatic, castration-resistant prostate cancer [158] 15) enzalutamide & darolutamide also FDA-approved for non-metastatic, castration-resistant prostate cancer [191] 16) 13% of men surveyed experienced treatment-related regret - 16% of men who opted for prostectomy regretted their decision - 11% of men who opted for radiotherapy regretted their decision - 7% who chose active surveillance regretted their decision [205] === regional involvement or metastatic disease === 1) hormonal therapy (androgen deprivation therapy) a) bilateral orchiectomy (cost-effective, rapidly-acting) [2] b) intermittent vs continuous androgen deprivation - continuous androgen deprivation may improve outcomes in patients with metatatic disease relative to intermittent androgen deprivation [73] - intermittent androgen deprivation of no benefit [84] c) pharmacologic agents 1] LHRH agonist with or without androgen antagonist [2] a] starting LHRH agonist can cause a tumor flare & clinical worsening b] flare can be attenuated with androgen antagonist c] first line therapy 2] GnRH analogues (LHRH agonist) a] use in conjunction with androgen antagonists begun several days earlier# b] goserelin (Zoladex) c] leuprolide (Lupron) d] buserelin e] histrelin f] triptorelin 3] defarelix (GnRH antagonist) 4] abiraterone actetate in combination with prednisone or prednisolone & androgen deprivation therapy - abiraterone actetate blocks androgen synthesis [149] 5] diethylstilbestrol 6] agents that suppress adrenal androgen production [37] a] ketoconazole b] aminiglutethimide d) as effective as bilateral orchiectomy in reducing serum testosterone, but NOT curative e) duration of therapy (in combination with radiation): 3 years better than 6 months [47] f) increases 5 year risk of cardiovascular death (5.5% vs 2.0%) [35] g) increased mortality in men with heart failure due to CAD or history of MI [50] h) docetaxel with androgen-deprivation therapy results in longer survival in men with metastatic prostate cancer [99,120] - LHRH agonist with androgen antagonist (androgen-deprivation therapy) plus docetaxel ([2] i) supplemental calcium & vitamin D j) bisphosphonates 1] may reduce osteoporosis, fractures 2] do not increase survival, slow disease progression, improve quality of life, diminish pain [2] k) denosumab may be more effective than zoledronate in preventing complications from bone metastases [123] l) androgen deprivation therapy is associated with - osteoporosis - possibile increased cardiovascular risk - increased risk for venous thromboembolism [2] 2) androgen antagonists may be used in combination with androgen deprivation therapy a) bicalutamide (Casodex) b) flutamide (Eulexin) c) nilutamide d) apalutamide (Erleada) e) enzalutamide for androgen deprivation therapy failure (see Prevail trial, NICE) [125] 3) surgery a) radical prostatectomy Plus combined (GnRH agonist plus antiandrogen) therapy for 2 years [63] b) robotic surgery associated with a higher rate of urinary incontinence than radical prostatectomy [68] c) radical prostatectomy no better than observation for localized prostate cancer in men >= 65 years of age [60,76] d) relative contraindications for radical prostatectomy 1] extension of malignancy outside the prostate 2] serum PSA > 20 ng/mL [60] 3] Gleason score >= 8 [2,60] 4) radiation therapy [25] a) preferred modality for stage T3 (C) b) impotence is less frequent than with surgery c) men with positive surgical margins benefit most [34,49] d) a 6 month course of androgen-deprivation therapy prior to radiation therapy improves mortality by 50% in men with locally-advanced prostate cancer [57] **** [2]) e) does not improve survival or distant metastases after radical prostatectomy in patients with T3 disease or positive surgical margins [80] f) early salvage radiotherapy after prostatectomy for high-risk cancer [194] g) external beam radiotherapy for localized painful bone metastasis [2,112] - not needed in the absence of neurologic deficits or pain [2] h) IV radium-223 for multiple painful bone metastases (see bone metastases) - bone-targeted alpha-emitting radiation may improve survival in metastatic castrate-resistant prostate cancer [180] - beta-emitting radiation not as helpful - intensification with higher dose or prolonged radium-223 of no benefit & is associated with increased harm [181] i) radiation therapy for prostate cancer results in small increase in risk for bladder cancer & colorectal cancer [131] j) increased short-term risk for cystitis & enteritis & long-term risk for erectile dysfunction [2] 5) high-intensity focal ultrasound [70,161,189] 6) surgery vs radiation vs observation for localized prostate cancer (2-3 year outcomes) [145] a) androgen deprivation therapy + external beam radiotherapy + brachytherapy or radical prostatectomy for Gleason score 9-10 [168] b) radical prostatectomy & radiation therapy (external beam or brachytherapy) associated with with worse sexual dysfunction relative to observation [145] c) radical prostatectomy associated with more sexual dysfunction & urinary incontinence than observation, but less dysuria [145] d) external beam radiotherapy associated with bowel symptoms & with short-term worsening of urinary obstruction & irritation [145] e) ultra-high single-dose radiotherapy is an alternative to curative extreme hypofractionated stereotactic body radiotherapy in organ-confined prostate cancer [200] f) brachytherapy associated with short-term worsening of urinary obstruction & irritation [145] g) 10 year outcomes for brachytherapy compares favorably to surgery & external beam radiation therapy [182] 7) chemotherapy (androgen-independent metastatic disease) a) continue androgen-deprivation therapy indefinitely [112] b) docetaxel 36 mg/m2 IV weekly for 4 weeks, with or without calcitriol 45 mg PO 1 day prior to docetaxel (androgen-independent prostate cancer) [29] c) docetaxel + prednisone every 3 weeks (androgen-independent prostate cancer) [38,112] d) no benefit from addition of carboplatin to docetaxel - combination results in more toxicity [192] e) cabazitaxel + prednisone f) no benefit of chemotherapy in addition to androgen deprivation prior to androgen-independence [44,82] g) inhibition of CYP17 with abiraterone acetate +/- dexamethasone or predisone may be useful in treatment of castration-resistant prostate cancer [51,53,112] h) cabozantinib shows promise in clinical trial [83] i) enzalutamide (androgen receptor antagonist) for metastatic castration-sensitive [179] & castration-resistant prostate cancer [167] - prior to chemotherapy may be useful [108] (Pevail trial) - reduces risk of radiographic progression or death [159] j) apalutamide (Erleada) or abiraterone may be also be used with androgen-deprivation therapy rather than enzalutamide - increased risk of cardiovascular events when androgen receptor antagonist used in combination with conventional androgen deprivation therapy [223] k) PARP inhibitor may be of benefit [197] - FDA has approved 2 PARP inhibitors for androgen-independent metastatic prostate cancer (rucaparib & olaparib) [199] - olaparib may benefit 1/3 of patients with metastatic androgen-insensitive prostate cancer (median overall survival of 10.1 months) [128, 186] - benefit for patients with BRCA1, BRCA2, or ATM aberrations [190] k) abiraterone + glucocorticoid after failed androgen deprivation therapy, before chemotherapy (NICE) 8) Astenar in phase 3 clinical trials 9) GM-CSF secreting allogeneic irradiated prostate cancer cell lines may be of some benefit [33] 10) sipuleucel-T (Provenge) immunotherapy for metastatic disease 11) 5-alpha reductase inhibitors may reduce prostate cancer mortality in men with prostate cancer [110]; not so (MKSAP19) [2] === follow-up including relapse === 1) serum PSA & digital rectal exam every 6-12 months - serum PSA every 6 months for 1st 5 years, then annually [107] 2) bone scan yearly (only if specifically indicated by clinical signs & symptoms) [2] 3) evaluation for complications of prostatectomy or radiation - patients with radiation treatment may be at increased risk for bladder cancer & colorectal cancer & may need to screening as high-risk patients [107] 4) androgen deprivation therapy increases risks for - osteoporosis - bone mineral density (DEXA) assessment [2] - bisphosphonate therapy for osteoporosis [54] - no evidence for routine administration of zoledronate [104] - zoledronate & denosumab reduce bone loss & risk of fractures due to androgen deprivation therapy [2] - vitamin D & calcium [2] - anemia - complete blood count annually [107] 5) relapse confined to elevated serum PSA without other signs of cancer recurrence - androgen deprivation therapy if serum PSA doubling time is < 10 months [2,127] - no harm in delaying androgen deprivation therapy until other signs or symptoms of local recurrence or metastases [105] - if already on androgen deprivation therapy, add androgen receptor blocker (apalutamide or enzalutamide) 6) assess for erectile dysfunction [107] using validated tools 7) manage cardiovascular risk, includin dyslipidemia & hypertension [2] === prognosis === 1) factors associated with progression of disease include: - younger age - higher clinical stage - higher Gleason score - 36 month cancer-specific mortality for Gleason score = 6 higher in blacks than non-blacks (0.4% vs 0.22%) [174] - higher serum PSA at diagnosis - smoking increases disease-specific mortality [62,132] 2) average duration of survival in patients with metastatic disease is 2-3 years - 32% of deaths 2-5 years after diagnosis; 9% > 5 years after diagnosis [201] - 78% of deaths from prostate cancer, 5.5% from other cancers [201] - 17% of deaths from noncancer causes, including cardiovascular diseases, COPD, & cerebrovascular diseases [201] - in cases of multiple comorbidities, the time horizon for benefit from additional treatment (chemotherapy) is most useful to patients [135] - 50% survival with hormone-sensitive metastatic prostate cancer [225] - ~75 months 70-74 years, ~63 months 75-79 years, ~55 months >= 80 years - 50% survival with hormone-resistant metastatic prostate cancer [225] - ~49 months 70-74 years, ~38 months 75-79 years, ~36 months >= 80 years 3) prognosis better for those with PSA < 4 ng/mL & even better for those with PSA < 0.2 ng/mL after androgen deprivation therapy [24] 4) survival in localized prostate cancer - 99% 10 year survival with or without treatment [141] - 20 year mortality for untreated local disease is ~ 15% [16] - surgery or radiotherapy associated with lower 10-year disease progression (9 vs 23 per 1000 person-years) & metastatic disease (2-3 vs 6 per 1000 person-years) [141] 5) older patients with localized disease unlikely to die as a result of prostate cancer; mortality is dependent on comorbidities [59,79] 6) mortality lower with anticoagulant (enoxaparin, warfarin) or antiplatelet agent (aspirin, clopidorel) use [77] 7) mortality lower when statin used with androgen deprivation therapy in patients with advanced prostate cancer (27% lower overall mortality & 35% lower prostate cancer-specific mortality) [211] 8) erectile dysfunction is common 2 years after treatment - 37% of all patients & 48% of those with functional erections before treatment [65] 9) a healthy diet reduces risk of disease progression [226] - study underway to examine effect of diet on survival in active surveillance patients with prostate cancer [160] 10) high-intensity interval training aerobic exercise improved cardiorespiratory fitness & suppressed prostate cancer progression in a phase 2 trial in patients with very low risk to favorable intermediate risk prostate cancer [203] 11) quality of life diminished by active treatment of localized disease [193] === prophylaxis & screening === 1) finasteride & 5-alpha reductase inhibitors in general may decrease risk of prostate cancer without paraxodical excess of high-grade tumors [41,162] a) see finasteride prophylaxis study & ref [41] b) number needed to treat: 71 men for up to 7 years to prevent one case of prostate cancer [48] c) no increase in life expectancy demonstrated for prophylaxis in men without prostate cancer [2,97,210] 2) role of diet uncertain a) lycopenes in tomatoes may have some benefit [119] b) pumpkin seeds have been claimed to have benefit c) foods rich in boron may provide protective effect [12] d) resveratrol in red wine may reduce risk [17] e) green tea may be prophylactic [19] f) isothiocyanates & curcumin may have some benefit g) cruciferous vegetables & to a lesser extent spinach may diminish risk of extra-prostatic disease [32] h) no significant associations between fruit & vegetable consumption (including cruciferous vegetables) & prostate cancer risk [165] i) 20 grams of soy protein/day of no benefit in preventing recurrence of locally-advanced prostate cancer [94] j) vitamin E 400 IU/day, vitamin C 500 mg/day, or selenium 200 ug/day (as selenomethionine) of no benefit [43] - men with higher baseline selenium levels show increased risk of prostate cancer with selenium supplementation [100] - men with lower baseline selenium show increased risk of prostate cancer with vitamin E supplementation [100] 3) NSAIDS may reduce risk [20] - low-dose aspirin does not improve survival in men with prostate cancer [176] 4) statins - may reduce risk of metastatic, but not localized prostate cancer [21] - post-diagnosis statin may reduce risk of prostate cancer- specific mortality (RR=0.81) & all-cause mortality (RR=0.85) [152] - benefit may be restricted to men on androgen-deprivation therapy [152] 5) increased frequency of ejaculation may diminish risk [13,117] 6) smoking cessation may diminish prostate-specific mortality [132] 7) screening: see screening for prostate cancer === Investigational === - inhibition of CYP11A1 may improve survival in castration-resistant prostate cancer [218] * aggressive surgery is sometimes used for stage T3 (C) disease # may be no benefit to combined GnRH analogue/androgen antagonist therapy [6] Comparative biology: - lower levels of androgen in mice after castration result in an increase in production of androgen by intestinal bacteria [204] Notes: 1) overscreening & overtreatment of elderly men common [61] 2) advanced treatment technologies for prostate cancer common among men who are least likely to benefit [86]

Interactions

disease interactions

Related

benign prostatic hyperplasia (BPH) Gleason scoring system for prostate cancer prostate prostate cancer outcomes screening for prostate cancer staging of prostate cancer

Specific

androgen-independent prostate cancer; castration resistant prostate cancer (CRPC) prostate adenocarcinoma

General

malignant neoplasm of male genital organ prostatic neoplasm

References

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