84 William G. Nelson, H. Ballentine Carter, Theodore L. DeWeese, Emmanuel S. Antonarakis, and Mario A. Eisenberger

SUMMARY OF KEY POINTS Incidence Screening, Diagnosis, and treated with external • Prostate cancer is the most Staging beam . commonly diagnosed life-threatening • Prostate cancer screening using • Adjuvant external radiation improves cancer in men (241,740 cases and specific antigen (PSA) testing survival for some men treated with 28,170 deaths in 2012). reduces the risk of prostate cancer radical . • Small prostate are present death but may also lead to Treatment of Advanced Disease in 29% of men between ages 30 and overdiagnosis of non-life-threatening • Androgen suppression, most often 40 and 64% of men between ages disease. accomplished via the use of 60 and 70. • Transrectal ultrasound (TRUS)- luteinizing hormone–releasing • The lifetime risk of a prostate cancer guided core needle are hormone (LHRH) analogs or diagnosis is 1 in 6, and the risk of used to diagnose prostate cancer. antagonists, with or without dying from prostate cancer is 1 in • Stage, histologic grade (Gleason antiandrogens, is the most 35. score), and serum PSA levels are commonly used treatment. • Age, family history, diet and lifestyle, prognostic factors. • Side effects can include loss of and ethnicity are risk factors for Primary Therapy libido, hot flashes, gynecomastia, prostate cancer development. • Management options include loss of lean muscle mass and Biological Characteristics observational strategies (watchful density, and the development of • Germline mutations in RNASEL and waiting and active surveillance), metabolic syndrome. MSR1, encoding proteins that anatomic radical prostatectomy (with • Docetaxel and cabazitaxel function in host responses to or without robot-assisted improves the survival infection, appear responsible for laparoscopic techniques), external of men with progressive androgen- some cases of hereditary prostate beam radiation therapy, and independent prostate cancer. cancer. . • Second-line treatments targeting the • An inflammatory lesion, termed • A progressive rise in the serum PSA androgen-signaling pathway, proliferative inflammatory atrophy after treatment indicates prostate including abiraterone acetate and (PIA), is an early precursor to cancer recurrence. enzalutamide, prolong survival of prostate cancer. • Depending on the approach used, men previously treated with • Somatic inactivation of GSTP1, side effects associated with androgen suppression and taxane encoding a -detoxification treatment of localized prostate chemotherapy. enzyme, may initiate prostatic cancer can include urinary, bowel, • Bisphosphonates and denosumab by increasing the and sexual dysfunction. antagonize loss of bone density vulnerability of prostate cells to • Salvage therapy for prostate cancer accompanying androgen deprivation, damage mediated by oxidant and recurrences after initial treatment and reduce skeletal complications electrophilic . include external radiation after associated with metastatic prostate • Gene fusions, involving TMPRSS2 , or include surgery, cancer progression. and ETS family transcription factor brachytherapy, or cryosurgery after • Sipuleucel-T, a dendritic cell vaccine, genes, may contribute to the external beam radiation. has shown a survival benefit in men androgen dependence of prostate Adjuvant Therapy with advanced prostate cancer. Other immunotherapies are under cancers. • Adjuvant androgen suppression can development in clinical trials. • Defects in the functions of NKX3.1, improve survival for some men with PTEN, and CDKN1B are common in prostate cancer cells.

1463 1464 Part III: Specific Malignancies

INTRODUCTION the pelvis, the prostate sits adjacent to the bladder and , is surrounded incompletely by a thin capsule composed of collagen, In 2012, an estimated 241,740 prostate cancer diagnoses will be elastin, and smooth muscle, and at the apex of the gland, forms part made in the United States, accompanied by an estimated 28,170 of the urethral sphincter apparatus.4 Nerves to the corpora cavernosa prostate cancer deaths.1 Beginning around 1994-1996, with wide- of the penis, needed for penile erection, travel through fascia along spread use of serum prostate-specific antigen (PSA) testing and digital the posterolateral surface of the prostate. These nerves can be recog- (DRE) for prostate cancer screening, and with nized as a neurovascular bundle by urologists and preserved during increased treatment of clinically localized prostate cancer with surgery radical prostatectomy to minimize sexual dysfunction postopera- or radiation therapy, age-adjusted prostate cancer death rates have tively.5,6 The prostate parenchyma has been divided into three zones fallen steadily. Although this trend might indicate a beneficial impact that can be seen by transrectal ultrasonography, and recognized of prostate cancer screening and/or early prostate cancer treatment readilyy b surgical pathologists examining radical prostatectomy on prostate cancer mortality, mass screening of the general population specimens: a central zone, surrounding the ejaculatory ducts and for prostate cancer remains controversial.2 One challenge for prostate accounting for some 25% of the prostate; a transition zone, near the cancer screening is the prevalence of the disease in the United States: prostatic urethra with 10% of prostate tissue normally; and a periph- autopsy series have revealed small prostate cancers in as many as 29% eral zone, with the bulk of prostate tissue encompassing the postero- of men between ages 30 and 40 and 64% of men between ages 60 lateral region of the prostate (Figure 84-2).7,8 and 70.3 Obviously, not all of these men are at risk for symptomatic In addition to prostate cancer, the prostate also frequently mani- or life-threatening prostate cancer progression. In fact, many such fests benign enlargement (benign prostatic or BPH) and men, if diagnosed with prostate cancer, may be at greater risk for chronic or recurrent inflammation (). Like prostate cancer, treatment-associated morbidity. each of these conditions can elevate the PSA, confounding the use of Currently, for U.S. men, the lifetime risk of a diagnosis of prostate serum PSA testing for prostate cancer screening. When present, BPH cancer is about 1 in 6, whereas the lifetime risk of death from prostate tends to be located near the prostatic urethra (in the transition zone), cancer is on the order of 1 in 35.1 Over the past two decades, treat- whereas prostate cancer and the prostate cancer precursor lesions ment approaches for men with prostate cancer have changed dramati- proliferative inflammatory atrophy (PIA) and prostatic intraepithelial cally, with improvement in established prostate cancer treatments and neoplasia (PIN) usually arise in the periphery (the peripheral zone). the introduction of new prostate cancer treatment approaches. Now, Prostatic inflammation, though often prominent in the peripheral men diagnosed with prostate cancer often face a bewildering array of zone, can be seen throughout the prostate. Remarkably, although treatment choices. Clearly, the that care for these men prostate cancer, BPH, and prostatitis all commonly afflict U.S. men, must weigh the risks of prostate cancer progression against the poten- and can be simultaneously present in a single prostate gland, mecha- tial for side effects from treatment, in the context of other health risks nistic associations of the three diseases have been difficult to and life choices, to best use the current collection of treatments for demonstrate. the greatest benefit. The prostate requires androgenic hormones, and an intact andro- To aid physicians who care for men with prostate cancer, this gen receptor, for normal growth and development. In the prostate, chapter will provide an overview of prostate cancer etiology, biology, the major circulating androgenic hormone, testosterone, produced by screening, detection, diagnosis, prevention, and treatment. Leydig cells in the testes upon stimulation by luteinizing hormone (LH), is converted by 5α-reductase (nicotinamide-adenine dinucleo- 4 PROSTATE ANATOMY AND FUNCTION tide phosphate-dependent δ -3-ketosteroid 5α-oxidoreductase) to 5α-dihydrotestosterone (DHT).9 ,eDHT a mor potent androgen than The prostate is a male sex accessory gland that surrounds the urethra testosterone, binds to intracellular androgen receptors, alters andro- and contributes secretions to the ejaculate (Figure 84-1). Located in gen receptor conformation to promote dissociation from chaperone

Dorsal v. complex Seminal vesicle Symph.

Striated Bladder urethral Prostate Ureter sphincter

Urethral lumen

Rectum Left neurovascular bundle

Pelvic plexus Figure 84-1 • The anatomy of the prostate: rectum, bladder, dorsal vein complex, striated urethral sphincter, pelvic plexus, and neurovascular bundle. Prostate Cancer • CHAPTER 84 1465

Transition zone

Central zone

Anterior fibromuscular stroma Figure 84-2 • Zones of the prostate. The peripheral zone, accounting for 70% of the prostate gland, is the site of origin of ≥70% of prostate cancers; the central zone, approximately 25% of the prostate gland, gives rise to only 1% to 5% of prostate cancers; and the transition zone, ~5% to 10% of the prostate gland, gives rise to Peripheral zone 20% of prostate cancers and is the site of origin of benign prostatic hyperplasia (BPH). (From Green DR, Shabsign R, Scardino PT. Urological ultrasonography. In: Walsh PC, Rettic AB, Stamey CA, Vaughan ED Jr, editors. Campbels’s Textbook of . 6th ed. Philadelphia: Saunders; 1992.)

Glandular Secretory lumen cell Epithelial Golgi Secretory Epithelial compartment Microvilliaparatus granule compartment Desmosome

Smooth Nerve Basal Fibroblast Capillary Basement Neuroendocrine muscle cell terminals cell membrane cell Figure 84-3 • The prostate epithelium. proteins, triggers androgen receptor dimerization and transport into androgen receptor, PSA, cytokeratins K8 and K18, prostate-specific the cell nucleus, and activates the expression of selected target genes.10 membrane antigen (PSMA), and prostate-specific acid phosphatase Stereotypically, androgen receptor target genes are characterized by (PAP); and rare neuroendocrine cells, that secrete chromogranin A, the presence of androgen response element (ARE) DNA sequences neuron-specific enolase, and synaptophysin (Figure 84-3).13 The basal within the transcriptional regulatory region, permitting direct binding epithelial cell compartment likely contains pluripotent prostatic stem and trans-activationy b the androgen receptor.11 For genes like KLK3 cells, capable of self-renewal proliferation and of differentiation. In (encoding PSA), which are activated by the androgen receptor selec- contrast, columnar secretory cells, specialized to produce secretions tively in prostate cells, and not in cells of other tissues, the transcrip- for the ejaculate, are terminally differentiated, particularly under the tional regulatory region also contains additional DNA sequences influence of androgenic hormones. The prostate epithelium is in turn (prostate-specific enhancer or PSE) conferring prostate-specific supportedy b a stroma containing fibroblasts, smooth muscle cells, expression.12 nerves, and blood vessels. Stromal cells, which also express the andro- The normal prostate epithelium is composed of basal epithelial gen receptor, secrete polypeptide growth factors, such as keratinocyte cells, characterized by the expression of cytokeratins K5 and K14, growth factor (KGF), that contribute to the regulation of epithelial and p63, columnar secretory epithelial cells, which express the homeostasis via a paracrine signaling mechanism.14,15 Abnormal 1466 Part III: Specific Malignancies

stromal–epithelial interactions, with disordered regulation of epithe- scavenger receptor capable of binding bacterial lipopolysaccharide lial cell proliferation and differentiation, may contribute to the patho- and lipoteichoic acid, and oxidized high and low density serum lipo- genesis of both prostate cancer and BPH.16 proteins (oxidized HDL and LDL).29 For both RNASEL and MSR1, Prostate cancer cells, and PIN cells, arise from the prostatic epi- note only hav mutations been linked to prostate cancer susceptibility thelium. Even though transformed, such cells typically retain many in families but variant alleles have been predicted to account for as of the phenotypic attributes characteristic of differentiated columnar many as 13% and 3% of sporadic prostate cancer cases, respec- secretory cells, including the expression of androgen receptor, PSA, tively.27,30,31 The identification of RNASEL and MSR1 as candidate PSMA, and PAP. Prostate cancers reminiscent of basal epithelial cells prostate cancer susceptibility genes has intensified interest in the pos- are exceptionally rare; prostate cancers with features of neuroendo- sibility that infection and/or inflammation might contribute to the crinee cells ar somewhat more common.17 However, unlike normal pathogenesis of human prostate cancer. In mice, targeted disruption columnar epithelial cells, neoplastic prostate epithelial cells are of RnaseL leads to diminished interferon-α activity and increased capable of proliferation. This has led to the concept that the target susceptibility to viral infection,32 whereas targeted disruption of cell for neoplastic transformation in the prostate may be an “inter- Msr-A leads to increased vulnerability to infection with Listeria mono- mediate” cell, in transit from a basal epithelial stem cell to a differenti- cytogenes, Staphylococcus aureus, Escherichia coli, and Herpes simplex ated columnar secretory epithelial cell, with properties of both stem virus type 1.29,33-35 Further genetic support for this etiologic mecha- cells and differentiated cells.18,19 Another feature of neoplastic prostate nism has come from analyses of common variants of other genes epithelial cells, as compared with normal basal or columnar secretory encoding participants in host inflammatory responses, including cells, is that the neoplastic cells appear to use androgen receptor TLR4 and other members of toll-like receptor signaling pathways, signaling not only for differentiation, but also for proliferation, as MIC-1, IL1-RN, and COX-2,e hav also been associated with prostate most prostate cancer cells tend, at least initially, to display some cancer risk.36-40 dependence on androgens for maintenance of growth and survival. An increased risk for prostate cancer has long been known for men Somatic fusions between an androgen-regulated gene, TMPRSS2, at in breast cancer families carrying BRCA2 mutations, characterized by chromosome 21q22, and genes encoding members of the ETS family disease with an aggressive natural history arising before age 55 years.41 of transcription factors, commonly found in prostate cancers, may Nonetheless, a role for BRCA2 genotyping in general prostate cancer provide a mechanistic explanation by which androgen signaling can practice has not been established. However, as evidence has accumu- promote prostate growth.20,21 Ultimately, in life-threatening lated that several additional germline DNA sequence variants may be prostate cancer, prostate cancer cells escape from the prostate gland, associated with prostate cancer, the possibility that genetic testing proliferate in lymph nodes, in , and in other organs and become might be used to aid in prostate cancer screening, detection, diagnosis, less and less dependent on androgenic hormones. or risk stratification has emerged. In one analysis, five such sequence variants, three single nucleotide polymorphisms (SNPs) at 8q24 and one each at 17q12 and 17q24.3, were found to have a marked asso- GENETICS AND EPIDEMIOLOGY ciation with prostate cancer, especially for men with a family history Genetic Predisposition to Prostate Cancer of the disease, showing a 9.46-fold increased risk (with 95% confi- dence interval of 3.62 to 24.72) for a prostate cancer diagnosis.42 Familial clusters of prostate cancer have been recognized since at least 1956, when Morganti et al. reported that men with prostate cancer Epidemiology of Prostate Cancer weree mor likely to have relatives with prostate cancer than men without a prostate cancer diagnosis.22 nI a study conducted more than Accumulated epidemiological evidence implicates the environment three decades later, when detailed family histories were collected from as the major contributor to the development of most prostate cancers. men with prostate cancer and their spouses, the men with prostate Prostate cancer incidence and mortality display wide geographic cancer were more likely to have a brother or father with prostate variation, with high rates of prostate cancer incidence and mortality cancer.23 Twin studies, comparing the tendency for concordant pros- in the United States and Western Europe, and low prostate cancer tate cancer development between monozygotic twins, sharing all of riske mor characteristic of Asia.43 African Americans in the United their genes, and dizygotic twins, sharing half of their genes, have also Statese hav very high prostate cancer risk.44 The geographic variation hinted at a significant contribution of hereditary to prostate cancer: in prostate cancer incidence and mortality can best be explained by in a study of 44,788 pairs of twins in Sweden, Denmark, and lifestyle influences, because Asian immigrants to North America typi- Finland,24 42% of the prostate cancer cases (with a 95% confidence cally adopt a higher prostate cancer risk.45-47 interval of 29% to 50%) were attributed to heredity. In principle, The key aspect of lifestyle in the United States most likely respon- familial clustering of prostate cancer cases could be a result of inher- sible for high prostate cancer incidence and mortality is the diet, ited susceptibility genes, shared exposure to carcinogenic stresses, or generally rich in animal fats and meats and poor in fruits and vege- tot some sor of detection or diagnosis bias (e.g., the brother of a man tables.n I the Health Professions Follow-up Study, a prospective diagnosed with prostate cancer may be more likely to pursue screen- cohort study involving 51,529 men, total fat intake, animal fat ing for prostate cancer). To discover the genetic contributions to intake, and consumption of red meats were associated with increased prostate cancer in spite of these potential sources of bias, both linkage risks of prostate cancer development.48 Red meat consumption was analyses of genetic loci in high-risk prostate cancer families and similarly correlated with prostate cancer risks in the Physicians Health genomewide association studies (GWAS) of prostate cancer suscepti- Study49 and in a large cohort study in Hawaii.50 The cooking of red bility in large populations have been conducted. Each approach has meats at high temperatures, or on charcoal grills, is known to lead to generated a number of candidate genes or gene regions (as many as the formation of both heterocyclic aromatic amine and polycyclic 30 or more), with several in common, confirming the contribution aromatic hydrocarbon carcinogens.51,52 Ingestion of 2-amino-1- of heredity to prostate cancer risk but underscoring the complexity methyl-6-phenylimidazopyridine (PhIP), one of the heterocyclic of inherited prostate cancer susceptibility.25 amine carcinogens that appear in “well-done” red meats, leads to Among the growing number of prostate cancer susceptibility prostate cancer in rats.53 Consumption of dairy products also appears genes discovered by mapping studies are RNASEL and MSR1.26,27 to increase prostate cancer risk, an effect that may be more attribut- RNASEL encodes a latent endoribonuclease component of an able to calcium intake than to dietary fat or protein.54 nI contrast, interferon-inducible 2’,5’-oligoadenylate-dependent RNA decay adequate consumption of vegetables and antioxidant micronutrients pathway that functions to degrade viral and cellular RNA upon viral is accompanied by reduced prostate cancer risk. Consumption of infection.28 MSR1 encodes subunits of a trimeric class A macrophage tomatoes, which contain lycopene, and of cruciferous vegetables, Prostate Cancer • CHAPTER 84 1467 which contain sulforaphane, may protect against prostate cancer Areas of the prostate, containing epithelial cells that do not fully dif- development.55,56 Antioxidant micronutrients, such as vitamin E and ferentiate into columnar secretory cells, have long been recognized as selenium, may reduce prostate cancer risk only when correcting focal atrophy lesions by prostate pathologists.58,67 IAThe term P has dietary deficiencies: a large trial (SELECT) of supplementation with been used to describe those focal atrophy lesions that contain prolif- vitamin E and selenium to prevent prostate cancer failed to show a erating epithelial cells, are associated with chronic inflammation, and benefit.57 are often located adjacent to PIN lesions and/or prostate cancers.68 The epithelial cells in PIA lesions typically express high levels of Prostate Inflammation and Prostate Cancer stress-response polypeptides such as GSTP1, GSTA1, and cyclooxy- genase 2 (COX-2). Loss of GSTP1 expression in rare PIA lesions, Chronic or recurrent inflammation is known to play a causative role attributable to de novo GSTP1 CpG island hypermethylation, may in the development of many human cancers, including cancers of the be what leads to the development of PIN and prostate cancer.69 liver, esophagus, stomach, large intestine, and bladder. Inflammatory The hypothesis that inflammation might promote prostate cancer changese hav been recognized in prostate tissues for many years, development offers new challenges to prostate cancer epidemiology, leading to speculation that inflammation might contribute in some to the search for prostate cancer susceptibility genes, and to the way to prostate cancer development.58 However, over the past few molecular pathogenesis of prostate cancer. Although prostatic inflam- years, evidence has accumulated in support of a more critical role for mation is common in regions of the world with high prostate cancer prostatic inflammation in the pathogenesis of prostate cancer. Inflam- risks, whether regions of the world with low prostate cancer risks have matory changes are present in almost all radical prostatectomy speci- less prostatic inflammation has not been determined. Provocative new mens from men with prostate cancer. Because inflammation in the data hint that PIA lesions appear to be more common in the prostate prostate is not usually associated with symptoms, the prevalence of peripheral zone in men from high-risk prostate cancer regions than prostate inflammation is not known, and the association with pros- in men from low-risk prostate cancer regions. To better test the asso- tate cancer has been difficult to test.59,60 A syndrome of irritative ciation of prostate inflammation and prostate cancer, perhaps new voiding symptoms and pelvic pain, perhaps attributable to inflam- biomarkers of prostate inflammation, assayable in blood, urine, or mation near the prostatic urethra, is reported by some 9% or more prostate fluid, can be developed for use in epidemiology studies. of men between 40 and 79 years of age, with as many as 50% of such In addition, polymorphic genes encoding regulators of immune men suffering more than one episode by age 80 years.61 Most episodes responses will likely need to be systematically evaluated for prostate of symptomatic prostatitis are not clearly attributable to specific cancer risk associations. Ultimately, if the hypothesis is correct, pros- infectious agents. Even so, sexually transmitted infections do appear tate cancer risks may be reduced by therapeutically attenuating pros- to increase prostate cancer risk.62,63 Nonetheless, if prostate infection tate inflammation. and inflammation lead to prostate cancer, the mechanism does not appear likely to involve direct transformation of prostate epithelial ETIOLOGICAL AND BIOLOGICAL cellsy b microbial DNA. Instead, the production of microbicidal CHARACTERISTICS oxidantsy b inflammatory cells, such as superoxide, nitric oxide, and peroxynitrite, may promote prostate cancer development by trigger- Somatic Genome Alterations in Prostate 64,65 ing cell and genome damage. Increased production of oxidants by Cancer Cells inflammatory cells in the prostate may be why decreased prostate cancer risk has been associated with intake of a variety of antioxidants Prostate cancer cells typically contain a plethora of somatic genome or of nonsteroidal antiinflammatory drugs, and why RNASEL and alterations, including gene mutations, gene deletions, gene amplifica- MSR1, two of the prostate cancer susceptibility genes identified thus tions, chromosomal rearrangements, and changes in DNA methyla- far, encode proteins that function in host responses to infections. tion (Figure 84-5). In the United States, prostate cancer diagnoses Despite these provocative hints, the contribution of prostate are typically made in men between 60 and 70 years of age, whereas inflammation to prostatic carcinogenesis has been difficult to assess. small prostate cancers have been detected at autopsy in nearly 30% However, in 1999, De Marzo et al. provided the most compelling of men between 30 and 40 years of age.3 Thus, the somatic genome linkage of prostate inflammation to prostate cancer by proposing that changes present in prostate cancers have often accumulated over a prostate lesion, termed proliferative inflammatory atrophy (PIA), many decades. The acquisition of somatic genome changes in the might be a precursor to PIN and to prostate cancer (Figure 84-4).66 prostate may be influenced by lifestyle as well: although small prostate

Normal Proliferative Prostatic Prostate prostate inflammatory intraepithelial cancer atrophy neoplasia Columnar cells

Basal cells

Figure 84-4 • Proliferative inflammatory atrophy (PIA) as a precursor to prostatic intraepithelial neoplasia Inflammatory (PIN) and prostate cancer. (Adapted from Nelson WG, cells DeMarzo AM, Isaacs WB: Prostate cancer. N Engl J Med 2003;349:366-381.) 1468 Part III: Specific Malignancies

Germ line mutations Normal RNASEL, MSR1, HOXB13 prostate epithelium Chromosome Proliferative 8q gain inflammatory Chromosome atrophy 8p loss GSTP1 CpG island Prostatic TMPRSS2-ETS family hypermethylation intraepithelial gene fusions neoplasia Loss of sequences Decrease in p27 10q, 13q, 16q Localized Decrease in NKX3.1 prostate Gains of sequences cancer at 7p, 7q, Xq

Loss of PTEN Metastatic prostate TP53 mutation cancer hAR gene mutation/ amplification Androgen independent cancer

Figure 84-5 • The molecular pathogenesis of prostate cancer.

cancerse hav been detected at autopsy in men from geographic dependence of prostate cancer cells on androgenic hormones for regions with low prostate cancer mortality, these small prostate growth and survival, as the expression of ETS family transcription cancerse ar usually only present in much older men.70-72 Also, in factors can be stimulated by androgen action. TMPRSS2-ERG fusions the United States, removed at radical prostatectomy for have been detected in ~60% of prostate cancers and in >20%IN of P prostate cancer usually contain more than one prostate cancer lesion lesions.81 ERG is highly expressed by many prostate cancers, and not (Figure 84-6). aty all b others, though neither ERG expression nor the presence of Over the years, several techniques have been used to catalog ERG fusion transcripts appears to have great prognostic significance.81-84 genome accidents in prostate cancer cells, including karyotyping, Nonetheless, the presence of TMPRSS2-ERG fusion transcripts does fluorescence in situ hybridization (FISH), comparative genome seem to define a molecular subset of prostate cancer. Rarer somatic hybridization, loss of heterozygosity analyses, and genomewide alterations, including SPOP mutations (6% to 15%) and SPINK1 microarray and/or sequencing approaches. In one such study, each overexpression (~10%), are restricted to cases devoid of TMPRSS2- prostate cancer case exhibited a mean of 3866 base mutations (range ETS family rearrangement rearrangements.85,86 3192 to 5865), 20 nonsilent coding sequence mutations (range 13 Hypermethylation of CpG island sequences encompassing the to 43), and 108 rearrangements (range 43 to 213).73 n,I another DNA regulatory region of GSTP1, encoding the π–class glutathione hypermethylation was found at 5408 regions of the genome, with S-transferase (GST) is the most common somatic genome change yet 73% of the regions near genes (5′, 3′, or intron–exon junctions), and reported for prostate cancer.87,88 sGST catalyze the detoxification of 27% of the regions at conserved intergenic sites.74 Often, these analy- carcinogens, and of other reactive chemical species, via conjugation ses reveal different chromosomal abnormalities in different cancer with the intracellular scavenger glutathione. In mice, targeted disrup- cases, in different cancer lesions in the same cancer case, and in dif- tion of π-class GST genes leads to increased skin tumors after treat- ferent areas within the same cancer lesion. The propensity to develop ment with the carcinogen 7,12-dimethylbenzanthracene (DMBA).90 such a heterogeneous collection of somatic genome lesions over so Similarly, human prostate cancer cells devoid of GSTP1 appear espe- many years, and in a manner so sensitive to environment and lifestyle, cially vulnerable to genome damage mediated by exposure to N-OH- suggests strongly that prostate cancers likely arise as a consequence PhIP, the charred meat carcinogen that causes prostate cancer when of either chronic or recurrent exposure to genome-damaging stresses, fed to rats, and by exposure to oxidant stresses.91 nI the normal pros- defective protection against genome damage, or some combination tate epithelium, GSTP1 is present at high levels in basal cells, and in of both processes. The resultant genomic instability may be the reason lower levels in columnar secretory cells, though the enzyme can be some prostate cancers progress to threaten life.75,76 induced in columnar epithelial cells subjected to genome-damaging One characteristic somatic genome alteration, a rearrangement, stresses.n I contrast, the enzyme is almost never present in prostate drives the production of fusion transcripts between an androgen- cancer cells. In nearly all cases, the absence of GSTP1 expression in regulated gene, TMPRSS2, at chromosome 21q22, and members of prostate cancer cells can be attributed to hypermethylation of GSTP1 theS ET family of transcription factors (Figure 84-7).20 tFusion par - CpG island sequences, a somatic genome change that prevents ners for TMPRSS2 include ERG (also at chromosome 21q22), ETV1 GSTP1 transcription. Absence of GSTP1 expression and GSTP1 (at chromosome 7p21), and ETV4 (at chromosome 17q21).20,77,78 CpG island hypermethylation may also be characteristic of cells com- The gene rearrangements may result from a mishap during the andro- prisingIN P lesions, thought to be precursors to prostate cancer.92 gen receptor transcriptional trans-activation of TMPRSS2 in which The mechanism by which hypermethylated GSTP1 CpG island tangling or untangling of DNA by TOP2B triggers DNA double- alleles arise during prostatic carcinogenesis remains to be elucidated. strand breaks that recombine with ETS family partner genes via Nonetheless, prostate cells carrying inactivated GSTP1 genes appear nonhomologous end-joining (Figure 84-8).79,80 The appearance of the toy enjo some sort of selective growth advantage early during the resultant fusion transcripts provides a plausible mechanism for the development of prostate cancer. Prostate Cancer • CHAPTER 84 1469

TMPRSS2 ERG 1 4 5-9 10 HERPUD1 ERG Transition 1 4 5–9 10 zone SLC45A3 ERG ERG 45% 1 4 5–9 10 NDRG1 ERG 1 4 5–9 10 TMPRSS2 ETV1 1 4 5–11 12 ETS ETV1 5% Peripheral SLC45A3 ETV1 zone 1 5 6–11 12 TMPRSS2 ETV4 1 1 2-12 13 ETV4 1%

TMPRSS2 ETV5 A 1 2 3 2 3-12 13 SLC45A3 ETV5 ETV5 1% 2 cm 1 8-12 13

ESRP1 CRAF 1 2–10 1112 13 6 7 8 9 10–16 17

RAF CRAF 1 2–45 14–15 16 RAF 1%

SLC45A3 1 8 9 10 11-17 18

SPINK1 SPINK1 8% SPOP Mutations SPOP 13%

Carcinoma Figure 84-7 • Fusion transcripts and other genetic alterations in prostate High-grade prostatic intraepithelial neoplasia cancers. The schematic shows gene fusions involving ETS transcription B Atrophy factors and RAF kinase. Also shown are genetic alterations in two other genes (SPINK1 overexpression and SPOP mutations), which are mutually exclusive withS ET rearrangements. The estimated frequencies of each genetic altera- tione ar also included. (From MacMillan Publishers Ltd: Asian Journal of Andrology 2012;14(3):393-9.)

NKX3.1 encodes a prostate-specific homeobox gene essential for normal prostate development that may be a target for somatic loss on chromosome 8p21.93 NKX3.1 has been shown to bind DNA and to repress PSA expression via interactions with ETS transcription factors.94,95 Mice carrying one or two disrupted Nkx3.1 alleles mani- fest prostatic epithelial hyperplasia and .96,97 nI men, loss of 8p21 DNA sequences occurs early during prostatic carcinogenesis, with 63% of PIN lesions and >90% of prostate cancers, showing loss of heterozygosity at polymorphic 8p21 marker sequences in one report.98 However, although mapping studies have indicated that NKX3.1 lies within a common region of deletion, encompassing 2 megabases at 8p21, molecular analyses have not yet estab- lished NKX3.1 as a somatic target for inactivation during prostatic carcinogenesis because somatic NKX3.1 mutations have not been C identified. Nonetheless, loss of NKX3.1 expression does appear to accompany prostate cancer progression. Figure 84-6 • Multiple foci of prostate cancer, and of prostate cancer PTEN, a encoding a phosphatase active precursor lesions, in the peripheral zone of the prostate. (From Nelson WG, against both proteins and lipid substrates, appears to be a common DeMarzo AM, Isaacs WB, et al. Prostate cancer. N Engl J Med 99-106 2003;349:366-381.) target for somatic alteration during prostate cancer progression. PTEN is an inhibitor of the phosphatidylinositol 3′-kinase/protein kinase B (PI3K/Akt) signaling pathway needed for cell cycle progres- sion and cell survival. Although PTEN is expressed by normal pros- tate epithelial cells, and by cells present in PIN lesions, the expression of PTEN is often diminished in prostate cancers, with many prostate cancers containing collections of neoplastic cells with no PTEN.107 1470 Part III: Specific Malignancies

AR

DHT DNA double strand break

DHT TOP28 AR AR

DHT

TOP28 DHT

AR POLII Ku80 Ku70 DNA-PK

PARP1 ATM Other repair proteins? ROS Fork collision Dietary carcinogens Repair infidelity Repair, movement to transaction hubs, and active transcription

Persistent DSBs Illegitimate repair Senescence Formation of structural rearrangements Apoptosis Geonomic instability

Figure 84-8 • Initiation of transcription by androgen receptor leads to DNA strand breaks mediated by TOP2B, which recombine to generate gene rearrangements. (From Haffner MC et al. Transcription-induced DNA double strand breaks: both oncogenic force and potential therapeutic target? Clin Cancer Res 2011;17:3858-3864.)

PTEN edefects hav been found in a wide variety of cancers and cancer p27 levels appear complex: somatic loss of DNA CDKN1B sequences cell lines.101 For prostate cancer, a number of somatic PTEN altera- at 12p12-13 have been reported for only 23% of localized prostate tionse hav been reported, including homozygous deletions, loss of cancers, 30% of prostate cancer metastases, and 47% of heterozygosity, mutations, and probable CpG island hypermethyl- distant prostate cancer metastases.113 nI place of CDKN1B gene ation. However, despite common losses of 10q sequences near alterations, p27 polypeptide levels may be lowered indirectly by inad- PTEN in prostate cancers, somatic mutations at the remaining PTEN equate PTEN repression of the PI3K/Akt signaling pathway.114-116 nI allelese ar not as frequent. In a study of prostate cancer metastases this,w way lo p27 levels may be as much a result of loss of PTEN recovered at autopsy, somatic PTEN alterations were even more function as of CDKN1B alterations. The critical contribution of common than in primary prostate cancers, and a significant hetero- PTEN to epithelial growth regulation in the prostate is evident in geneity in PTEN defects in different metastatic deposits from the mice,e wher disruption of Cdkn1b alleles leads to prostatic hyperpla- same patient was also evident.106 Haploinsufficiency for PTEN may sia, and Pten+/–Cdkn1b–/– mice develop prostate cancer by 3 months contribute to the phenotype of transformed cells in the prostate. of age.111,117 Pten+/– mice display prostatic hyperplasia and dysplasia, and crosses Metastatic prostate cancer is almost always treated with androgen of Pten+/– mice with Nkx3.1+/– emice hav revealed that Pten+/–Nkx3.1+/– deprivation, antiandrogens, or a combination of androgen deprivation mice and Pten+/–Nkx3.1–/– mice develop lesions reminiscent of human and antiandrogens.118,119 However, despite such treatment, androgen- PIN.108-110 independent prostate cancer cells eventually emerge and progress to Defective regulation of p27, a cyclin-dependent kinase inhibitor threaten life. Curiously, in these cells, androgen receptor expression encodedy b CDKN1B, may also accompany prostatic carcinogene- and androgen receptor signaling remain intact despite the absence of sis.111,112 nINI P cells and prostate cancer cells, p27 levels are almost androgens.120,121 Somatic alterations of AR ehav been reported for always diminished, though the mechanism(s) for the reduction in many prostate cancers, especially for androgen-independent prostate Prostate Cancer • CHAPTER 84 1471 cancers. AR amplification, accompanied by high-level expression of bothIN in P lesions and in prostate cancer.155-157 tA some point, most androgen receptors, may promote the growth of androgen-independent cancer cells activate the expression of telomerase, providing some prostate cancer cells by increasing the sensitivity of the cells to low maintenance of chromosome termini. Telomerase expression has been androgen levels.122 AR mutations, encoding androgen receptors with detected in prostate cancers, but not at high levels in normal prostate altered ligand specificity have also been detected; for some of the tissues or in BPH.155 mutant androgen receptors, even antiandrogens can act as agonist 123-125 ligands. When 44 mutant androgen receptors from prostate PROSTATE CANCER SCREENING, EARLY cancers were evaluated for transcriptional regulatory capabilities, 16% of the receptors had lost transcriptional activation activity, 45% of DETECTION, AND PREVENTION the receptors had gained some transcriptional regulatory ability, 32% Clinical Evaluation of the receptors maintained some partial transcriptional modulatory activity, and the remaining 7% behaved like wild-type receptors.126 With widespread opportunistic prostate-specific antigen (PSA)–based In addition to somatic AR gene changes, androgen-independent pros- screening for prostate cancer, most cases are diagnosed at a stage when tate cancer cells with wild-type androgen receptors may activate symptoms due to the disease are absent. Nevertheless, locally advanced androgen receptor signaling even in the absence of androgens, via disease can cause lower urinary tract symptoms (obstructive or irrita- posttranslational modifications of the androgen receptor and/or tive), hematospermia, a decrease in ejaculate volume, and erectile androgen receptor coactivators in response to other growth factor dysfunction if the cancer extends beyond the prostate to involve the signaling pathways.120,127-130 bladder neck, urethra, ejaculatory ducts, , or erecto- genic nerves, respectively. Metastatic involvement of the skeleton, Changes in Gene Expression bone marrow, pelvic lymph nodes, or periureteral lymphatics can lead in Prostate Cancers to bone pain, pancytopenia, lower extremity edema, or retroperito- neal fibrosis, respectively. Paraneoplastic syndromes from ectopic Alterations in gene expression in prostate cancers have been cata- hormone production by small cell variants of adenocarcinoma, and logued using cDNA microarray technologies.131-142 Among the many disseminated intravascular coagulation (DIC) have been associated genes exhibiting over- or underexpression in prostate cancers, the with metastatic prostate cancer. products of at least two genes appear consistently increased, and the product of a third gene appears to become elevated during androgen- Digital Rectal Examination independent progression. Hepsin, located at 19q11-13.2, encodes a transmembrane serine protease, expressed at high levels in many In men with early-stage prostate cancers, physical findings, if present, normal tissues.143 Hepsin may contribute to prostate cancer progres- are usually limited to an abnormal DRE, used for both screening and sion: forced overexpression of hepsin in mouse prostates leads to staging. Palpable areas of induration, or asymmetric firmness of the disorganization of the epithelial basement membrane and increased gland, suggest the presence of prostate cancer, but these findings can .144 α-Methylacyl-CoA racemase (AMACR), a mitochon- also be caused by prostate inflammation (especially granulomatous drial and peroxisomal enzyme that acts on pristanoyl-CoA and C27- prostatitis), by benign prostatic hyperplasia (BPH), and by prostatic bile acyl-CoA substrates to catalyze the conversion of R- to stones. DRE has only fair reproducibility in the hands of experienced S-stereoisomers in order to permit metabolism by β-oxidation, has examiners.158 When used alone for detection of prostate cancer, DRE been reported to be overexpressed in almost all prostate cancers.145,146 misses from 23% to 45% of the cancers that are subsequently detected Germline AMACR mutations lead to adult-onset neuropathy.147 by prostate biopsies done for serum PSA elevations or for transrectal Immunohistochemistry studies, which have revealed that AMACR is ultrasound (TRUS) abnormalities.159-161 nI addition, prostate cancers occasionally present in normal prostate cells, increased in PIN cells, detectedy b DRE are at an advanced pathological stage in more than and further elevated in prostate cancer cells, have prompted the use 50% of men.162,163 of antibodies against AMACR as tools for prostate cancer diagnosis Thee positiv predictive value of DRE (the fraction of men who by surgical pathologists.146,148 The polycomb protein enhancer of zeste have prostate cancer if the DRE is abnormal) ranged from 4% to homolog 2 (EZH2), a transcriptional regulatory protein, is elevated 11% in men with PSA levels from 0.0 to 2.9 ng/mL, and from in metastatic androgen-independent prostate cancer.149 The mecha- 33% to 83% in men with PSA levels of 3.0 to 9.9 ng/mL or nismy b which EZH2 contributes to prostate cancer progression has more.164 When DRE and PSA are used in prostate cancer screening, not been established. However, elevated EZH2 expression in primary detection rates are higher with PSA than with DRE and highest prostate cancers portends a poor prognosis.149 with both tests together.165 Furthermore, a DRE abnormality tends to be associated with the presence of high-grade cancer.166 Thus Telomere Shortening During Prostatic DRE and PSA are generally considered to be complementary tests Carcinogenesis and a prostate is usually recommended for men with an abnormality on DRE that is suspicious for prostate cancer regardless Telomeres, containing repeat DNA sequences at the termini of chro- of the PSA level. mosomes, protect against loss of chromosome sequences during genome replication. DNA ends tend to shorten each generation as a Serum PSA consequence of bidirectional DNA synthesis (the “end-replication” problem); the telomere repeat sequences serve as templates for the PSA is a member of the human kallikrein gene family of serine pro- enzyme telomerase, which can extend the chromosome termini and teases encoded by KLK3 located on chromosome 19.167 A component maintain chromosome integrity through cell division.150 Growth dys- of the ejaculate, PSA is produced by columnar secretory cells in the regulation accompanying the development of most human cancers prostate. PSA expression is regulated by androgens, becoming detect- tends to lead to cell proliferation in the absence of telomerase, and able in serum at puberty accompanying increases in luteinizing to shortened chromosome telomeres.151 Critically shortened telomere hormone and testosterone. In the absence of prostate cancer, serum sequences may promote genome instability by increasing illegitimate PSA levels increase with age and prostate volume and are generally DNA recombination.152,153 Mice carrying disrupted genes needed for higher in African Americans. Cross-sectional population data suggest a functioning telomerase show increased numbers of cancers, espe- that the serum PSA increases 4% per milliliter of prostate volume, cially when crossed to mice with defective p53 genes.154 nI the pros- and that 30% and 5% of the variance in PSA can be accounted for tate,t shor telomere repeat sequences appear characteristic of cells by prostate volume and age, respectively.168 1472 Part III: Specific Malignancies

Serum PSA elevations likely occur as a result of disruption of the appropriately thought of as measures of a continuum of prostate normal prostate architecture, permitting PSA to diffuse into the cancer risk, with the risk of cancer (and of high-grade cancer) rising prostate parenchyma and gain access to the circulation. This can directly with the PSA level, an observation first made by Gann et al. occur in the setting of both benign and malignant prostate diseases using a cohort population study design.171 nI recent years, more (prostatitis, BPH, and prostate cancer) and as a result of prostate emphasis has been placed on integrating several variables associated manipulation (prostate and ).169 Although the with the risk of prostate cancer (e.g., age, family history, race, DRE presence of some type of prostate disease is the most important findings, prior biopsy results) to construct risk calculators for estimat- determinant driving elevation of the serum PSA, an increased serum ing the need for a prostate biopsy.177,178 eThe futur will likely see PSA is not specific for prostate cancer. Furthermore, not all men with further integration of genome and other molecular biomarker tools prostate disease have elevated serum PSA levels. in prostate cancer screening algorithms. Treatments targeting the prostate gland (for BPH or for prostate cancer) can lower serum PSA by decreasing the number of prostatic PSA “Density” epithelial cells capable of producing PSA, and by decreasing the amount of PSA produced by each cell. Modulation of sex steroid The major source of serum PSA in men without prostate cancer is hormone levels for treatment of BPH or prostate cancer, radiation the transition zone (TZ) epithelium, not the epithelium of the therapy for prostate cancer, and surgical ablation of prostate tissue peripheral zone.179 Because benign prostate enlargement is a growth forH BP or prostate cancer can all lead to decreases in serum PSA. 5α-Reductase inhibitors, like finasteride and dutasteride, lower PSA 170 levelsy b 50% after 12 months of treatment. Thus for men treated 14 AUTOPSY PROSTATE with these agents for 12 months or more, the serum PSA level CANCER CASES should be doubled to estimate the “true” PSA value. Interpretation of serum PSA values should always take into account the presence of prostate disease, previous diagnostic procedures, and prostate-targeted treatments. R humerus 75% L humerus 64%

Serum PSA and Prostate Cancer Detection The serum PSA value, along with the findings at DRE, correlate directly with the risk of prostate cancer at biopsy (Table 84-1). Fur- Sternum 83% thermore, the PSA level at a young age anticipates the future risk of Ribs 80% being diagnosed with prostate cancer decades later (Figure 84-9). Gann et al. first showed that the risk of a prostate cancer diagnosis, including the diagnosis of life-threatening disease, incrementally and directly with PSA over the decade after a baseline measurement, even atw lo PSA levels (below 4.0 ng/mL); a finding that has now been T8 64% 171-173 confirmedy b many others. These observations may allow a T9 80% more targeted approach to prostate cancer screening using a baseline T10 80% 174,175 PSA value to direct screening intensity. T11 75% In the early years of PSA testing, most clinicians used PSA as a T12 88% dichotomous test (i.e., the PSA was “elevated” or not) with elevations L1 90% triggering a prostate biopsy. However, data from the placebo arm of 176 L2 93% the Prostate Trial (PCPT ), which accrued men L3 85% < with a serum PSA value 3.0 ng/mL, has suggested that there is no L4 92% PSA cut-off level with both high sensitivity and high specificity for L5 100% prostate cancer, and that virtually no level is low enough to exclude the presence of prostate cancer. Instead, serum PSA tests may be more

Table 84-1 Positive Predictive Value of DRE and PSA in a Multicenter Screening Trial R iliac 100% L iliac 92% DRE PSA PPV (%) Abnormal Any 21.4 Any >4 31.5 4–10 26.1 >10 52.9 Normal >4 24.4 Abnormal <4 10.0 4–10 40.8 R femur 80% L femur 80% >10 69.1

Data from Catalona WJ, Richie JP, Ahmann FR, et al. Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6,630 men. J Urol 1994;151:1283. Figure 84-9 • Distribution of bone metastases in men dying of prostate DRE, Digital rectal examination; PPV, positive predictive value; PSA, prostate- cancer. (Data from Roudier MP et al. Phenotypic heterogeneity of end-stage specific antigen. prostate metastatic to bone. Hum Pathol 2003;34:646-653.) Prostate Cancer • CHAPTER 84 1473 of the transition zone tissue, and because serum PSA levels are largely using one assay for cPSA versus two assays to determine the %fPSA a reflection of transition zone volume in men with benign prostate (measuring both tPSA and the %fPSA). enlargement, adjusting the serum PSA for either prostate volume Benign PSA (BPSA), a degraded isoform of fPSA, is preferentially (PSA density) or more specifically, the transition zone volume (PSA- found in nodular tissue involved in benign prostatic enlargement and TZ), has been shown to improve the distinction between those with has been shown to be elevated among men with benign prostatic prostate cancer and those with benign prostate enlargement.180-183 hyperplasia.194 A second isoform, proPSA, is an inactive precursor of PSA density is also directly associated with the presence of high-grade PSA that contains differing leader sequences of amino acids. When cancer on prostate biopsy, and is therefore useful for identifying those compared to men without prostate cancer, the tissues and serum of men less likely to have high-grade cancer most appropriate for active prostate cancer patients have an increased proportion of proPSA that surveillance.184 is fPSA, a difference that has been used to improve the discrimination of men with and without prostate cancer.195 A Beckman Coulter PSA “Velocity” “Prostate Health Index” (PHI) uses proPSA, fPSA, and tPSA in a formula (proPSA/fPSA) × (tPSA)1/2 that was shown to improve pros- Carter et al., using frozen serum samples from an aging study cohort, tate cancer detection over total and %fPSA.196 Additionally, there is demonstrated that a PSA “velocity” (PSAV; the rate of change of some evidence that proPSA is associated with a more aggressive serum PSA in ng/mL per year upon repeated testing) of 0.75 ng/mL prostate cancer phenotype.197 per year or greater had a specificity of 90% for distinguishing men with prostate cancer in the setting of benign prostatic enlargement, Urine Biomarkers of Prostate Cancer and a specificity of 100% for distinguishing men with prostate cancer in the absence of benign prostatic enlargement when PSA levels were PCA-3, a noncoding prostate-specific RNA, was found to be overex- in the range of 4.0 to 10.0 ng/mL (Figure 84-9).185 pressed in prostate cancer tissue compared with benign tissue.198,199 TheV PSA tends to be higher in men with high-grade and high- Urine assays for PCA3 ehav been developed that appear to improve stage prostate cancer as compared to men with lower grade and stage the specificity of prostate cancer detection in response to an abnormal disease.186,187 Furthermore, men with a PSAV above 2.0 ng/mL per serum PSA,200 When compared with %fPSA, a PCA3 escor (the ratio year in the year before a diagnosis of prostate cancer appear to be at of PCA3 RNA to PSA mRNA × 1000) has been shown to be a supe- an increased risk of prostate cancer death after surgical intervention rior predictor of prostate cancer on a repeat biopsy when an initial when compared with men with a PSA velocity of 2.0 ng/mL per year biopsy was negative.201 Although PCA3 emay hav a higher specificity or less.188 VFor PSA measured 10 to 15 years before prostate cancer when used for prostate cancer detection, urine testing for PCA3 diagnosis (when most men had PSA levels below 4.0 ng/mL), a PSAV exhibits a lower sensitivity when compared with serum PSA testing. less than 0.35 ng/mL per year has been associated with a prostate A number of other urinary molecular biomarkers have been evalu- cancer–specific survival 25 years later of 92%, compared with 54% ated for prostate cancer detection, including hypermethylated GSTP1 withV a PSA greater than 0.35 ng/mL per year.189 eTher is also a genes,CR AMA proteins, and TMPRSS2-ERG fusion mRNA tran- direct relationship between the number of times the PSAV exceeds a scripts.n I a multicenter evaluation of urinary DNA methylation given threshold (e.g., 0.4 ng/mL per year), a concept known as “risk markers, including GSTP1,e the negativ predictive value of the urine count,” and the risk of high-grade cancer.190,191 Thus a continuously test for prostate cancer diagnosis was 87% for men with a PSA of 4.1 increasing serum PSA should raise the suspicion of high-grade pros- to 10.0 ng/mL.202 Although such DNA methylation urine tests might tate cancer if there is no other explanation for the rise. spare men unnecessary repeat biopsies, the addition of TMPRSS2- ERG mRNA urine testing (expected to be present in half of men with Molecular Forms of PSA prostate cancer) to PCA3 RNA urine testing may provide a positive predictive value as high as 95%, steering men who harbor prostate PSA in the bloodstream circulates in both bound and unbound cancer despite a previous negative biopsy toward a definitive diagno- forms. Most of the detectable PSA in the serum (65% to 90%) is sis.199,203 The discovery and development of new molecular biomark- bound to α1-antichymotrypsin (“complexed” PSA or cPSA, whereas ers is progressing very quickly; in the future, such biomarkers (or the rest (10% to 35%) remains unbound (“free” PSA or fPSA).167 biomarker panels) will need to be incorporated into algorithms along The serum PSA tests in common use for prostate cancer detection withd standar measures of risk (e.g., age, family history, race) to and monitoring effectively measure the sum of fPSA and cPSA, selectively identify men who should undergo further evaluation for providing a determination of the “total” serum PSA (tPSA). Assays the presence of prostate cancer.204 that can distinguish fPSA and cPSA have been developed and approvedy b the U.S. FDA specifically for use in the early detection TRUS-Guided Prostate Biopsy of prostate cancer. In general, men with prostate cancer have a greater fraction of serum tPSA bound to α1-antichymotrypsin (cPSA), and TRUS is not an accurate method for localizing early prostate cancer a commensurately lower fraction of tPSA that is unbound (fPSA), and is not recommended for use in prostate cancer screening. The than men without prostate cancer. This difference is thought to be primary role of TRUS in prostate cancer detection and diagnosis is due to the differential expression of PSA isoforms by cells in the toe ensur accurate sampling of prostate tissue by prostate biopsies in transition zone (the zone of origin for BPH) tissue as compared with men suspected of harboring cancer based on serum PSA levels and peripheral zone (the zone where most prostate cancers arise) tissue. DRE.205 This is best accomplished by targeting peripheral zone The %fPSA appears most useful in distinguishing men with and lesions that appear hypoechoic by TRUS for biopsy, along with per- without prostate cancer in the setting of tPSA levels between 2 and forming systematic sampling biopsies of areas without hypoechoic 10 ng/mL.192 An fPSA of 25% and a PSA density of 0.078 were lesions in the prostate periphery. shown to have comparable specificity for prostate cancer diagnosis at TRUS-guided prostate biopsies are performed routinely with an biopsy (at a sensitivity of 95%), but %fPSA does not require a TRUS 18-guage needle fired from a spring-loaded gun through a port for determination.193 Most urologists use %fPSA determinations for mounted on the TRUS probe. Most commonly, in preparation for a decisions about the need for a repeat biopsy in a man with a persis- biopsy procedure, men are administered a fluoroquinolone antibiotic tently elevated serum PSA and previous negative prostate biopsies, and given a cleansing enema. Injection of a local anesthetic around where the possibility of a missed prostate cancer may be a concern. they peripher of the prostate is used by most urologists to reduce New assays for cPSA exhibit comparable specificity and sensitivity for discomfort associated with prostate biopsy. Major complications, prostate cancer diagnosis as %fPSA, with the potential advantage of such as bleeding and/or infection requiring hospitalization, are rare, 1474 Part III: Specific Malignancies

although hematuria and hematospermia are common sequelae of the compelling reasons for prostate cancer prevention. In addition, epi- procedure. More recently, a rise in fluoroquinolone-resistant E. coli demiological data, indicating a dominant role for lifestyle factors in strainse hav been implicated in higher rates of hospitalization prostate cancer development, suggest that prostate cancer risk modi- for postbiopsy sepsis,206 leading to more liberal use of targeted fication may be feasible, if only through lifestyle modification. Also, antibiotic prophylaxis, based on rectal swab cultures done prior to because prostatic carcinogenesis takes many decades, there may be a a. biopsy 207 broadw windo of opportunity to change lifestyle in an effort to retard The optimal biopsy technique, including the number and place- prostate cancer development. Clearly, although the specific lifestyle ment of biopsies for tissue procurement that will minimize the chance factors fostering prostate cancer development have not been conclu- of missing a relevant cancer remains controversial. Nonetheless, the sively identified, it is likely that consumption of a diet rich in fruits, best evidence available suggests that biopsies placed more laterally vegetables, and antioxidant micronutrients, and poor in saturated fats within the peripheral zone of the prostate may be important to and “well-done” red meats, may significantly reduce risks of prostate exclude prostate cancer in men with elevated serum PSA values and cancer development, and of the development of other diseases char- a nonsuspicious DRE. Magnetic resonance imaging (MRI) may have acteristic of life in the developed world. As the etiology of prostate a role in improving the specificity of prostate cancer detection and in cancer is even better understood, new opportunities for prostate identification of sites within the prostate for directing prostate biop- cancer prevention may also arise. For example, if prostate inflamma- sies.208 tA this point, it is not clear whether this use of MRI will tion contributes to prostate cancer development, antiinflammatory improve health outcomes or reduce (vs. increase) the costs of care. drugs might be considered candidate prostate cancer prevention drugs.219 For drugs to be developed and tested for prostate cancer Screening for Prostate Cancer prevention, randomized clinical trials, capable of assessing both drug safety and drug efficacy, will be required.220 Ideally, such trials can be Opportunistic PSA-based screening has been widespread in the targeted at men with a high risk for prostate cancer development. United States since the early 1990s. It has been estimated that 45% Thus, far two classes of agents, 5α-reductase inhibitors and anti- to 70% of the 30% decline in prostate cancer mortality that occurred oxidant micronutrients, have been subjected to large randomized in the 1990s could be attributed to the stage migration and earlier clinical trials; neither class of agents has shown a convincing prostate treatment of prostate cancer associated with PSA testing.209 Ecological cancer prevention benefit. In the Prostate Cancer Prevention Trial studies of prostate cancer mortality comparing countries with differ- (PCPT), the propensity for the 5α-reductase inhibitor finasteride to ent rates of PSA uptake, suggest that the detection of more aggressive reduce the prevalence of prostate cancer in healthy men age 55 years disease with PSA testing could explain mortality differences.210 and older when given for 7 years was tested.221 For the trial, men (n Two randomized trials of prostate cancer screening reported dif- = 18,882) with a PSA of 3.0 ng/mL or less and a normal DRE were ferent results in 2009.211,212 nI the Prostate, Lung, Colon, and Ovary randomized to treatment with finasteride (5 mg/d) or to placebo.221 (PLCO) trial, no difference in mortality was found between the While on study, men with a PSA elevation or an abnormal rectal screening and control groups, whereas in the European Randomized examination were subjected to prostate biopsy; in addition, at the Study of Screening for Prostate Cancer (ERSPC), there was a 21% end of the treatment period, a prostate biopsy was planned for all of reduction in prostate cancer deaths in men randomized to screening the men in the trial. Prostate cancer was detected in 18.4% of the at a median follow-up of 9 years. However, the absolute reduction in men treated with finasteride versus 24.4% of men receiving placebo deaths for men screened was only 0.71 per 1000 men, with 48 men (P < 0.001).221 However, high-grade prostate cancers appeared more diagnosed with prostate cancer and treated to prevent one death, commonly associated with finasteride treatment than with placebo raising a concern about overdiagnosis and overtreatment even despite (6.4% vs. 5.1%).221 Similarly, in the REDUCE trial, men (n = 6729) the mortality reduction. Updated reports from both trials have shown with an elevated serum PSA (2.5 to 10.0 ng/mL) and a recent nega- few changes with longer follow-up.213,214 With these conflicting data, tive prostate biopsy were randomized to receive the 5α-reductase as might be expected, champions of prostate cancer screening dismiss inhibitor dutasteride (0.5 mg/d) or placebo.222 For this trial, men the results of the PLCO trial because of high contamination rates in underwent prostate biopsies after 2 and 4 years of treatment. With a the control arm, high rates of prescreening in the population prior result reminiscent of PCPT, overall prostate cancer detection was to initiation of the trial, and low rates of follow-up for positive screen- reduced from 25.1% to 19.9% for men receiving dutasteride, but ing tests. Nevertheless, the findings of the PLCO trial do hint that high-grade prostate cancer, which was similar in the first 2 years of in the setting of ongoing widespread screening as is seen in the United the trial for men treated with dutasteride versus placebo, was increased States, further intensification of screening would not likely improve in dutasteride-treated men in the last 2 years of the trial from <0.1% health outcomes.215 to 0.5%. The findings of PCPT and REDUCE may mean that They worr about overdiagnosis and overtreatment of prostate 5α-reductase inhibitors prevent or treat low-grade cancers better than cancer in the United States has led many to reconsider the value of high-grade cancers. These mixed results, a reduction in overall pros- serum PSA testing for prostate cancer screening. A draft recommen- tate cancer prevalence but an increase in high-grade prostate cancers, dation on prostate cancer screening from the U.S. Preventive Services make prescribing 5α-reductase inhibitors to healthy men for the Task Force (USPSTF) was released in the fall of 2011 recommending purpose of preventing prostate cancer very problematic, an opinion against prostate cancer screening for men of all ages, regardless of race sharedy b the FDA, which has not approved either drug for such an or family history.216 These USPSTF guidelines may prompt an indication.223 increase in shared decision making between patients and physicians Epidemiological studies have provided compelling evidence that prior to pursuing prostate cancer screening,217 ea mor nuanced and intake of selenium and of vitamin E might diminish prostate cancer targeted approach to screening for those who desire to pursue it,175 risks, especially in the setting of inadequate dietary consumption.224-230 and an individualized approach to prostate cancer treatment that As a result, a prospective, randomized, placebo-controlled clinical includes active surveillance if a diagnosis of prostate cancer is made trial of selenium and vitamin E (SELECT; n = 35,533) was under- rather than the rush to curative intervention for all.218 taken to test the ability of the antioxidant micronutrients to prevent prostate cancer.231 Selenium (200 µg selenomethionine), α–tocoph- Prostate Cancer Prevention erol (400 mg), the combination of selenium and α–tocopherol, or neither, were given to men randomized to four different treatment The high lifetime risks of prostate cancer development, the morbidi- groups using a 2 × 2 factorial design, for 7 to 12 years.231 The men ties associated with treatment of established prostate cancer, and the studied were age 55 years or older (50 years or older for inability to eradicate life-threatening metastatic prostate cancer offer African Americans) with an unremarkable DRE and a serum PSA of Prostate Cancer • CHAPTER 84 1475

4.0 ng/mL or less.231 Unfortunately, the trial failed to show any ofIN HGP in a prostate biopsy in the apparent absence of prostate reduction in prostate cancer and showed a slight increase in prostate cancer is that prostate cancer may have been missed by the prostate cancer incidence among men taking α–tocopherol.57,232 When this sampling strategy used for the biopsy procedure. On repeat biopsy of result is considered in the context of the findings from epidemiology men with HGPIN on initial biopsy, the cancer detection rate was studies and previous smaller clinical trials, the data tend to suggest 20% among men who underwent standard extended biopsy sampling that men with low blood levels of the antioxidant micronutrients, (14 cores or less), and 31% among men who underwent a “satura- who tend to be at the highest risk for prostate cancer development, tion” biopsy sampling (20 biopsy cores or more).242 The National might be the only men with any chance for benefit from supplemen- Comprehensive Cancer Network (NCCN) recommends a repeat tation.225,226,230,233 For this reason, correction of antioxidant micronu- biopsy within 1 year for men with HGPIN if the lesion was multifo- trient deficiencies might ultimately prove more generally safe and cal (2 cores or more involved) and/or the initial biopsy was not effective than widespread supplementation (and its risk of oversup- performed using an extended approach (more than 6 cores).243 plementation), which may carry a threat of harm with little benefit. Of interest, unlike prostate cancer, prostate inflammation, or BPH,IN HGP lesions are not thought to perturb prostate architec- ture enough to elevate the serum PSA. Recently, increasing attention PATHOLOGY AND PATHWAYS OF SPREAD has been afforded the notion that PIA (proliferative inflammatory 244 Histopathology of Prostate Cancer atrophy) lesions might be precursors to PIN and/or prostate cancer. Like IA PIN, P lesions tend to arise in the peripheral zone of the Microscopic analysis of prostate tissue by a surgical pathologist is prostate, where prostate cancers arise, and some PIA cells acquire needed for the diagnosis of prostate cancer, for determining prostate somatic genome alterations reminiscent of prostate cancer cells.66,245 cancer stage after prostatectomy, and for histologic , via the At present, men with PIA lesions are not subjected to any kind of assignment of a Gleason score, to predict the behavior of prostate treatment, and presence of PIA on an initial prostate biopsy is not cancer. The majority of prostate cancers are adenocarcinomas, though thought to predict the detection of prostate cancer on repeat biopsy. other types of cancers can appear. Most often, prostate cancer diag- The major significance of PIA to the diagnosis of prostate cancer by nosese ar made using core-needle biopsy specimens, which sample prostate biopsy may be propensity for such lesions to occasionally small amounts of prostate tissue. For many prostate cancer cases, exhibit features that mimic prostate cancer.234 needle biopsies contain only small numbers of prostate cancer cells The most frequently used approach to histologic grading of pros- amonge mor plentiful noncancerous glands. Also, several prostate tate cancer is the application of Gleason scoring.246 The Gleason conditions, including acute, chronic, or granulomatous prostate grade refers to architectural prostate cancer patterns, numbered 1 inflammation, epithelial atrophy, and PIN, exhibit histologic features (well differentiated) to 5 (poorly differentiated). Because prostate that mimic some of those present in prostate cancers.234 Thus, pros- cancerse ar often heterogeneous, Gleason scoring (sometimes referred tate cancers can be difficult to recognize in needle biopsy specimens, to as the “combined” Gleason grade) is accomplished by adding the and difficult to distinguish from other prostate abnormalities. Expe- Gleason grade of the most abundant pattern to the Gleason grade of rienced prostate pathologists use a combination of architectural, cyto- the second most abundant pattern (e.g., a Gleason score of 4 + 3 = logic, and ancillary findings to make a diagnosis of prostate cancer 7). The Gleason score, when applied by an expert pathologist, is one on needle biopsy.234-236 nI addition, because normal prostate glands, of the best tools available for predicting cancer-specific outcomes; the but not glands present in prostate cancers, contain basal epithelial higher the Gleason score the greater the risk of cancer progression cells, immunohistochemical staining for basal epithelial cell markers, with or without treatment.247 f O note, because Gleason scoring such as cytokeratins K5 and K14 and the nuclear marker p63, can applies pattern grades to the architecture of cancer within the pros- be used to help distinguish benign from malignant glands in prostate tate, metastatic prostate cancers detected by biopsies of metastatic tissue samples. Immunohistochemical staining for AMACR, a pros- depositse ar not assigned a Gleason score. Gleason grading practices tate cancer biomarker discovered through cDNA microarray tran- have evolved over time. As part of a 2005 International Society of scriptome profiling, can aid in prostate cancer diagnosis.146,148,237 Urological Pathology (ISUP) Consensus Conference, a revised Neither of these immunohistochemistry reagents perfectly distin- approach was formulated and adopted, subtly changing the defini- guishes prostate cancer: the absence of basal epithelial cell markers is tions of Gleason patterns 3 and 4 and improving the interrater not always diagnostic of prostate cancer, and AMACR expression is reproducibility of Gleason grading.248 With the newer ISUP grading absent in some prostate cancers and present in PIN.234 For all of these strategy, a Gleason score of 3 + 3 = 6 can be expected to have a very reasons, second-opinion interpretations of prostate biopsy findings, low risk of prostate cancer recurrence after primary therapy. especially when foci of atypical glands suspicious for cancer are identi- fied,e ar often helpful. Life-Threatening Prostate Cancer Progression High-grade PIN (HGPIN), a lesion characterized by the prolifera- tion of malignant-appearing prostate epithelial cells within the con- Prostate cancer progression has long been understood to involve fines of otherwise normal glandular structures, is identified in about metastases to bones, which are often painful, and to lymph nodes. 5% of men subjected to prostate biopsies.238,239 The evidence that The predilection of the disease for bones may reflect a hospitable HGPIN is a likely precursor to prostate cancer includes the findings microenvironment capable of providing growth factor support in a that (1) HGPIN is more commonly present in prostates that also collaboratively malignant milieu (Figure 84-10).249 nI turn, prostate contain prostate cancer, (2) HGPIN and prostate cancer both tend cancer cells perturb bone homeostasis in such a way as to increase to arise in the peripheral zone of the prostate and are often directly osteoblast activity, which can be readily discerned by bone scanning. contiguous, and (iii) HGPIN and prostate cancer express similar This activity forms the basis for bone scan imaging, such as with biomarkers and share many somatic genome abnormalities.240,241 The 99mTc-methylene diphosphonate (MDP) and 18F-sodium fluoride notion that HGPIN lesions might be prostate cancer precursors has (NaF), in which osteoblastic activity can be visualized throughout the stimulated interest in possibly treating men with HGPIN to prevent entire skeleton.250 Reportedly, NaF positron emission tomography/ prostate cancer.241 Unfortunately, the natural history of individual computed tomography (NaF PET/CT), in which osteoblastic activity HGPIN lesions is not known. Furthermore, HGPIN lesions, which is coregistered with bone radiography, offers the highest sensitivity can only be recognized by sampling prostate biopsies, are not easily and specificity for bone metastasis.251 monitored. These limitations have hindered the use of HGPIN as a More recent autopsy studies have provided newer insights into the response surrogate for cancer prevention drug development. Because phenotype(s) of lethal prostate cancer. In addition to expected bone HGPIN is not currently treated, the major significance of the finding and lymph node metastases, men dying of prostate cancer tend to 1476 Part III: Specific Malignancies

CLINICAL MANIFESTATIONS/PATIENT EVALUATION/STAGING Evaluation of the Extent of Prostate Cancer 1 The extent of prostate cancer is correlated with clinical tumor stage (Table 84-2), Gleason score (the sum of two Gleason grades; Figure 84-11), and serum PSA level.256 Nomograms, incorporating clinical stage (estimated using DRE findings), the serum PSA level, and the Gleason score, have been shown to be capable of predicting both pathological prostate cancer extent determined on radical prostatec- tomy specimens and the long-term outcome following treatment.257-259 The most commonly used risk stratification 2 scheme today is that of D’Amico et al., who suggested that men with prostate cancer can be stratified into low risk (stages T1c to 2a, and serum PSA less than 10 ng/mL, and Gleason score of 6 or less), intermediate risk (stage T2b, or serum PSA between 10 and 20 ng/ mL, or Gleason score of 7), and high risk (stage T2c, or serum PSA greater than 20 ng/mL, or Gleason score of 8 or greater) groups. The fraction of men free of prostate cancer 10 years after radical prosta- tectomy is significantly different for the risk categories: 83% of men 3 with low-risk prostate cancer, 46% of men with intermediate-risk prostate cancer, and 29% of men with high-risk prostate cancer.259 A number of pretreatment tools are available for prediction of the pathological extent of tumors and the probability of biochemical recurrence.260,261 When used before initiating prostate cancer treat- ment, risk stratification of men with prostate cancer aids in counsel- ing such men about the expected outcome of prostate cancer treatment, providing estimates of the chance that local treatments 4 might be curative.

Radiographic Imaging Although CT scanning is used routinely by radiation oncologists for prostate cancer treatment planning, no imaging technique available today has been proven to add additional useful information when used to evaluate the extent of prostate cancer in men with low- and 5 intermediate-risk disease.262 USTR and MRI give the most accurate definition of prostatic architecture and anatomy, but current imaging technologies do not provide very precise assessments of cancer extent within the prostate or the presence of microscopic foci of prostate cancer that have escaped the confines of the prostate gland. Radio- Figure 84-10 • Modified for prostate cancer. nuclide bone scans detect metastatic prostate cancer in less than 1% Gleason patterns 1 to 5 are assigned different patterns of growth for prostatic of men with a serum PSA value less than or equal to 20 ng/mL and adenocarcinomas. A Gleason score is the sum of the two most common are not recommended for the initial evaluation of men with low- or Gleason grades (e.g., Gleason 4 + 3 = 7). (From Epstein JI, An update of the intermediate-risk prostate cancer.263 ETP has not yet been found to Gleason grading system. J Urol 2010;183:433-440.) be useful in the evaluation of men with prostate cancer and has no place in the prostate .264 New imaging technologies, including three-dimensional color Doppler, contrast-enhanced color exhibit common metastases to liver (64%), the dura (43%), and Doppler, magnetic resonance spectroscopy, and high-resolution MRI elsewhere.252 The most troubling feature of lethal prostate cancer may with magnetic nanoparticles, have great potential for improving the be its heterogeneity. In different metastases from the same case, the assessment of local and distant prostate cancer extent.262,265,266 Cross- expression of androgen receptor, and its target PSA, appears markedly sectional imaging of the pelvis, by CT scan or MRI, for the purpose variable, present in the majority of cells in some lesions but mostly of detecting lymph node metastases, and radionuclide bone scans for absent for others.253 This likely reflects ongoing genome and epig- the detection of bony metastases, should be reserved for men with enome instability. Genomewide assessment of somatic genetic and high-risk prostate cancer. epigenetic defects in lethal prostate cancers at autopsy show that 111In-capromab pendetide, a radioimmunoconjugate featuring a although disseminated metastatic disease emerges from a single clone, monoclonal antibody to an intracellular domain of prostate-specific new defects continue to appear in individual metastases.254 fO inter- membrane antigen was approved by the FDA for use in the evaluation est, DNA hypermethylation changes tend to be maintained in all of men with clinically localized prostate cancer but is rarely used metastatic lesions in most cases, at least as much as any of the genetic today for assessment of prostate cancer extent, even for men with alterations, whereas DNA hypomethylation, leading to activation of high-risk prostate cancer, in large part because of low scan sensitivity repressed embryonic genes, continues to evolve variably lesion to and frequent difficulties in scan interpretation. There may be a role lesion.255 fO course, the greatest worry about ongoing genomic, epi- for 111In-capromab pendetide imaging with single photon emission genomic, and phenotypic heterogeneity in metastatic prostate cancer computed tomography used in coregistration with computed tomog- is the likelihood that treatment resistance will almost certainly raphy (SPECT/CT) for prognostic staging.267 New nuclear medicine emerge, regardless of the agent used. agents capable of detecting PSMA appear promising in early Prostate Cancer • CHAPTER 84 1477

Table 84-2 TNM Staging for Prostate Cancer (from http://www.cancerstaging.org)

PRIMARY TUMOR (T) pT2b Unilateral, involving more than one-half of side but not CLINICAL both sides pT2c Bilateral knee TX Primary tumor cannot be assessed pT3 Extraprostatic extension T0 No evidence of primary tumor pT3a Extraprostatic extension or microscopic of T1 Clinically inapparent tumor neither palpable nor visible bladder neck4 by imaging pT3b Seminal vesicle invasion T1a Tumor incidental histologic finding in 5% or less of tissue resected REGIONAL LYMPH NODES (N) T1b Tumor incidental histologic finding in more than 5% of CLINICAL tissue resected NX Regional lymph nodes were not assessed T1c Tumor identified by needle biopsy (e.g., because of N0 No regional lymph node metastasis elevated PSA) N1 Metastases in regional lymph node(s) T2 Tumor confined within prostate1 T2a Tumor involves one-half of one lobe or less PATHOLOGIC T2b Tumor involves more than one-half of one lobe but not pNX Regional nodes not sampled both lobes pN0 No positive regional nodes T2c Tumor involves both lobes pN1 Metastases in regional node(s) T3 Tumor extends through the prostate capsule2 DISTANT METASTASIS (M)5 T3a Extracapsular extension (unilateral or bilateral) M0 No distant metastasis T3b Tumor invades seminal vesicle(s) M1 Distant metastasis T4 Tumor is fixed or invades adjacent structures other than M1a Nonregional lymph node(s) seminal vesicles, such as external sphincter, rectum, bladder, levator muscles, and/or pelvic wall M1b Bone(s) PATHOLOGICAL (PT)3 M1c Other site(s) with or without bone disease pT2 Organ confined pT2a Unilateral, one-half of one side or less

1Tumor found in one or both lobes by needle biopsy, but not palpable or reliably visible by imaging, is classified as T1c. 2Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is classified not as T3 but as T2. 3There is no pathological T1 classification. 4Positive surgical margin should be indicated by an R1 descriptor (residual microscopic disease). 5When more than one site of metastasis is present, the most advanced category is used. pM1c is most advanced. development.250 Perhaps, one of these tools may overcome the inad- mRNAs or prostate cancer DNAs, polymerase chain reaction (PCR) equacies of 111In-capromab. approaches, capable of astonishing sensitivity, are typically used. Cir- culating tumor cells (CTCs) appear early in the course of prostate Serum Biomarker Assays and “Molecular” cancer, though simple enumeration of the cells does not provide clear 276,277 Classification for Prognosis prognostic information for those with localized cancers. Further, the presence of CTCs at diagnosis does not accurately predict the The serum PSA level at the time of a prostate cancer diagnosis is development of metastatic disease posttreatment. correlated with both intermediate and long-term outcomes including tumor volume, stage, grade, and freedom from relapse after treat- ment.268 However, the serum PSA cannot be used alone to predict PRIMARY THERAPY disease extent for an individual patient. Instead, PSA values are more Selection of Treatment Approach typically used as part of multivariable models for predicting the extent of disease and the probability that a cancer will behave in an aggressive Men thought to have localized prostate cancer face a number of manner.269,270 The NCCN recommends the use of the D’Amico clas- management options, including observational strategies (watchful sification scheme using serum PSA, clinical stage, and biopsy Gleason waiting, active surveillance), radical prostatectomy, interstitial brachy- score to stratify men into low-, intermediate-, and high-risk groups therapy, and external beam radiation therapy. Furthermore, cryo- for selecting management strategies and for counseling patients about therapy, high-intensity focused ultrasound (HIFU), and focal therapy prognosis.271 Other PSA forms used in the detection and diagnosis are also being presented to some patients as treatment alternatives of prostate cancer, such as %fPSA, proPSA, and so forth, are not part despite limited long-term data to support their use. A number of of commonly employed risk stratification and prognosis tools. issues should be considered by patients and physicians before decid- “Molecular” classification of tumor cells for prognosis refers to the ing on a management strategy. These include the specific side effect detection of circulating prostate cancer cells and/or cell fragments, profile of different treatments, the possibility that certain comorbid either indirectly, by identifying mRNA species, like those encoding conditions might increase the severity of side effects or the risk of PSA or PSMA, characteristically expressed by epithelial cells from the complications, the characteristics of the cancer and the risk of pro- prostate,272 yor directly, b recovering “circulating” prostate cancer cells gression without treatment, patient comorbidities that might limit by a variety of isolation methods.273-275 oT detect prostate lineage the need for treatment, and individual patient preferences.278 1478 Part III: Specific Malignancies

Death from any cause, total cohort Death from prostate cancer, total cohort

0.6 0.6 P = 0.007 by Gray’s test P = 0.01 by Gray’s test 0.5 0.5 Radical 0.4 Watchful 0.4 prostatectomy 0.3 waiting 0.3 0.2 0.2 Watchful waiting

Probability Radical Probability 0.1 prostatectomy 0.1 0.0 0.0 0 3 6 9 12 15 0 3 6 9 12 15 A Years B Years No. at risk No. at risk Radical prostatectomy 347 339 311 271 214 109 Radical prostatectomy 347 339 311 271 214 109 Watchful waiting 348 334 306 251 192 96 Watchful waiting 348 334 306 251 192 96

Death from any cause, men ≥65 yr of age Death from prostate cancer, men ≥65 yr of age

0.7 0.7 P = 0.89 by Gray’s test P = 0.41 by Gray’s test 0.6 0.6 0.5 0.5 0.4 Radical 0.4 Watchful prostatectomy 0.3 0.3 Radical waiting Watchful prostatectomy Probability 0.2 waiting Probability 0.2 0.1 0.1 0.0 0.0 0 3 6 9 12 15 0 3 6 9 12 15 C Years D Years No. at risk No. at risk Radical prostatectomy 190 185 166 135 99 42 Radical prostatectomy 190 185 166 135 99 42 Watchful waiting 182 177 162 133 101 42 Watchful waiting 182 177 162 133 101 42

Death from any cause, men <65 yr of age Death from prostate cancer, men <65 yr of age

0.6 0.6 P < 0.001 by Gray’s test P = 0.008 by Gray’s test 0.5 0.5 0.4 Watchful 0.4 Radical Watchful 0.3 waiting 0.3 prostatectomy waiting 0.2 0.2 Probability 0.1 Radical Probability 0.1 prostatectomy 0.0 0.0 0 3 6 9 12 15 0 3 6 9 12 15 E Years F Years No. at risk No. at risk Radical prostatectomy 157 154 145 136 115 67 Radical prostatectomy 157 154 145 136 115 67 Watchful waiting 166 157 144 118 91 54 Watchful waiting 166 157 144 118 91 54

Figure 84-11 • Results of a randomized trial of radical prostatectomy versus watchful waiting. (From Bill-Axelson A et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2011;364:1708-1717.)

During the past two decades, both surgery and radiation therapy Observational Strategies for prostate cancer have improved dramatically, providing effective local control of cancer in the prostate while reducing the threat of Watchful waiting was a common strategy in the pre-PSA era when side effects. The absence of unbiased comparative studies makes it most cancers were detected at an incurable stage and the morbidity difficult for patients to choose an approach that offers a clear advan- ofy primar treatments was high. The primary intent of watchful tage in terms of disease-free survival or quality of life outcome. Thus waiting was to avoid treatment until symptoms emerged and non- patient preferences should play a large role in a shared decision curative palliative treatment might be necessary.279 nI contrast, active process between patient and . surveillance,e a mor modern approach, involves the selective delayed The NCCN guidelines for the management of clinically local- curative treatment of men found to have disease progression while ized prostate cancer reflect the needed consideration of both life being carefully monitored. Active surveillance implies a much more expectancy and the risk profile of the individual patient’s cancer diligent monitoring regimen than watchful waiting. in making management recommendations (http://www.nccn.org; The Scandinavian Prostate Cancer Group Study 4 (SPCG-4), see Table 84-3).271 a trial conducted before the PSA screening had been adopted, Prostate Cancer • CHAPTER 84 1479

Table 84-3 Management Options for Localized Prostate Cancer by Risk Profile and Life Expectancy

Risk Profile Criteria Management Option Very low Stage T1c, and Gleason score ≤6, and PSA <10 ng/mL, Active surveillance if life expectancy <20 years and <3 biopsy cores with cancer, ≤50% involvement of any core with cancer, PSA density <0.15 ng/mL/cm3 Low Stage T1c or T2a, and Gleason score ≤6, and PSA Active surveillance if life expectancy <10 years; radiation <10 ng/mL (external beam or brachytherapy) or surgery if life expectancy ≥10 years Intermediate Stage T2b or T2c, or Gleason score 7, or PSA 10–20 ng/ Active surveillance or external radiation with/without mL brachytherapy or surgery if life expectancy <10 years Surgery or external radiation with/without ADT with/without brachytherapy if life expectancy ≥10 years High Stage T3a, or Gleason score 8–10, or PSA >20 ng/mL External radiation + ADT or surgery

Adapted from Carter HB. Management of low (favourable)-risk prostate cancer. BJU Int 2011;108:1684-1695. ADT, androgen deprivation therapy.

Dose-volume histogram 1.0 0.9 0.8 0.7 0.6 0.5 0.4

Normal volume 0.3 0.2 0.1 0.0 0 1000 2000 3000 4000 5000 6000 7000 8000 A B Dose (cGy)

Figure 84-12 • Intensity-modulated radiation therapy (IMRT). A, Representative axial CT slice from a man with low-risk prostate cancer treated by using a seven-field IMRT plan. The isodose distribution is displayed. Dark inner line, prescription isodose curve. B, TThe IMR treatment plan shown as a dose/”volume histogram: the curves from left to right represent bladder, rectum, and prostate. randomized men (n = 695) with localized prostate cancer to surgery intervene early with curative therapy if the disease should progress,279 or watchful waiting (Figure 84-12).280 Although these men would not while sparing men with more indolent prostate cancer the side effects have been considered optimal candidates for active surveillance by of aggressive primary therapy.282,283 This management approach, current criteria, as most of the men had palpable disease by DRE, which relies on diligent monitoring for signs of disease progression, surgery was accompanied by a 40% reduction in prostate cancer has been called a variety of names, including “expectant management deaths for men with 15 men needing treatment to prevent a single withe curativ intent” and others, but active surveillance is the termi- prostate cancer death. Of note, the benefits of surgery were restricted nology most often used today.270,278,284 to men under the age of 65 years. The Prostate cancer Intervention The rationale for active surveillance has been derived from Versus Observation Trial (PIVOT), a study conducted in the setting medical evidence reflecting a variety of reported studies, including of common PSA screening, randomized men (n = 731) with a mean competing risk analyses, surgical series, nonrandomized cohort age of 67 years to surgery or watchful waiting.281 The distribution of studies, and randomized trials. Taken together, the findings indicate prostate cancer cases among the study subjects included 43% low- that using a time horizon of 10 to 15 years, less than 3% of men risk, 36% intermediate-risk, and 20% high-risk disease. These data, diagnosed with well-differentiated tumors (Gleason score 6 or below) whiche hav been presented but not yet published, suggest that classified as low-risk (based on a serum PSA <10.0 ng/mL and tumor through 12 years of follow-up there has been no difference in cancer- stage of T2a or less) will die of prostate cancer whether treated or specific survival attributable to treatment. Thus older men with low- not.281,285-288 Such data clearly call into question the need for treating risk, screen-detected, prostate cancers may not derive great benefits men with low-risk disease and a life expectancy of less than 10 to 15 from radical prostatectomy. years. Unfortunately, curative intervention for favorable-risk prostate Active surveillance seeks to individualize prostate cancer care pri- cancer appears to be undertaken as commonly as curative interven- marily among men thought to harbor low-grade prostate cancers who tion for higher-risk disease.289-291 This is of concern because at least would otherwise be fit for curative treatment. The intent is to half of newly diagnosed men with prostate cancer have favorable risk 1480 Part III: Specific Malignancies

disease, and 80% to 90% of these men undergo some form of prostatectomy (RRP) that dramatically decreased operative morbid- treatment even when the age at diagnosis is above 75 years. Over- ity, to the widespread use of PSA testing that led to an earlier diag- treatment of nonthreatening prostate cancer probably reflects the nosis of disease, and to the ease of detection of prostate cancer with combination of a fear of harm from cancer, of litigation if aggressive TRUS-directed prostate biopsies.6 treatment is not recommended, and of misaligned incentives that Radical prostatectomy can be performed under regional or general favor treatment in spite of evidence that nonintervention may be the anesthesia using a perineal, retropubic, or laparoscopic approach. most rational option. Radical perineal prostatectomy is not a commonly performed proce- Despite these biases driving overtreatment of favorable-risk pros- dure today; rather, the most common approach to removal of the tate, cancer there has been a growing interest in active surveillance prostate for treatment of prostate cancer is robot-assisted laparoscopic approaches as evidenced by the number of academic centers reporting radical prostatectomy (RALRP). With RALP, the robotic system (a outcomes from single-arm cohort studies.184,218,270,278,284 As of yet, console connected to robotic arms) translates the movement of the there is no standard approach to selection of men for active surveil- surgeon’s fingers into movement of robotic arms attached to the lapa- lance,e nor ar there established guidelines for monitoring regimens, roscopic instruments used to perform the surgery. Claims of advan- or for criteria to be used as triggers for curative intervention, for men tages of RALP over other approaches have been widely touted by managedy b active surveillance. The “ideal” candidate may be a man surgeons, hospitals, and the device manufacturer, resulting in with favorable-risk prostate cancer (very low-risk to low-risk), a life increased usage of surgery overall, especially in older men.296 However, expectancy less than 15 years, and a personal desire to avoid the side there is no evidence for improved disease-free or functional outcomes effects of prostate cancer treatments. Typical monitoring strategies with RALP compared to RRP.297-299 Instead, both disease-free and tend to involve DRE and serum PSA determinations at 3- to 6-month quality-of-life outcomes after radical prostatectomy depend more on intervals, with repeated prostate biopsies at intervals of 1 to 4 years. the experience of the surgeon than on the surgical approach used.300 The most common intervention triggers are a rising serum PSA and With any surgical approach, prior pelvic surgery or radiation an increase in Gleason score of cancer seen on repeat biopsy, a finding therapy tends to be associated with an increased risk of surgical that may result from undersampling by the initial biopsy or from complications. “dedifferentiation” of a low-grade cancer. When managed in this way, Regardless of the surgical technique used, in most cases (especially approximately 25% to 50% of men will undergo curative interven- in the setting of intermediate-risk or high-risk disease), the radical tion within 5 to 10 years of surveillance. Of the men proceeding to prostatectomy proceeds via a staging pelvic lymphadenectomy, focus- curative treatment, 25% will do so because of personal preference ing on the pelvic lymph nodes surrounding the external iliac vein and and without any trigger, 30% to 40% will do so because of a higher obturator fossa. The remaining steps of the operation include ligation Gleason score, and 30% to 40% will do so because of an inexorably of the dorsal vein complex anterior to the prostate to control blood rising serum PSA.270,284 neI one activ surveillance series for men with loss, division of the urethra, identification and preservation of the prostate cancer (30% intermediate-risk disease and 70% with neurovascular bundles containing branches of the pelvic nerves inner- favorable-risk disease), the 10-year prostate cancer actuarial survival vating the corpora cavernosa necessary for penile erection (unless was 97%.292 An ongoing trial, the Prostate Testing for Cancer and wide excision of a neurovascular bundle is necessary for cancer Treatment (ProtecT) trial, which started in the United Kingdom in control), division of the bladder neck, resection of the seminal vesi- 2001, has randomized men with prostate cancer, ages 50 to 69 years cles, and construction of a urethrovesical anastomosis. to conformal radiotherapy, radical prostatectomy, or active surveil- Hemorrhage and injury to surrounding structures (blood vessels, lance.293 Results from this trial may further inform the difficult deci- obturator nerve, ureter, and rectum) are the most common intraop- sion that men with localized prostate cancer face in choosing between erative complications of radical prostatectomy. In the immediate active surveillance and curative intervention. postoperative period, complications can include deep venous throm- bosis and pulmonary emboli, urine anastomotic leak, and postopera- Radical Prostatectomy tive bleeding. The operative mortality rate (death within 30 to 60 days) after radical prostatectomy is from 0.4% to 1.6%, depending Radical prostatectomy is most often recommended for treatment of on age and comorbidity.301 Following surgery, most men spend 1 to men with clinically localized prostate cancer who have a life expec- 2 nights in the hospital and have an indwelling urinary catheter for tancy of at least 10 years or more (Table 84-3). Although there are 1 to 2 weeks to allow healing of the vesicourethral anastomosis. After not specific or universally accepted age limits for radical prostatec- catheter removal, the most common long-term complications of tomy, increasing age is associated with a lower likelihood of receiving surgerye ar urinary incontinence as a result of intrinsic sphincter surgical treatment for prostate cancer. For example, among men with deficiency, and erectile dysfunction from injury to the cavernous low-risk or intermediate-risk disease, 3 in 4 at ages 56 to 65 years, 2 nerves innervating the corporal bodies of the penis, both of which in 5 at ages 66 to 75, and 1 to 2 in 10 at age >75 years undergo surgi- negatively impact quality of life. cal intervention for prostate cancer.294 Preoperative assessment of men for radical prostatectomy typically Urinary Function after Radical Prostatectomy includes a history and physical examination, hematology studies, serum electrolyte studies (with a serum creatinine determination), a Urinary incontinence rates after radical prostatectomy vary greatly in urinalysis, coagulation studies, and an electrocardiogram. Many sur- different reports: from 5% to as high as 50%, with as many as 5% geons recommend a delay of 6 to 8 weeks after prostate needle biopsy to 10% of men undergoing another procedure for incontinence after to permit resolution of hematomata/inflammation caused by the radical prostatectomy.297 Some of the variation in reported inconti- biopsy procedure. In anticipation of surgery, men avoid aspirin, non- nence rates may be attributable to differences in definitions of incon- steroidal antiinflammatory agents, or high doses of vitamin E that tinence (stress incontinence vs. more severe difficulties with urinary might promote excess bleeding. control), in the time after surgery when urinary continence was Radical prostatectomy was not commonly recommended for assessed (urinary control can improve over as long as a year following localized prostate cancer prior to the 1980s because of blood loss, and surgery), in whether incontinence was reported by treating surgeons associated complications of incontinence and erectile dysfunction. in case series or by patients in survey questionnaires, and in the age Buty b 1990, surgery was the most commonly chosen option for of the patients undergoing surgery (older age is associated with higher management of prostate cancer.295 The increasing rates of radical incontinence rates). In the best case series, as many as 95% of men prostatectomy relative to other management options was in large part are completely dry 2 years after radical prostatectomy, and as many due to the description of an anatomic approach to radical retropubic as 98% of men report no significant urinary problems.302,303 Using Prostate Cancer • CHAPTER 84 1481

Table 84-4 Percentage of Men’s Quality-of-Life Concerns 24 Months after Treatment of Localized Prostate Cancer

External Beam Quality-of-Life Domain Prostatectomy Radiation Therapy Brachytherapy Urinary irritation or Dysuria <1 1 5 obstruction Hematuria 0 <1 1 Weak stream 4 10 11 Frequency 10 14 20 Urinary incontinence Leaking >1 time per day 14 7 10 Frequent dribbling 5 2 3 Any pad use 20 5 8 Leaking problem 8 5 6 OVERALL URINARY PROBLEM 7 11 16 Bowel function Urgency 2 16 9 Frequency <1 10 7 Fecal incontinence <1 2 5 Bloody stools <1 5 3 Rectal pain 2 4 4 OVERALL BOWEL PROBLEM 1 11 8 Sexual function Poor erections 58 60 48 Difficulty with 42 50 38 Erections not firm 64 66 54 Erections not reliable 51 51 40 Poor sexual function 53 58 43 OVERALL SEXUALITY PROBLEM 43 37 29

Adapted from Sanda MG et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med 2008;358:1250-1261. validated questionnaires to assess urinary incontinence and bother, in erectile function following radical prostatectomy, and this approach Sanda et al.304 found urinary incontinence (any pad use) two years is routinely used today when preservation of these nerves will not after treatment in 20% of men postsurgery, with a moderate-to-severe compromise removal of all cancer. urinary problem in 7% (Table 84-4). Most men after radical prosta- As is the case with urinary continence after radical prostatectomy, tectomye hav some degree of stress incontinence for a period of time reports of return of erectile function vary greatly from 31% to 86% that usually resolves within the first postoperative year, after which with study differences likely due to definitions of potency used, the incontinence is not likely to improve further. methods for assessing return of sexual function, the cohort studied, Surgical technique has significant consequences for urinary control and timing of assessment after surgery.309 Return of erections after following radical prostatectomy. Both the striated urinary sphincter surgery inversely correlates with age, and is directly associated with musculature and smooth muscle surrounding the urethra can be the quality of preoperative erections, the frequency of sexual activity injured during surgery.305 Postoperative strictures at the site of the preoperatively, and the quality and extent of nerve preservation. In a vesicourethral anastomosis can also affect return of urinary control.306 study using validated questionnaires to assess sexual function, sexual Avoidance of strictures (scars) by performance of a careful, tension- dysfunction was found to remain a big problem one year after treat- free, vesicourethral anastomosis has led to improved urinary control ment in 26% of men who underwent radical prostatectomy, with ratesy b expert surgeons.307,308 Men with persistent or severe urinary distress related to sexual dysfunction described by 44% of sex partners incontinence after radical prostatectomy can be treated with periure- postoperatively.304 Most of the improvement in erections occurs thral injections of bulking agents (silicone) that increase resistance at within the first 2 years after surgery.310 the bladder outlet, a pelvic sling placed through the perineum that Common approaches to managing erectile dysfunction after repositions the urethra, and an artificial urinary sphincter—a three- surgery include PDE-5 inhibitors, vacuum erection devices, vasoac- piece device made up of a compressing urethral cuff, a fluid-filled tive agents placed intraurethrally or injected directly, and placement reservoir placed in the abdomen that transmits pressure to the ure- of a penile prosthesis. Current thinking is that injury to the nerves thral, cuff and an activating pump placed in the scrotum that transfers (even when preserved at surgery) supplying corporal tissues results in fluid from the cuff to the reservoir allowing the cuff to open and the injury to the corporal tissues that may be ameliorated by increased bladder to empty. penile blood flow. Thus most sexual medicine experts encourage men to aggressively pursue attempts to achieve erections as soon as possible Erectile Function after Radical Prostatectomy after surgery. If spontaneous erections do not occur with stimulation and PDE-5 inhibitors, men are encouraged to pursue other options In 1982, Walsh and Donker described the anatomy of the nerves described above, the greatest success achieved being with penile injec- traversing the lateral surface of the prostate en route to the corpora tion. therapy 311 cavernosa of the penis, discerning the proximity of the nerves to vascular structures (the neurovascular bundles) visible at the time of Control of Prostate Cancer by Radical 5 radical prostatectomy. This revelation led Walsh et al. to propose a Prostatectomy modification of the radical prostatectomy procedure to preserve the neurovascular bundles in an effort to maintain erectile function post- Because PSA is a prostate-specific biomarker, successful removal of operatively.6 Wide adoption of this modification led to improvements all prostate tissue after radical prostatectomy should result in an 1482 Part III: Specific Malignancies

undetectable serum PSA. A detectable PSA after surgery, and/or a These types of low-energy radiation machines were used until cobalt rising PSA, is an indication of residual prostate cancer that is referred machines became available and provided the first opportunity to treat to as a biochemical recurrence. Most series define a biochemical more deeply seated tumors in the body. The first reported series of recurrence after surgery as a serum PSA that is above 0.2 ng/mL or prostate cancer patients treated with 60Co therapy was by George rising. Biochemical recurrence rates vary directly with the risk assign- et al. in 1965 and featured men with unresectable disease.318 During mente befor surgery (low-risk, intermediate-risk, high-risk; see Table this time (beginning in the late 1950s), the megavoltage linear accel- 84-3), age, the extent and grade of the cancer found on final patho- erator was being developed at Stanford University.319 Using this new logical assessment. In modern surgical series, for men with localized technology, the pioneering work of Bagshaw, Kaplan, Del Regato, prostate cancer, biochemical recurrence-free survival at 5, 10, and 15 and others, ushered in the modern era of radiation therapy for pros- years is reported at 84%, 74%, and 66%, respectively.312 tatey cancer b offering the possibility of cure with radiation therapy Biochemical recurrence is not a surrogate for cancer-specific mor- in this disease.320,321 tality because most men with a biochemical recurrence as the only Now men with prostate cancer have several different radiotherapy evidence of residual disease do not die of prostate cancer. A study options, each of which can be employed with very high precision and of the natural history of biochemical recurrence in a cohort of men with great effectiveness. The integration of computer-based technol- (n = 450) who underwent surgery for presumed localized prostate ogy for the design of three-dimensional conformal treatment plans, cancer, had rising serum PSA, and received no treatment until the and use of high-energy accelerators with sophisticated dynamic development of overt metastases, at a median follow-up of 8 years, shielding, allows men with prostate cancer to be treated with high revealed that only 30% of the men had developed metastatic disease.313 doses of radiation, while at the same time sparing surrounding normal For these men, the median time from surgery to biochemical recur- tissues.n I addition, the development of permanently implantable rence was 3 years and the median metastasis-free survival was 10 radioactive sources, along with the use of real-time imaging and treat- years. The Gleason score and PSA doubling time were independent ment planning, has also provided the opportunity for sophisticated predictors of metastasis-free survival, with no evidence of metastases techniques resulting in safe and efficacious in 94% of men with prostate cancer and a Gleason score of 6 or less treatment of men with prostate cancer. versus 19% of those with Gleason scores of 8 to 10, and no evidence Traditionally, men with prostate cancer referred for radiation of metastases in 72% of men with recurrent prostate cancer and a therapye hav tended to be older, to be in poorer health, and to have PSA doubling time of >15 months versus 7% of those with a PSA with higher risk, more advanced tumors than those patients treated doubling time of 3 to 9 at 10 years, respectively. surgically. As such, results using less sophisticated radiation therapy Cancer-specific survival after radical prostatectomy was recently techniques were less than optimal, raising concerns that radiation evaluated in a multiinstitutional study of men (n = 11,521) with therapy might not be as effective as radical prostatectomy. However, prostate cancer diagnosed in the PSA era, revealing a cumulative with long-term results obtained across a broad range of patients, it is incidence of prostate cancer deaths at 15 years of only 7%.287 Predic- now clear that radiation therapy for prostate cancer provides excellent tors of prognosis include the Gleason grade and the presence of disease-free survival, comparable to radical prostatectomy for men at seminal vesicle invasion, with prostate cancer mortality rates of 0.2% similar risk of prostate cancer recurrence. In this section, a brief to 1.2%, 4.2% to 6.5%, 6.6% to 11%, and 26% to 37% for Gleason description of how men are evaluated and risk-stratified for radiation scores of 6 or less, 3+4, 4+3, and 8 to 10, respectively, and 0.8% to therapy will be provided, followed by a description of treatment 1.5%, 2.9% to 10%, 15% to 27%, and 22% to 30% for organ- techniques and a review of treatment outcomes for men with low-, confined cancer, cancer with extraprostatic extension, cancer with intermediate-, and high-risk prostate cancer. The use of radiation seminal vesicle invasion, and cancer accompanied by lymph node therapy to treat local prostate cancer recurrences after radical prosta- metastasis, respectively.287 Because these results were from a single- tectomy will also be reviewed. arm study without a comparison group, it is not possible to know to what extent the favorable surgical results for screen-detected cancers were a result of surgical intervention for a lethal phenotype versus the External Beam Radiotherapy for Localized intrinsic indolent biological behavior of many such cancers. Hope- Prostate Cancer using 3D-Conformal and fully, results from PIVOT, comparing surgery with watchful waiting, Intensity-Modulated Approaches and from ProtecT, comparing conformal radiotherapy, prostatec- tomy, and active surveillance will provide more definitive answers to Fore mor than four decades, external beam radiotherapy has been this question. widely used for the definitive management of clinically localized prostate cancer. More recently, technical advances have permitted the Radiation Therapy safe delivery of 80 Gy to the prostate, while minimizing radiation exposure of nearby normal tissues. Historically, a four-field pelvic box Radiation therapy has been used in the management of prostate with shielding of the posterior wall of the rectum and anal canal was cancer for nearly a century. Following Roentgen’s discovery of the used to treat the prostate, seminal vesicles, and proximal lymphatic x-ray in 1895,314 and the isolation of radium by Pierre and Marie drainage to a dose of 45 to 50 Gy in 1.8- to 2.0-Gy fractions, with Curie in 1898,315 several pioneering physicians began treating pros- a boost to the prostate to 65 to 70 Gy. Even at these doses, external tate disorders, including prostate cancer, with radiation. In 1910, beam radiation therapy was fairly effective: although overall survival Paschkis and Tittinger inserted radium into the prostatic urethra with numbers were generally higher for men treated with radical prosta- a cystoscope in what may be the use of radiation for prostate cancer. tectomy (often younger and healthier men), cause-specific survival Not long after, Hugh Hampton Young from Johns Hopkins reported rates were not significantly different.322 Although the four-field box the relatively large experience of treating prostate cancer patients with radiation therapy technique is of historic significance only, it is worth urethral and rectal radium “applicators.”316 These and other early noting that side effects (rectal bleeding, dysuria, bowel dysfunction, studies revealed that even when radiation was applied in this crude etc.) associated with this technique were higher than those seen with manner, it could improve symptoms and kill prostate cancer. However, contemporary technologies and delivery. treatment was technically difficult for the physician and uncomfort- To improve on these outcomes, new technical innovations, able for the patient. In 1928, the first report on the use of externally such as CT-based simulation/treatment planning, the introduction delivered low-energy kilovoltage radiation for prostate cancer was of multileaf collimators in modern linear accelerators, and advances profferedy b Barringer.317 The associated dosimetry was not well in treatment planning software have allowed for increased precision worked out and, thus men were treated until their skin turned red. and accuracy in prostate cancer radiotherapy. For three-dimensional Prostate Cancer • CHAPTER 84 1483 conformal radiation therapy (3D-CRT), three-dimensional recon- Complications of 3D-CRT and IMRT structions of pelvic CT images are generated to create more accurate target volumes (e.g., prostate and seminal vesicles) for treatments, Although the use of 3D-CRT was intended to minimize the effects enabling better identification of critical structures (e.g., bladder and of high-dose radiation on normal tissues, increased late complica- rectum) to be avoided. An iterative process is then used to design tions, such as rectal and urinary toxicity, have been noted with escalat- beam arrangements that will deliver a prescribed dose to the regions ing radiation doses used in 3D-CRT.323,324 Rectal toxicity encompasses of interest and minimize dose to a given volume of an adjacent organ. urgency, frequency, pain, fecal incontinence, or bleeding. In a Fox In, this way the incident radiation volume “conforms” to target Chase Cancer Center case series, the 5-year incidence of grade 3 or volume. The treatment target volumes and normal organs can then 4 rectal toxicity at a dose of 75 to 76 Gy was 8%, which upon better be visualized in three dimensions, creating a “beam’s-eye view,” a shielding of the anterior rectal wall, could be reduced to 2%. IMRT portrayal of the target area as if looking straight down the path of the seems to be accompanied by less rectal complications. In one case radiation beam. During treatment delivery, computerized multileaf series, men with clinically localized prostate cancer treated with collimators then shape each individual beam to conform to the shape IMRT to a total dose >81y G at Memorial Sloan-Kettering Cancer of the target in the beam’s-eye view. Intensity-modulated radiation Center exhibited a reduction in late rectal toxicity when compared therapy (IMRT) builds on the advantages of 3D-CRT by using treat- with 3D-CRT.325 With a median follow-up of 24 months, grade 2 or ment planning software capable of even further optimizing dose higher rectal bleeding was seen in 4% of men receiving IMRT, with distribution for prostate cancer treatment, by modifying not just the grade 3 rectal toxicity in only 0.5% (and no grade 4 rectal toxicity) orientation and shape of the incident beams but also the intensity at 3 years. Urinary toxicity, including urethral strictures, tends to be across the designated treatment volume (Figure 84-13). similar for both 3D-CRT and IMRT, with as many as 15% of men suffering late grade 2 urinary complications. Because this may be the result of high-dose radiation to the urethra, decreasing urethral doses for men with prostate cancer limited to the peripheral zone of the prostate may be a means of reducing late urinary toxicity, but better PSA ≤ 10 ng/mL diagnostic imaging will be necessary to identify men with such 1.0 cancers. Overall, for external beam radiation therapy, 9% to 11% of 78 Gy men treated can expect to have some level of rectal or urinary distress 0.9 70 Gy 1 year after treatment (Table 84-4).304 0.8 Data on the incidence of erectile dysfunction after external beam 0.7 radiotherapy has been widely variable. Sexual function has many 0.6 facets that are difficult to evaluate or quantify. A commonly used qualitative definition of sexual potency is the ability to achieve spon- 0.5 taneous erections sufficient for intercourse. Although potency rates 0.4 after radical prostatectomy have increased with use of nerve-sparing 0.3 techniques, the mechanism of radiation-related erectile dysfunction

Fraction free of failure 0.2 appears unrelated to the neurovascular bundles. Zelefsky et al. specifi- cally addressed this topic by performing duplex ultrasound studies 0.1 P=0.46 before and after prostaglandin injection to stimulate erections in men 0.0 with radiation-related erectile dysfunction.326 A diminished peak 0 20 40 60 80 100 penile blood flow rate (<25 mL/min) was evident in 63% of such A Months after radiotherapy men, with abnormal distensibility of the corpora cavernosa in 32%. Thus, the primary mechanism of radiation therapy-associated impo- tence may be vascular damage rather than nerve damage. Fisch et al. PSA>10 ng/mL demonstrated a correlation between incidence of erectile dysfunction 1.0 postradiotherapy and radiation dose to the vascular penile bulb.327 78 Gy 0.9 70 Gy Men receiving >70y G to >70% of the bulb of the penis are at greatest 0.8 risk of experiencing radiation therapy–associated erectile dysfunction. A steady decline in potency rates over time is characteristic for men 0.7 treated with external beam radiation therapy. In a large series (n = 0.6 434) of men treated with radiation therapy at Stanford University, 0.5 86% of the men remained potent at 15 months after treatment, but 0.4 only 50% were potent 6 years later, and only 30% maintained erectile function for the remainder of their lives.328 Sildenafil administration 0.3 resulted in improvement of erectile function in 74% of men with Fraction free of failure 0.2 radiation therapy–associated erectile dysfunction in a study at Memo- 0.1 329 P=0.012 rial Sloan-Kettering Cancer Center. Men who do not respond to 0.0 sildenafil may respond to intracavernosal prostaglandin injections. 0 20 40 60 80 100 Cancer Control by External Beam B Months after radiotherapy Radiation Therapy Figure 84-13 • Kaplan-Meier actuarial probability of relapse-free sur- With the ready availability of serum PSA testing, outcome compari- vival after radiation therapy for prostate cancer, stratified by radiation dose sons between primary prostate cancer treatments tend to focus on (78y G vs. 70 Gy). A, Men with favorable-prognosis prostate cancer (serum prostate-specific antigen [PSA] ≤10 ng/mL). B, Men with poorer-prognosis PSA as a marker of prostate cancer recurrence (“PSA relapse”–free prostate cancer (serum PSA, 10 ng/mL). (From Pollack A, Zagars GK, Stark- survival).f O course, if successful in controlling cancer, surgical schall G, et al. Prostate cancer radiation dose response: results of the M.D. removal of the prostate eliminates PSA production by both nonneo- Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys plastic and neoplastic cells, whereas radiation therapy may not abolish 2002;53:1097-1105.) PSA production by residual prostate epithelial cells even as cancer 1484 Part III: Specific Malignancies

cellse ar killed. Nonetheless, a rising serum PSA after radiotherapy for prostate cancer is correlated with the appearance of progressive or metastatic prostate cancer upon further follow-up.330 Furthermore, the rate of serum PSA rise may help distinguish between local versus distant treatment failure. Men with slow rates of serum PSA increases aree mor likely to have local prostate cancer recurrences, whereas men with a rapid serum PSA rise appear more likely to have distant pros- tate cancer metastates.331 nI 2006, the American Society for Thera- peutic Radiology and (ASTRO) issued a consensus statement establishing the definition of recurrence following radia- tion therapy as a serum PSA level that is 2.0 ng/mL over the nadir value.332 This definition is an update to the 1997 ASTRO criteria for biochemical recurrence (three consecutive rises of the serum PSA determined at least 3 months apart333)w and is no preferred for evalu- ating and comparing radiation treatment strategies. Before these cri- teria were formulated, treatment outcomes in different studies and case series were difficult to compare because of the lack of uniformity in defining treatment failure. External beam radiation therapy using 3D-CRT and IMRT approaches achieves effective prostate cancer control.324,334-336 nI a larget cohor of men (n = 1100) treated with 3D-CRT at Memorial Sloan-Kettering Cancer Center, the PSA relapse-free survivals for men with low-risk prostate cancer treated to radiation doses of 64.8 toy 70.2 G versus 81 Gy, were 77% and 98%, respectively.336 Men with intermediate-risk and high-risk prostate cancers also showed A significant improvement. In a randomized trial of radiation dose escalation, higher-dose treatment was associated with improvement in prostate cancer control rates for men with prostate cancer, espe- cially men with a pretreatment PSA >10 ng/mL (Figure 84-14).334,337 In this study, men (n = 305) with stage T1–T3 prostate cancer received either radiation therapy to a total dose of 70 Gy using con- ventional radiotherapeutic techniques, or to 78 Gy using a 3D-CRT approach. Results revealed a freedom-from-PSA relapse of 64% and 70% at 6 years for the 70-Gy and 78-Gy groups, respectively (P = 0.03). Men with a pretreatment serum PSA >10 ng/mL were found toe hav the most significant benefit from radiation dose escalation, with freedom-from-PSA relapse rates of 62% for the 78-Gy arm and 43% for the 70-Gy arm (P = 0.01). Overall survival was not signifi- cantly different between the two radiation doses, but a trend toward an improved freedom-from-distant metastasis was evident in men treated on the 78-Gy arm, 98% versus 88% at 6 years (P = 0.056). B

Figure 84-14 • Interstitial brachytherapy for prostate cancer. A, Radio- Brachytherapy graph obtained after implantation of radioactive seeds. B, CT image showing radioactive seed location within prostate. (From Speight JL, Roach M III: Prostate brachytherapy involves the implantation of radioactive Imaging and radiotherapy of the prostate. Radiol Clin North Am sources into the prostate using image guidance (Figure 84-15). In 2000;38:159-177.) principle, brachytherapy offers an attractive means for radiation dose escalation and conformality in the treatment of clinically localized prostate cancer. However, the most attractive feature for many men with prostate cancer is that this option may be most convenient, Brachytherapy may exhibit its greatest benefits in the treatment allowing a rapid return to normal lifestyle and activity. A typical of men with low-risk, clinically localized, prostate cancer, though in brachytherapy procedure is performed in 2 hours, often under spinal the absence of a prospective randomized trial, this recommendation anesthesia, and does not require an overnight hospital stay. The most has been based on retrospective studies with varying follow-up time. common sources in use today are 125I (Iodine) and 103Pd (Palladium) One of the largest of these studies reported outcomes for more than (Table 84-5). Thus far, there have been no compelling data to support 2500 men with prostate cancer treated at 11 different institutions the superiority of one isotope or the other. Theoretically, the higher with permanent interstitial brachytherapy.342 The median follow-up initial dose rate emitted by 103Pd might be advantageous for the treat- for this group of men with stage T1 or T2 prostate cancer was 63 ment of cancers, like prostate cancer, with a relatively low αβ ratio months and all were treated with either 125I or 103Pd without use of (more radioresistant); however, retrospective data for prostate cancer hormonal therapy. Men with low-risk, intermediate-risk, and high- have been inconclusive.338 oT date, no long-term prospectively ran- risk prostate cancer had 8-year actuarial PSA relapse-free survivals of domized data exist directly comparing 125I with 103Pd. Most experi- 82%, 70%, and 48%, respectively, using ASTRO criteria. The dosi- ence with prostate brachytherapy has been with permanent low metric quality of the implant was critical to outcome: for men in dose-rate (LDR) implants. Several centers have collected experience which 90% of the prostate (D90) received ≥130 Gy, the 8-year PSA with temporary high dose-rate (HDR) implants for prostate cancer relapse-free survival was 93%, whereas for men in which the prostate 339-341 brachytherapy. Although this treatment approach is not widely D90 was <130 Gy, the 8-year PSA relapse-free survival was 76%. used, the available results appear comparable with permanent brachy- There were few, if any, differences attributable to the use of 125I versus therapy for clinically localized prostate cancer. 103Pd implants. Prostate Cancer • CHAPTER 84 1485

100 Radiotherapy alone 90 Combined treatment 80 70 60 50 40 30 Overall survival (%) 20 Log-rank test P<0.0001, hazard ratio 0.51 10 (95% Cl 0.36–0.73) 0 0 1 2 3 4 5 6 7 8 Time since randomization (yrs)

O N No. of patients at risk 81 206 199 177 146 106 70 46 30 16 50 207 197 183 166 142 93 71 43 24 A

100 Radiotherapy alone 90 Combined treatment 80 70 60 50 40 30

Biochemically defined 20 Log-rank test P<0.0001, disease-free survival (%) hazard ratio 0.42 10 (95% Cl 0.28–0.64) 0 0 1 2 3 4 5 6 7 8 Time since randomization (yrs)

O N No. of patients at risk 36 66 64 59 50 29 17 9 4 3 56 170 169 157 138 116 76 50 26 13 B

Figure 84-15 • Kaplan-Meier estimates of survival for men with prostate cancer from a prospective randomized clinical trial comparing a combination of androgen-deprivation therapy (goserelin acetate for a total of 3 years with cyproterone acetate for 1 month) and radiation therapy with radiation therapy alone. A, Overall survival. B, Relapse-free. O, number of deaths; N, number of subjects. (From Bolla M, Collette L, Blank L, et al. Long-term result with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer [an EORTC study]: a phase II randomized trial. Lancet 2002;360:103-106.)

The addition of supplemental external beam radiotherapy to Table 84-5 Physical Differences Between 125I and 103 brachytherapy remains somewhat controversial. Davis et al. exam- Pd Radioactive Seeds ined the radial distance of extraprostatic extension of prostate cancer 125I 103Pd and found it to be almost always 5 mm or less, which would be within a typical brachytherapy dose distribution.343 Thus generous Year introduced 1965 1986 periprostatic margins in brachytherapy planning should obviate the Photon energy (keV) 28 21 need for supplemental external beam radiotherapy. Proponents of Half-life (d) 59.4 17 combinations of brachytherapy and external beam radiation therapy emphasize both the advantage of higher delivered doses and the Initial dose rate (for monotherapy) 7 cGy/h 18–20 cGy/h ability to smooth out cold spots inherent with brachytherapy, the RBE 1.4 1.9 so-called spackle effect. Sylvester et al. have recently reported a ret- rospective review of 232 men with clinically localized prostate cancer RBE, relative biological effectiveness. treated with either 125I or 103Pd brachytherapy and external beam radiation therapy administered before the implant.344 tA a median follow-up of 9.4 years, the biochemical relapse-free survival for the entire study group was 74%, with biochemical relapse-free survival for low-risk prostate cancer of 85.8%, for intermediate risk disease 1486 Part III: Specific Malignancies

of 80.3%, and for the high-risk group of 67.8%. These results after brachytherapy tend to emerge within 3 years of implant place- compare favorably with all other surgical and/or radiation series with ment, with rectal injury in 5% to 10% of men treated.356,355,357,304 respect to long-term durable prostate cancer control. As popularity of prostate brachytherapy for clinically localized Relative contraindications to the use of prostate brachytherapy are prostate cancer grew in the 1990s, a commonly cited advantage of large prostate size, pre-implant obstructive urinary symptoms, history the treatment modality was a lower incidence of treatment-associated of prior TURP, and the presence of perineural prostate cancer inva- erectile dysfunction compared to external beam radiotherapy or sion on prostate biopsy. Large prostate size has been perceived to be radical prostatectomy. Undoubtedly, this selling point tipped the associated with a higher risk of urinary morbidity postimplant and scales in favor of brachytherapy for many men faced with selecting a with unsuitability for implant because of pubic arch interference. treatment for early-stage prostate cancer. For instance, Stock et al. Men with a prostate volume of greater than 50 mL have been either reported a 2-year potency rate of 94% after implant, whereas Wallner counseled against brachytherapy or placed on androgen deprivation et al. reported a 3-year potency rate of 86%.358,359 Studies with longer therapy (ADT) in an attempt to reduce gland size. Nonetheless, the follow-up, however, have shown a continued decrease in sexual implantation of large prostates with radioactive seeds has been potency over time. With more long-term follow-up in other case described with acceptable morbidity.345,346 nI one case series, postim- series, only 57% of men retained potency at 5 years.356 Even Stock plant dosimetry quality was found to be independent of prostate size et al. subsequently reported a 6-year potency rate of 59% in their or use of ADT.346 The correlation of preimplantation obstructive case series.360 Notably, their study found that 70% of men with urinary symptoms and postimplantation urinary obstruction has not normal erectile function before implant retained potency at 6 years, been fully resolved. Terk et al. reported that a high International whereas men with “erectile function sufficient for intercourse” but Prostate Symptom Score (I-PSS), a measure of obstructive urinary suboptimal erections had only a 34% 6-year potency rate. Using symptoms, predicted postimplant urinary retention.347 With the use postimplant dosimetry studies, Merrick et al. demonstrated that dose of α–blockers before and after implant procedures, others have noted to the penile bulb correlated with postimplant erectile dysfunction. no association between preimplant I-PSS and urinary obstruction.348 In the majority of men who retained potency, the dose delivered to A prospective study examining preimplant urinary flow rate and 50% of the penile bulb was less than 50 Gy.361 Potentially, this postvoid residual, in addition to I-PSS, showed no association of knowledge may result in improved morbidity outcomes with techni- obstructive urinary symptoms with postimplant urinary retention or cal attention to this dose threshold. Erectile dysfunction is not the long-term urinary function.349 TURP is thought to be a relative sole complication of prostate brachytherapy with the potential to contraindication to prostate brachytherapy as it has been associated affect sexual quality of life, however, with reports of hematospermia with unacceptably high rates of urinary incontinence. This could in 28%, orgasmalgia in 15%, and alteration in the intensity of orgasm possibly be attributable to seed placement approaches that result in in 38%.362 These side effects tend to be transient in most men. a high central dose to the TURP defect. However, by using a periph- eral source loading approach to limit dose to the TURP defect to Proton Beam Radiotherapy 110% of the prescription dose, the incidence of urinary incontinence may be reduced.350 Though only available at a few centers worldwide, there has been an A phenomenon peculiar to prostate brachytherapy that deserves interest in proton beam therapy for prostate cancer. The unique mention is the so-called PSA spike. With a time of onset between 12 physical properties of protons make them ideal for the treatment of and 30 months postimplantation, approximately one-third of men disease in proximity to critical strictures. Specifically, protons deposit with prostate cancer treated with brachytherapy will experience a the majority of their energy at the very end of their linear tracks, a transient increase in serum PSA.351 This spike may be due to radiation- phenomenon termed the “Bragg peak.” The dose falls off very rapidly associated prostatitis that compromises prostate architecture, permit- at depths beyond the Bragg peak. This is particularly useful in the tinge mor PSA to appear in the serum. Notably, such PSA spikes treatment of prostate cancer, to minimize rectal and bladder dose. portend no worse long-term outcome. Investigators from Loma Linda University reported their experience treating men (n = 1255) with T1–T3 prostate cancer.363 Men were Toxicity of Brachytherapy treated with protons alone to 74 cobalt Gray equivalents (CGE) or with photons to 45 Gy followed by proton boost to 75 CGE. The The short- and long-term sequelae of brachytherapy for prostate median follow-up was 62 months and the 8-year actuarial biochemi- cancer differ from those of external beam radiotherapy and radical cal disease-free survival rate was 73%. In a recent prospective, ran- prostatectomy. Kleinberg et al. described the morbidity outcomes of domized trial of 70.2 GyE versus 79.2 GyE (combination of photons the early Memorial Sloan-Kettering Cancer Center experience with plus protons) for men (n = 393) with stage T1b-T2b prostate cancer permanent transperineal brachytherapy, reporting that the most and a serum PSA <15 ng/mL, at a median follow-up of 5.5 years, common side effects were nocturia and dysuria (80% and 48%, 61.4% of the men treated with 70.2 GyE versus 80.4% of men respectively, 2 months after implantation).352 yB 12 months following treated with 79.2 GyE were free of biochemical treatment failure, implantation, these figures had declined (to 45% and 20%). Urinary supporting the concept that higher doses of radiation results in a retention is seen in 3% to 14% of men and usually lasts 1 week or statistically significant reduction in the risk of recurrence of localized less. The most bothersome late complications of prostate cancer prostate cancer.364 brachytherapy are urethral stricture and urinary incontinence. Ragde et al. reported a 5.1% incidence of urinary incontinence in men Adjuvant Endocrine Therapy treated with prostate cancer brachytherapy and followed for 7 years; each of the men with incontinence had a history of TURP.353 ADT has been found to improve treatment outcomes in randomized Urethral stricture appeared in 14.4% of the men. Others have also trials of men with high-risk prostate cancer treated with external seen an increased incidence of urinary incontinence in the setting beam radiation therapy but not as convincingly for men treated with ofy a histor of TURP.354 ntI a cohor study of Medicare beneficiaries radical prostatectomy (Figure 84-16).365-367 D’Amico et al. reported (n = 2124) who were treated with brachytherapy, urinary inconti- results of a large retrospective study (n = 1586) of men treated with nence was noted in 6.6% and bladder outlet obstruction requiring 3D-CRT plus or minus ADT for low-risk, intermediate-risk, and intervention was found in 8.3%.355 nI all, as many as 16% of men high-risk prostate cancer.368 nI this study, the median radiation dose treated with brachytherapy for prostate cancer can expect to suffer wasy 70.2 G and ADT was used for 2 months before radiation distressful urinary symptoms 2 years after treatment (Table 84-4).304 therapy, during treatment, and for 2 months after treatment was As is the case for external beam radiation therapy, rectal complications completed. With a median follow-up of 51 months, the 5-year PSA Prostate Cancer • CHAPTER 84 1487

Bone therapy for osteoporosis and bone metastases Bisphosphonates zoledronic acid Primary therapy surgery, radiation therapy, RANK ligand inhibitor Immunotherapy active surveillance denosumab sipuleucel-T

Castration- Metastatic Localized Recurrent Metastatic resistant - prostate cancer (rising prostate cancer (rising resistant cancer serum PSA) cancer serum PSA) cancer

Adjuvant hormonal therapy Androgen deprivation Chemotherapy (with radiation) LHRH analogs, LHRH docetaxel, cabazitaxel antagonists, anti-androgens, Figure 84-16 • Treatment of life-threatening androgen synthesis inhibitors prostate cancer.

relapse-free survival for men with low-risk prostate cancer was 92% improved PSA relapse-free survival with the addition of adjuvant with the addition of ADT versus 84% without. Men with intermedi- radiation therapy following radical prostatectomy in men with these ate- and high-risk prostate cancer also fared significantly better when risk factors.378-380 n,I one study men (n = 149) with pathological stage given. ADT Radiation Therapy Oncology Group (RTOG) Trial T3N0 prostate cancer and an undetectable postoperative serum PSA, 94-08, which completed accrual in 2001 and was reported in 2012, adjuvant radiation therapy was given to a median dose of 64.8 Gy to was designed to ascertain whether men (n = 1917) with stage T1b–T2 some men (n = 52), whereas the remainder (n = 97) underwent no prostate cancer and a serum PSA of 20 ng/mL or less benefit from further treatment.378 nI a matched-pair analysis, the 5-year freedom- the addition of “complete androgen blockade” given for 4 months from-PSA relapse rate was 89% in the adjuvant radiation therapy before and concomitantly with external beam radiation therapy.369 group versus 55% for treatment with surgery alone (P < 0.01). Results of this trial revealed that the addition of androgen suppression Three prospective randomized trials have been completed that to radiation significantly improved disease-specific and overall sur- tested the benefits of adjuvant radiation therapy versus observation vival, reducing overall deaths from 8% to 4% at 10 years. following radical prostatectomy in men with prostate cancer and poor ADT has also been used with prostate cancer brachytherapy, both pathological features. The European Organization for Research and to reduce the size of the prostate gland and to improve outcomes. Treatment of Cancer (EORTC) has published clinical trial results Most prostate glands exhibit some decrease in volume after 3 months revealing an improvement in biochemical relapse-free survival and of, ADT with an average 30% to 40% reduction, and little further locoregional progression-free survival for the men with pT3 tumors volume decreases.370 About 10% of prostate glands will show no or pT2/T3 prostate cancer and positive surgical margins treated with volume reduction at all in response to androgen deprivation. Decreas- adjuvant radiation therapy.366 nI a second study targeting the same inge the siz of the prostate may reduce pubic arch interference in patient population conducted by the Southwest Oncology Group selected men. Blank et al. reported that men treated with ADT (SWOG), men with prostate cancer who received adjuvant radiation tended to have smaller prostates that required fewer seed implants.371 not only enjoyed better biochemical and local control, but also However, at this point there are no data to suggest that smaller pros- appeared likely to have better metastasis-free survival and overall tate volumes correlate with reduced acute or late morbidity from survival; these improvements were not yet statistically significant even brachytherapy. Furthermore, although prospective randomized trials at a median follow-up of 10 years.381 Nonetheless, men treated with have demonstrated improved survival in those men with locally adjuvant radiation therapy were less likely to need hormonal therapy advanced prostate cancer treated with external beam radiotherapy and at 5 years (10% vs. 21%, P < 0.001). Avoidance of ADT is likely of ADT, it is not clear that these results can be extrapolated to men significant clinical benefit, reducing or delaying significant morbidity, treated with brachytherapy. A retrospective matched-pair analysis of including hot flashes, diminished bone density, sexual dysfunction, men (n = 60) with prostate cancer treated at Memorial Sloan- cognitive dysfunction, and overall reduced quality of life. Finally, a Kettering Cancer Center showed no benefit for the addition of ADT third randomized trial comparing adjuvant radiation and observation to brachytherapy for men with low-, intermediate-, or high-risk pros- after prostatectomy, which enrolled only men with pT3 disease tate cancers.372 regardless of surgical margin status, was reported by the German Cancer Study Group.382 As with the other two studies, men treated Postprostatectomy Adjuvant Radiation Therapy with adjuvant radiation experienced a superior biochemical relapse- free survival with median follow-up of only 3.3 years. Thus, overall, Pathological features that portend a higher risk of local recurrence are data available today provide a convincing case for adjuvant radiation common after radical prostatectomy. A positive surgical margin is treatment after prostatectomy. However, it is clear that not all men associated with an approximately 50% risk of prostate cancer benefit from such treatment. What is needed for the future is a more recurrence.373-377 Other features associated with recurrence are extra- precise way to stratify men for adjuvant radiation therapy: one such capsular extension, seminal vesicle invasion, and Gleason score of 7 group may be men with positive surgical margins after radical or greater. Several retrospective series have now demonstrated prostatectomy. 1488 Part III: Specific Malignancies

Salvage Radiotherapy after Radical androgen deprivation or androgen deprivation initiated at the time 391 Prostatectomy of PSA relapse. tA 5 years, 65% of men treated with immediate androgen deprivation versus 42% of men treated with delayed andro- Salvage radiotherapy refers to the use of radiation therapy postpros- gen deprivation were free of PSA relapse. There are no prospective tatectomy in the setting of recognized prostate cancer recurrence. As trials examining the addition of ADT to salvage radiation therapy for many as 27% to 53% of men who undergo radical prostatectomy for local prostate cancer recurrence after prostatectomy. Taylor et al. prostate cancer will have a detectable PSA within 10 years of surgery.383 reported a benefit to the addition of ADT to salvage radiation therapy Subsequently, approximately 25% of men who undergo radical pros- in a retrospective case series.392 nI this series, adjuvant ADT was given tatectomy will be treated with salvage radiation therapy for recurrent to men who received salvage radiation therapy for a median duration prostate cancer.384 nI the setting of persistent or rising serum PSA of 24 months. At 5 years, 81% of men receiving ADT (vs. 54% not following radical prostatectomy, it is important to rule out distant treated with androgen deprivation) were free of PSA relapse. In con- metastatic prostate cancer with bone scan, chest radiography, and CT trast, Song et al. reported identical median disease-free survivals of scan of the abdomen and pelvis, prior to the initiation of salvage 26 months for men treated with or without concurrent ADT along radiation therapy. Partin et al. correlated the rate of serum PSA rise with salvage radiation therapy for prostate cancer recurrence.387 The with likelihood of local versus distant relapse after surgery.385 A serum 1999O ASTR Consensus Panel concluded that there was insufficient PSA rise of 0.75 ng/mL/year was associated with local recurrence. In evidence to support routine use of ADT with postprostatectomy 1999, an ASTRO consensus panel concluded that treatment of men radiation therapy.386 with local prostate cancer recurrence after radical prostatectomy and In general, men receiving radiation therapy postprostatectomy a pre–radiation therapy serum PSA <1.5 ng/mL was more likely to experience little in the way of additional morbidity. The incidence of be successful.386 nI addition, doses above 64 Gy were recommended urinary incontinence does not seem to be increased and erectile func- in the salvage setting. Several studies have demonstrated a Gleason tion does not seem to be worsened in men treated with adjuvant score greater than 7 to be associated with a low likelihood of success- radiation therapy after prostatectomy.393,394 Bastasch et al. reported ful salvage after prostate cancer recurrence postprostatectomy.387,388 that 100% of men who were potent after nerve-sparing radical pros- Caddedu et al. reported no men free of PSA relapse treated with tatectomy remained potent after adjuvant IMRT.395 Despite these salvage radiation therapy after prostatectomy for prostate cancers with promising reports, side effects remain possible. Katz et al. noted that Gleason scores of 8 or above.388 Similarly, Song et al. found only 2 19% of men experienced grade 2 or 3 genitourinary toxicity (hema- of 14 men with Gleason score of 8 or above to be prostate cancer free turia or urethral stricture), and 12% of men experienced grade 2 at the time of analysis.387 These results indicate that men with recur- bowel toxicity (with no grade 3 or higher toxicity noted), following rent prostate cancer and a Gleason score of 8 or greater are unlikely salvage radiation with 3D conformal techniques.396 to benefit from salvage radiation therapy because of the likelihood of microscopic systemic prostate cancer metastases. LOCALLY ADVANCED DISEASE AND However, the largest multiinstitutional retrospective series to date PALLIATION (n = 501 men) has provided a clearer view of the likelihood of benefit for various subgroups of men with local prostate cancer recurrence Radiation Therapy and Adjuvant Endocrine 389 after prostatectomy. nI this study, predictors of a poor response to Therapy for Locally Advanced Prostate Cancer salvage radiation included Gleason scores of 8 to 10, preradiation PSA level of greater than 2 ng/mL, PSA doubling time after prosta- Combined modality treatment, using ADT hormonal manipulation tectomy of 10 months or less, negative surgical margins and seminal in conjunction with external beam radiation therapy, takes advantage vesicle invasion. Nonetheless, a significant fraction of men with one of separate and noncompeting modes of cell death such that cells that ore mor of these negative prognostic features still experienced a can survive the insult of one modality cannot survive the other or the durable response to salvage radiation, particularly if the radiation was additive/synergistic properties of the two.397 ADT has been used given prior to a PSA level of 2 ng/mL. Even for the group of men along with radiation therapy for many years in an attempt to modify 398 with the worst combination of prognostic features, a Gleason score the outcome of men with stage C (T3) prostate cancer. Historically, of 8 to 10 and a preradiation PSA of ≥2 ng/mL, salvage radiation the rationale for this treatment approach was that these men had an produced a progression-free survival of 12% at 4 years. In another inferior outcome when compared with men with earlier stage prostate large retrospective study, Trock et al. reported that men treated with cancer treated with radiation therapy. In addition, the tumors were salvage radiotherapy resulted in a 3-fold improvement in prostate often quite bulky, and it was thought that a course of cytoreductive cancer–specific survival compared with men who received no salvage therapy might provide a more favorable geometry for external irradia- treatment (HR = 0.32, 95% CI of 0.19 to 0.54; P < 0.001).390 tion. However, the use of ADT in combination with radiation was Importantly, this benefit was limited to men with a prostate-specific not universally accepted throughout the 1970s and 1980s. Radiation antigen doubling time of less than 6 months and remained after therapy techniques were improving, and the results from early case adjustment for pathological stage and other established prognostic series exploring the benefit of ADT before and/or during radiation factors. Although these findings hint at marked advantage to salvage therapy were often negative.399,400 radiation therapy after prostatectomy, the studies are retrospective In the early 1980s, two case series reported encouraging results and the results may be confounded by selection bias. Prospective with the use of ADT and external beam radiation therapy to treat studiese ar needed to definitively determine whether patients with men with locally advanced prostate cancer.401,402 Pilepich et al. also onee or mor poor prognostic features derive benefit from salvage found that men with histologically unfavorable prostate cancers who radiation. However, given the available data and considering the had been treated with ADT and external beam radiation therapy as limited morbidity of this treatment, especially with IMRT, it is rea- part of the RTOG 75-06 Trial exhibited similar disease-free survival sonable to consider salvage radiation for postprostatectomy patients and overall survival rates as men with more favorable prostate cancers with PSA recurrence regardless of prognostic factors. who did not receive ADT along with radiation therapy.403 Since these The role of ADT concomitant with radiation therapy given as an early experiences, phase 3 clinical trials have established the local adjuvant to surgery as salvage for prostate cancer recurrence following control and survival benefits of ADT given along with external beam surgery has not been established. In the RTOG 85-31 Trial, a sub- radiation therapy for locally advanced prostate cancer. group of men with pathological T3N0 prostate cancer who under- RTOG 86-10 was a randomized phase 3 clinical trial of external went radical prostatectomy received adjuvant radiation therapy to a beam radiation therapy alone (standard treatment arm) versus neo- dose of 60 to 65 Gy and then were randomized to immediate adjuvant and concomitant total androgen suppression and external Prostate Cancer • CHAPTER 84 1489 beam radiation therapy (experimental treatment arm).404 Eligible with those men treated with androgen suppression alone (11.9% vs. men had bulky (>25 cm2) locally advanced prostate cancer (stage 23.9%), a benefit also manifest as a reduction in overall mortality T2b-T4, N0-N1, M0). Total androgen suppression involved gosere- (29.6% vs. 39.4%). These data firmly establish the role of radiation lin acetate and flutamide; radiation therapy was accomplished with therapy both in optimizing local disease control and in promoting 45y G delivered to the pelvis followed by a 20- to 25-Gy boost to survival of men with high-risk and locally advanced prostate cancer. the prostate. Extended fields were used to treat the lymph nodes when they were involved. Findings were a significant advantage to androgen suppression, and radiation exhibited a significant benefit in local TREATMENT OF METASTATIC DISEASE control, disease-free survival, and cause-specific mortality over radia- Natural History of Metastatic Prostate Cancer tion alone. A second RTOG trial (85-31) also targeted men with locoregionally advanced prostate cancer, including men with adverse Over the past two and a half decades, widespread and routine clinical findings at radical prostatectomy.367,405 The aim of this phase 3 trial use of serum PSA testing has changed not only screening and diag- was to evaluate the role of long-term adjuvant androgen suppression nosis of prostate cancer, but virtually all aspects of prostate cancer in men with high-risk prostate cancer. Men enrolled on the trial had management.408,409 One consequence of this changing practice pattern clinical stage T3 (>25 cm2) prostate cancer, or T1–T2 disease and is that the conventional stage groupings (TNM staging), developed radiographic or histologic evidence of lymph node involvement. Men at a time when many men first presented for care with prostate cancer were eligible after prostatectomy if positive surgical margins or complicated by symptomatic distant metastases, no longer adequately seminal vesicle invasion was found. ADT featured goserelin acetate anticipate the clinical behavior of relapsed prostate cancer seen more alone; radiotherapy was given at a dose of 44 to 46 Gy to the whole commonly today. Before the availability of serum PSA tests, men with pelvis, with a 20- to 25-Gy boost to the prostate or postoperative newly diagnosed metastatic prostate cancer faced a median survival prostatic fossa for a total dose of 65 to 70 Gy. Again, the addition of of 24 to 30 months. Today, <5% of men with prostate cancer have androgen deprivation to radiation therapy improved local disease clinical evidence of distant metastasis at the time of presentation. control, freedom from distant metastases, and disease-free survival. Now, because most men initially are diagnosed with localized prostate For men with locoregionally advanced prostate cancers with a Gleason cancer and undergo primary therapy, the natural history of life- score of 8 to 10, a statistically significant difference in overall survival threatening prostate cancer tends to be more protracted, with the was also seen.405 The EORTC 22863 trial also tested the contribution disease stereotypically progressing through clinical states of relapse, of adjuvant ADT, given as goserelin acetate and cyproterone acetate hormone naïvety, and castration-resistance (Figure 84-17). for a month before radiation and goserelin acetate alone for 3 years Most prostate cancer relapses after local treatment are diagnosed after the radiation treatment course, to radiation therapy for men based on rising serum PSA levels without other clinical or radiological with high-stage or high-grade prostate cancer.365,366 Radiation therapy evidence of local or distant recurrence (M0 disease). Often, men with was delivered as 50 Gy to prostate and regional lymph nodes, fol- M0 prostate cancer go on to receive ADT before metastases appear, lowedy b a 20-Gy boost to the prostate, for a total prostate dose of usually resulting in a drop in serum PSA. For such men, a subsequent 70 t Gy. A 5 years, the overall survival for the men who received steady rise in PSA despite adequate hormonal therapy (serum testos- adjuvant endocrine therapy was 78% versus 62% for men who did terone <50 ng/dL) has been interpreted as disease progression to a not.366 nonmetastatic castration-resistant phenotype. In this setting, further The duration of adjuvant ADT given along with radiation therapy progression to clinically overt metastasis has been labeled metastatic for locally advanced prostate cancer has also been tested. In the castration-resistant prostate cancer. RTOG 92-02 Trial, short-term and long-term androgen suppression Antonarakis et al. reported the experience of a cohort of men (n were compared.406 All men in the study received 4 months of gosere- = 774) with biochemical recurrence after radical prostatectomy.410 tA lin acetate and flutamide, 2 months before and during radiation 8 years of follow-up after surgery, some 29% of these men had devel- therapy. Men were then randomized to receive either no further oped distant metastases. Recurrence was defined as a serum PSA therapy (short-term androgen deprivation) or to be treated with rising to at least 0.2 ng/mL; the median PSA level at the time of the goserelin acetate for an additional 24 months (long-term androgen first metastasis was 31.4 ng/mL. For men with recurrent prostate deprivation). Radiation dose was 65 to 70 Gy to the prostate and 44 cancer, the PSA doubling time (PSADT; <3.0 vs. 3.0 to 8.9, vs. 9.0 toy 50 G to pelvic nodes. At 5 years, the long-term androgen depriva- to 14.9, vs. ≥15.0 months; P < 0.0001), pathological Gleason score tion group showed significant improvement in disease-free survival (≤7 vs. 8 to 10; P = 0.005), and time from prostatectomy to PSA of 54% versus 34% (P = 0.0001), in clinical local progression of 6.2% recurrence (≤3 vs. >3 years; P < 0.021) all correlated with metastasis- versus 13% (P = 0.0001), and in freedom from distant metastasis of free survival and the 5-year probability of metastatic progression after 11% versus 17% (P = 0.001). Nonetheless, 5-year overall survival was PSA recurrence. Data from analyses of men undergoing radiation not significantly different between the two treatment arms (78% vs. therapy appear similar, with PSADT emerging as the strongest pre- 79%), except for the subset of men with Gleason 8 to 10 prostate dictor of outcome.411 cancer, who showed a benefit to longer duration adjuvant endocrine The clinical course of nonmetastatic castration-resistant prostate treatment (80% vs. 69%). Despite these results, the optimal sequenc- cancer is not as well described. Presumably, disease parameters such ing of ADT and radiation has not been fully established. To date, it as PSA and PSADT are also likely provide prognostic information in is not known whether the effects of ADT on prostate cancer control this setting, but the behavior of PSA as a biomarker in the castrate were merely additive to the tumoricidal effects of radiation or were state may differ from its behavior in the hormone-naïve setting.412,413 synergistic, providing an enhancement of tumor killing. The best data available thus far may be the experience of men with Finally, some have questioned whether the improved local control nonmetastatic castration-resistant prostate cancer patients enrolled in and survival benefits of combining androgen suppression with radia- therapeutic clinical trials. On the placebo arm of a randomized tion for men with high-risk prostate cancer were simply a result of blinded trial of atrasentan for progressive castration-resistant prostate the effects of long-term androgen suppression; that is, whether the cancer and no radiographic evidence of bone metastases, by 2 years radiation therapy might not have been needed in this setting. To help 46% of men had developed bone metastases and 20% had died.414 answer this question, Widmark et al. conducted a prospective ran- The median bone metastasis–free survival was 25 months. In a mul- domized trial (SPCG-7/SFUO-3) of long- term androgen suppres- tivariate analyses, baseline PSA ≥13.1 ng/mL was associated with sion versus long-term androgen suppression plus pelvic radiation.407 shorter overall survival (HR = 2.34, 95% CI of 1.71 to 3.21; P < In men (n = 875) receiving combined modality treatment, the 10-year 0.0001), time-to-first bone metastasis (HR = 1.98, 95% CI of 1.43 cause-specific mortality was significantly reduced when compared to 2.74; P < 0.0001), and bone metastasis–free survival (HR = 1.98, 1490 Part III: Specific Malignancies

Hypothalamus – – PR Antiandrogens GnRH analogs Cyproterone acetate and antagonists + – Megestrol acetate AR Flutamide GnRH-R Bicalutamide GnRH ER Nilutamide Enzalutamide Pituitary ACTH Estrogens Androgen synthesis ER Cholesterol – LH inhibitors Prolactin AR Glucocorticoids Adrenal androgens Ketoconazole Adrenal Abiraterone acetate glands LH-R Adrenal Androgen Cholesterol AR androgens Synthesis DHT Inhibitors Testosterone Testosterone T AR Gene expression Testis Prostate T DHT

Peripheral organs

5α-reductase inhibitors

Figure 84-17 • Sites of action of different treatments that affect androgen action. ACTH, adrenocorticotropic hormone; AR, androgen receptor; DHT, 5α-dihydrotestosterone; ER, estrogen receptor; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; PR, progesterone receptor; T, testosterone.

95% CI of 1.45 to 2.70; P < 0.0001). The PSAV was also associated median survival is >80 months, with the majority of men manifesting with overall and bone metastasis–free survival. In another placebo- only limited and asymptomatic metastatic disease.419 controlled trial (prematurely terminated) of the bisphosphonate zole- dronic acid versus placebo, one-third of men assigned to the placebo Treatments Targeting Androgen Signaling arm developed bone metastases by 2 years, with a median bone metastasis–free survival of 30 months.415 nI this trial, higher baseline Because androgen signaling contributes to the growth and survival of PSA and PSAV were also associated with a shorter time-to-first bone prostate cancer cells, interfering with the signaling axis tends initially metastasis and poorer survival.416 to benefit nearly all men with advanced prostate cancer (Figure The outcome of men with hormone-naïve metastatic prostate 84-18 ). Typically, the use of ADT for prostate cancer, triggering a fall cancer has changed substantially. Clinical trials employing similar in serum testosterone to levels <50 ng/mL, results in a decline in the hormonal therapies over the past two decades illustrate the differ- serum PSA, as a consequence of AR regulation of PSA expression, ences. From 1989 to 1993, the SWOG conducted a trial in men (n and in a diminution in metastatic lesions accompanied by relief of = 1387) with newly diagnosed metastatic prostate cancer treated with disease-associated symptoms. Unfortunately, despite continuous bilateral with or without the nonsteroidal antiandrogen androgen deprivation, most men develop castration-resistant prostate flutamide, which showed no significant differences between the treat- cancer (CRPC). Remarkably, CRPC often shows evidence of contin- ment arms and an overall median survival of 33 months.417 From ued addiction to androgen signaling even though serum androgen 1995 to 2009, the SWOG conducted another study in the same levelse hav been therapeutically reduced.420 This phenotype was first patient population, testing continuous versus intermittent treatment demonstrated in human prostate cancer xenograft models, where with GnRH analog and bicalutamide. In this trial, the median sur- progression to castration resistance was found to be attributable to vival for continuous hormonal treatment was 49 months, suggesting increased AR abundance, allowing transcriptional trans-activation at a 30% decrease in the risk of death for the same treatment in the lower androgenic hormone levels.421 AR itself is a known target for more recent trial versus the older one.418 This apparent improvement somatic genome alterations in prostate cancer, especially on progres- in outcome likely reflects the same type of stage migration effect as sion of the disease in the castrate state. AR mutations, encoding has been seen for almost all prostate cancer states in the PSA era. receptors with altered ligand specificity, can result in agonist activity In addition, fewer men contend with major disease-related symp- for antiandrogens, providing one molecular explanation for the toms, such as hemoglobin <10 g/dL, poor performance status, and curious “antiandrogen withdrawal” syndrome, in which men with extensive metastatic disease burden, a lead-time effect almost cer- prostate cancer progression, despite treatment with a combination of tainly attributable to serum PSA monitoring. For men with prostate androgen deprivation and antiandrogens, were found to benefit from cancer recurrence after local treatment followed without the use discontinuation of the antiandrogen.422 CCPR cells may also have of androgen deprivation until radiographic disease progression, the augmented androgen signaling as a consequence of posttranslational Prostate Cancer • CHAPTER 84 1491 modifications of AR or its coactivators driven by growth factor signal- of pharmacological doses of synthetic estrogens, such as diethylstil- ing pathways, of the expression of AR forms generated from mRNA bestrol, as the first “medical castration” (DES).426 eAn extensiv body splice variants, and of intratumoral production of androgenic of evidence from many prospective randomized clinical trials for men hormones.10,420,423,424 with metastatic prostate cancer supports the comparable efficacy of bilateral orchiectomy, LHRH analogs and antagonists, and DES. Androgen Deprivation Therapy However, treatment with DES, in contrast to orchiectomy or to treat- ment with LHRH analogs or antagonists, has been complicated by ADT for prostate cancer involves reduction of circulating testosterone serious treatment adverse events, including congestive heart failure levels to <50 ng/mL, most often accomplished via surgical removal and venous thromboemboli. As a consequence, estrogens have been of the testis (bilateral orchiectomy) or via inhibition of the synthesis virtually abandoned in favor of LHRH agonists and antagonists for and release of pituitary gonadotropins with long-acting luteinizing men with advanced prostate cancer. Also, many men find LHRH hormone–releasing hormone (LHRH) analogs (goserelin, leuprolide, therapye mor acceptable than bilateral orchiectomy. buserelin, histrelin, and triptorelin) and antagonists (abarelix, degare- lix, and cetrorelix) which cause suppression of testosterone produc- Antiandrogens and “Complete” Androgen tion (Figure 84-18). LHRH analogs first trigger LH release by the Blockade pituitary, triggering a short-lived elevation of serum testosterone that is occasionally associated with a symptomatic disease “flare” in men Antiandrogens interact directly with the AR to antagonize its trans- with extensive bone metastasis.425 LHRH antagonists more rapidly activation of target gene transcription (Figure 84-18). Many of the suppress testosterone levels without such a “flare.” Historically, reduc- current antiandrogen drugs (flutamide, nilutamide, and bicaluta- tions in testosterone were also accomplished via the administration mide) were developed initially to be used in combination with LHRH analogs, with the hope that such treatment combinations could achieve a “complete” androgen blockade by reducing androgen levels and neutralizing the propensity for adrenal androgen precursors, such 100 as androstenedione and dehydroepiandrosterone, to activate AR Androgen suppression only function.427 Early reports of the efficacy of this treatment combina- Androgen suppression and antiandrogen tion prompted the conduct of 27 clinical trials involving 7987 men 80 testing whether “complete” androgen blockade offered any advantage 428 8000 prostate cancer patients in over ADT alone for men with metastatic prostate cancer. A com- 27 trials of antiandrogen (nilutamide, prehensive review of these trials revealed that only 3 of the 27 studies 60 flutamide, or cyproterone acetate) showed any benefit to the combined approach (Figure 84-19).428 The Agency for Health Care Policy and Research (AHCPR; see report number 99-E012 at http://www.ahcpr.gov/clinic/index.html) con- 40 Treatment better ducted a meta-analysis of all published “complete” androgen blockade 25.4% by 0.7% (SE 1.1) clinical trials, finding no difference in 2-year survival rates, and only logrank 2p 0.1 Proportion alive (%) > a minimal difference in 5-year survival felt to be of questionable 20 23.6% clinical significance, for combined treatment. Absolute difference 6.2% Newer antiandrogens promise to overcome some of the mixed 1.8% (SE 1.8) agonist/antagonist properties of the first set of available AR-targeting 0 5.5% drugs.429 One of these agents, enzalutamide, which reduces AR 0 5 10 ingress into the cell nucleus and impairs its binding to target DNA sequences nuclear translocation, has been subjected to extensive clini- Time since randomization (yrs) cal trials for men with CRPC, earning FDA approval for this indica- tion in the summer of 2012 (Figure 84-20).430 nI one phase 3 trial Figure 84-18 • A meta-analysis of survival from metastatic prostate cancer with maximal androgen blockade versus androgen deprivation alone. (the AFFIRM Study), men (n = 1199) with metastatic CRPC that (From Prostate Cancer Trialists Cooperative Group. Maximum androgen had progressed despite treatment with docetaxel were randomized 431 blockade in advanced prostate cancer: an overview of the randomised trial. 2 : 1 to receive enzalutamide or placebo. n,I this study enzalutamide Lancet 2000;355:1491-1498.) therapy was accompanied by a survival benefit (HR = 0.63, 95% CI

No previous chemotherapy (n = 65) Previous chemotherapy (n = 75)

25

0

–25

–50

baseline (%) –75 PSA change from PSA –100 1 5 9 33 37 41 45 49 53 57 61 65 69 73 77 81 85 89 93 97 13 17 21 25 29 113 117 101 105 109 121 125 129 133 137 Patient number

Figure 84-19 • Responses to enzalutamide in men with castration-resistant prostate cancer who had or had not received previous chemotherapy. (From Scher HI et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet 2010;375:1437-1446.). 1492 Part III: Specific Malignancies

of 0.57 to 0.75; P < 0.0001), with an increase in median survival 95%. However, in men with prostate cancer, there can be continuous from 13.6 months to 18.4 months. The second phase 3 study ongoing production of androgens by the adrenal glands or by the (PREVAIL) randomized men (n = 1680) with metastatic CRPC who cancer. itself 10,433 This nongonadal source of androgens is significant: had not yet received docetaxel to enzalutamide or placebo; data from even in the castrate state, intraprostatic concentrations of testosterone thise study ar not yet available. A second agent, ARN-509, which and dihydrotestosterone appear sufficient to stimulate AR. In prostate also appears to lack partial AR agonist activity, to prevent nuclear cancers, such androgens may be able to arise both by local conversion translocation of AR, and to impair AR binding to DNA, has entered of adrenal precursors and by de novo synthesis through increased early clinical studies.432 The use of this new generation of antiandro- expression of steroidogenic enzymes such as CYP17.10,433 Many pros- gens, as single agents or in combination with ADT, for the initial tate cancer clinicians used high doses of ketoconazole to antagonize treatment of advanced prostate cancer is currently under active evalu- this process, often noticing benefits for some men with CRPC. More ation in clinical trials. recently, abiraterone acetate, a pregnenolone analog and much more potent inhibitor of CYP17 than ketoconazole, was approved by the Inhibitors of Adrenal Steroidogenesis FDA for the treatment of CRPC, based on improvements in survival in randomized trials (Figure 84-21).434 Adverse effects of abiraterone ADT, which principally targets gonadal production of androgenic treatment, though minimal, included stigmata of secondary miner- hormones, decreases total serum testosterone levels by approximately alocorticoid excess, including fluid retention (30.5%), hypokalemia (17.1%), and hypertension (1.3%). TAK-700, another selective CYP17 inhibitor, has reached phase 3 clinical trials for men with CRPC.435 Overall survival Optimal Timing of ADT 100 Although there is a general belief that immediate initiation of ADT 80 for men with metastatic prostate cancer may best improve disease- related quality of life, there is no compelling evidence of compro- 60 Abiraterone mised survival resulting from deferred treatment at the time of acetate symptomatic progression. The timing of ADT, and its effects on 40 Placebo quality of life and survival for men with recurrent or metastatic

Survival (%) prostate cancer, has become an even more critical issue recently 20 because an increasing number of men are recognized to have recur- rent or metastatic prostate cancer very early because of increases in 0 the serum PSA. Randomized studies conducted by the Veterans 0 3 6 9 12 15 18 21 Administration Cooperative Urological Group (VACURG) several Months decades ago indicated that men treated with placebo initially who subsequently received ADT at the time of clinical progression suf- No. at risk fered no worse a survival than men who were initially subjected to Abiraterone acetate 797 736 657 520 282 68 2 0 ADT.436 More recently, the Medical Research Council (MRC) con- Placebo 398 355 306 210 105 30 3 0 ducted a study in men (n = 934) with prostate cancer who did (n = Figure 84-20 • Results of a randomized trial of abiraterone acetate 434) or did not (n = e500) hav metastasis, randomizing the men versus placebo for men with castration-resistant prostate cancer (CRPC). either to immediate ADT or to ADT at the time of symptomatic 437 (Data from De Bono JS et al. Abiraterone and increased survival in metastatic disease progression. Though early results from this study hinted at prostate cancer. N Engl J Med 2011;364:1995-2005.) a survival advantage for men treated with early ADT, a phenomenon

100 90 80 70 60 50 Docetaxel 40 Weekly every 3 wk docetaxel 30 20 10 Mitoxantrone Probability of overall survival (%) 0 0 3 6 9 12 15 18 21 24 27 30 33

Months Figure 84-21 • Results of a randomized clinical trial of docetaxel, given at two different dosing schedules, and pred- No. at Risk nisone versus mitoxantrone and prednisone for men with Docetaxel every 3 wk 335 296 217 104 37 5 androgen-independent metastatic prostate cancer. (Data from Weekly docetaxel 334 297 200 105 29 4 Tannock, IF de Wit R, Berry WR, et al. Docetaxel plus pred- Mitoxantrone 337 297 192 95 29 3 nisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502-1512.) Prostate Cancer • CHAPTER 84 1493 that may have been attributable to underuse of ADT in the delayed mitosis, yet prostate cancers tend to have low growth fractions when therapy arm (54% of men died without endocrine treatment). Sub- compared to many normal cells and most other cancers. An unbiased sequent reports from the trial, with greater follow-up times, have screen of FDA-approved drugs for toxicity against prostate cancer cell shown no significant mortality difference form early versus delayed lines unmasked a striking activity of all microtubule-targeted drugs, ADT. including colchicine and many others in addition to taxanes, against Nonetheless, in a relatively small prospective randomized trial of prostate cancers.447 One possibility is that microtubule function may immediate ADT versus observation in men (n = 98) with node- be needed for other critical cell processes, such as nuclear-cytoplasmic positive prostate cancer after radical prostatectomy, a benefit to early shuttling of critical regulatory proteins essential for prostate cancer intervention was evident.438 This study is frequently cited as evidence cell, viability including translocation of AR from the cytoplasm into int suppor of earlier ADT in men with node-positive prostate cancer, the nucleus.448 and is often extrapolated to rationalize the use of early ADT for almost recurrent prostate cancer. Despite the limited data available Docetaxel in this clinical setting, the common use of serial PSA testing to diag- In early clinical trials, both paclitaxel and docetaxel showed promising nose early disease relapse following primary treatment has pushed activity against prostate cancer, but only docetaxel was subjected to practice patterns toward early ADT. Against this approach is the large-scale testing for improving survival of men with mCRPC. Early growing body of evidence about the health hazards of ADT, including experiences with docetaxel, given alone in two different dosing sched- increases in cardiovascular events, accelerated bone loss, and so ules and given along with estramustine, prompted the design and forth.439 For these reasons, the relative benefits of early ADT for a execution of two definitive randomized trials, TAX-327 and SWOG- rising serum PSA after primary therapy have not been established. 9916, which established the survival benefit of docetaxel for mCRPC. One popular approach for men with asymptomatic recurrent or The TAX-327 study (n = 1006), considered the pivotal trial for FDA metastatic prostate cancer has been the use of intermittent ADT. This approval of docetaxel in prostate cancer, included three treatment strategy was suggested from provocative preclinical models suggesting arms: docetaxel 75 mg/m2 every 3 weeks plus prednisone (10 mg that intermittent reductions in serum testosterone might delay the daily), weekly docetaxel 30 mg/m2 for 5 of 6 weeks with prednisone, emergence of CRPC.440,441 Unfortunately, available clinical trials have and mitoxantrone 12 mg/m2 every 3 weeks with prednisone.449 The provided little in the way of definitive conclusions regarding the rela- docetaxel regimen featuring every 3-week administration conferred a tive efficacy of intermittent versus continuous ADT, or definitive significantly improved survival (HR = 0.76; 85% CI of 0.62 to 0.92), guidance about the most effective ADT regimen for intermittent higher PSA responses (45% vs. 42%), and better pain relief (22% vs. administration, the optimal timing or duration of intermittent ADT 13%) than mitoxantrone. Weekly docetaxel showed a trend toward cycles,w ho to use serum PSA to aid treatment, and the best definition improved survival, a benefit that did not reach statistical significance. of treatment response versus treatment failure.442 Despite all the Grade 3/4 toxicity of docetaxel was limited mostly to neutropenia unanswered questions, intermittent ADT tends to be frequently used (32%), with an incidence of febrile neutropenia at only 3% or less. for prostate cancer in the clinic, especially for men with prostate Poor prognostic factors for survival of men with mCRPC treated cancer and no evidence of clinical metastasis, or with minimal meta- with docetaxel include liver metastases, many metastatic sites, static disease, who have had complete or near complete responses to significant pain, poor performance status, radiographic evidence of ADT,e hav no active disease-related symptoms, and may be tolerating disease progression, high PSA level, low PSA doubling time, high ADT. poorly Other practical advantages of intermittent ADT include tumor grade, elevated serum alkaline phosphatase, and low blood improvement of quality of life and attenuation of complications hemoglobin.450 accompanying long-term ADT.443 The second study, SWOG-9916, evaluated the combination of One fairly large randomized trial of men with nonmetastatic docetaxel plus estramustine versus mitoxantrone plus prednisone.451 recurrent prostate cancer (n = 1386) testing intermittent versus con- Again, the overall survival was superior in the group receiving tinuous ADT showed a similar overall survival for each treatment docetaxel (HR = 0.80, 95% CI of 0.67 to 0.97). The study subject schedule (HR = 1.02, 95% CI of 0.86 to 1.21; P for noninferiority characteristics were similar to the men enrolled in the TAX-327 study, = 0.009). Preliminary data from the trial presented in abstract form as were the survival outcomes. The incorporation of estramustine in hinted that men treated with intermittent ADT were less likely to the docetaxel regimen, however, was characterized by increased gas- die from prostate cancer, but more likely to die from non–prostate- trointestinal and peripheral vascular toxicity, including venous cancer-related causes.444 nI another large trial, men with metastatic thromboembolism (VTE). Because of the high rate of VTE on the prostate cancer (n = 3040) were randomized to intermittent versus trial, prophylactic low-dose warfarin and aspirin were added, although continuous ADT after an initial course of induction ADT over 7 this did not reduce the VTEs for men receiving estramustine and months.445 Responders to the induction regimen (men with a serum docetaxel. With the hazards associated with estramustine use, and PSA ≤4.0 ng/mL at 7 months) went on to receive intermittent ADT little evidence for a dramatic benefit for estramustine docetaxel versus or continuous ADT until the PSA rose to 20 ng/mL or clinical docetaxel alone, the estramustine and docetaxel regimen is not cur- disease progression was seen. Although the overall survival was not rently recommended. substantially different for the treatment arms, in a subset of men with Although the TAX-327 study was designed to include as many as minimal prostate cancer (axial skeleton ± lymph node metastasis), a 10 doses of docetaxel given at 3-week intervals, there were not strong ≥20% inferiority for intermittent ADT could not be excluded. data supporting the need for that many treatment cycles. Typically, in clinical practice, rather than delivering 10 consecutive docetaxel Cytotoxic Chemotherapy for Metastatic treatment cycles, the taxane is administered for 5 to 8 cycles until Castration-Resistant Prostate Cancer disease stabilization is evident, holding treatment for when subse- quent disease progression becomes evident, whether manifest as a Although many systemic chemotherapy drugs have been used for the rising serum PSA, clinical worsening, or both. This approach allows treatment of metastatic castration-resistant prostate cancer (mCRPC), for docetaxel retreatment before moving to second-line chemotherapy only taxanes have produced significant survival benefits. Taxane treatment, occasionally extending disease control without increasing drugs, including docetaxel and cabazitaxel approved for mCRPC by treatment toxicity.452,453 the FDA, disrupt microtubule function and promote apoptosis.446 Remarkably, the exact mechanisms by which these drugs act against Cabazitaxel prostate cancer cells is not entirely clear. Microtubule function is Cabazitaxel is a second-generation taxane that exhibited cytotoxic critically required for segregation of replicated chromosomes at activity against a broad range of cancer cell lines and tumor models 1494 Part III: Specific Malignancies

with greater potency than docetaxel in multidrug-resistant tumor against malignant cells while overcoming tumor-induced toler- cells, prompting its development as an agent to overcome docetaxel ance.457 Although not traditionally considered a disease amenable resistance, perhaps because of its weaker binding affinity to to immune-directed approaches, prostate cancer may be an ideal P-glycoprotein, a drug efflux pump that serves to reduce intracellular target for immunologic attack because of its slow growth, allowing concentrations of docetaxel.454 An additional characteristic of cabazi- a stimulated immune system time to generate an antitumor response, taxel is its ability to penetrate the blood–brain barrier in vivo, which and its propensity to produce lineage-specific proteins that may is not achievable with other taxanes. A phase 1 trial determined that serve as tumor antigens, including PSA and prostatic acid phospha- the principal dose-limiting toxicity of cabazitaxel was neutropenia, tase (PAP). A number of prostate cancer vaccine approaches have with other observed side effects, including nausea, vomiting, diar- been subjected to early clinical development to exploit this oppor- rhea, and fatigue, appearing generally mild to moderate.455 Two men tunity.458 One such approach, featuring sipuleucel-T, an autologous in the trial with mCRPC had partial responses, with reductions in PAP-loaded antigen-presenting cell preparation has been advanced measurable disease deposits and decrements in serum PSA levels. to FDA approval. The phase 3 trial (TROPIC) was a randomized, open-label, mul- To permit treatment with sipuleucel-T, antigen-presenting cells tinational study testing whether cabazitaxel plus prednisone improved (APCs)e ar collected by leukapheresis from men with prostate cancer overall survival compared with mitoxantrone plus prednisone in men and incubated ex vivo with a fusion protein formed from PAP linked (n = 755) with mCRPC that had progressed either during or after to. GM-CSF Subsequently, the primed APCs are reinfused, activating prior docetaxel chemotherapy.456 Men in the trial were given predni- T cells to promote a PAP-directed antitumor response.459 nI early sone 10 mg/d and then either cabazitaxel 25 mg/m2 or mitoxantrone randomized trials of sipuleucel-T, though only 5 of the 147 men with 12 mg/m2 every 3 weeks for 10 cycles. Of note, some 70% of men prostate cancer who received sipuleucel-T had PSA reductions of enrolled in the trial had had progressive prostate cancer within 3 ≥50%, and no objective tumor regressions were seen, an improve- months of completing docetaxel treatment, whereas the remainder ment in overall survival was evident.460 This prompted a phase 3 trial showed disease progression during docetaxel therapy. Trial results of men (n = 512) with mCRPC and no visceral metastases or need demonstrated that cabazitaxel improved survival in this clinical for narcotics for pain (IMPACT).461 The men were randomized to setting over mitoxantrone (HR = 0.70, 95% CI of 0.59 to 0.83; P < sipuleucel-T or a placebo, with an opportunity to receive sipuleucel-T 0.0001), doubling the median progression-free survival and objective at the time of disease progression (using APCs cryopreserved at the response rates. PSA response rates were also significantly higher for time of placebo preparation); the primary end point for the trial was cabazitaxel treatment. overall survival. When the trial results were reported, 61% of the men Men treated with cabazitaxel received a median of 6 cycles of treated with sipuleucel-T and 70.8% of the men receiving placebo treatment, and the most common adverse events were hematologic had died (HR = 0.78l, P = 0.03). Based on the results of this study, toxicities. For example, 81.7% and 7.5% of men in the cabazitaxel the FDA approved sipuleucel-T in April of 2010 for men with group experienced grade ≥3 neutropenia and febrile neutropenia, asymptomatic or minimally symptomatic mCRPC. As seen in the respectively, as compared with 58% and 1.3% for men in the mito- earlier studies, neither time to disease progression nor PSA response xantrone group. Cabazitaxel treatment also increased the incidence rates were improved by sipuleucel-T treatment compared with of nonhematologic toxicities, including diarrhea (46.6% vs. 10.5% placebo. Only one sipuleucel-T–treated subject in the IMPACT for mitoxantrone with grade ≥3 diarrhea in 6.2% vs. 0.3%) and study had partial radiographic response, and only 8 of 311 (2.6%) asthenia (20.5% vs. 4.6% for mitoxantrone with grade ≥3 asthenia men experienced PSA reductions of ≥50% with sipuleucel-T. in 12.4% vs. 2.4%). Some 5% of men on the cabazitaxel arm died Sipuleucel-T was well tolerated, with adverse events such as fatigue, from causes other than disease progression within 30 days of receiving influenza-like symptoms, chills, low-grade fever, arthralgias/myalgias, the drug. This compares with a 1% drug-related death rate in the and headaches appearing and resolving within 24 to 48 hours of mitoxantrone group. The most common cause of death in patients infusion. who were treated with cabazitaxel was neutropenia, including its clinical consequences such as septicemia. This problem was mini- Bone-Targeted Treatments mized during the conduct of the trial when TROPIC investigators were informed about events and directed to strictly adhere to the Men with metastatic prostate cancer are at increased risk of skeletal study protocol measures for dose delays and modifications, and for complications for two main reasons. First, chronic androgen depriva- the management of neutropenia with granulocyte macrophage tion increases bone resorption and reduces bone mineral density, colony-stimulating factor (GM-CSF) according to American Society resulting in osteopenia and/or osteoporosis. Second, bone involve- for Clinical Oncology (ASCO) guidelines. ment in prostate cancer is extremely common and occurs in up to Based on the results of the TROPIC trial, cabazitaxel was approved 75% of patients with metastatic disease. Complications of bone by the FDA in June 2010 and by the EMEA in 2011 for use metastasis include bone pain, hypercalcemia of malignancy (though in combination with prednisone for the treatment of docetaxel- rare for prostate cancer), and other skeletal-related events (SREs) pretreated mCRPC. Cabazitaxel is currently being evaluated as a including pathological fractures, need for radiation or surgery to first-line treatment of mCRPC in two separate clinical trials. The first bone, or spinal cord compression. study (FIRSTANA) is a standard multi-institutional, multinational phase 3 comparison between cabazitaxel (in two doses: 25 mg/m2 and Zoledronic Acid 20 mg/m2) versus standard every-3-weeks docetaxel (75 mg/m2) in For several years, intravenous bisphosphonates have served as the men with chemotherapy-naïve mCRPC. The second study (TAXYN- mainstay of adjunctive treatment to help maintain skeletal integrity ERGY) is a multicenter randomized phase 2 trial to evaluate the in patients with bone-metastatic prostate cancer. The benefits of benefit of an early switch from first-line docetaxel/prednisone to bisphosphonates were shown definitively in a landmark phase 3 study cabazitaxel/prednisone (or the opposite sequence) in men with involving men (n = 643) with mCRPC and asymptomatic or mini- mCRPC not previously treated with chemotherapy. mally symptomatic bone metastases, in which zoledronic acid was compared against placebo.462,463 This study demonstrated fewer SREs Immunotherapy using Sipuleucel-T in the zoledronic acid group compared with the placebo group (33.2% vs. 44.2%; P = 0.021) and an increased median time to first An alternative strategy for the treatment of mCRPC involves the SRE (16.1 vs. 10.6 months; P = 0.009). The results of this study led use of immunotherapeutic agents. refers to the FDA approval of zoledronic acid for men with bone-metastatic generally to attempts to treat cancer by activating immune responses CRPC, for the purposes of SRE prevention. Prostate Cancer • CHAPTER 84 1495

metastases is estimated nearly 40% to 60% of the administered Denosumab dose.470 Following encouraging phase 2 findings of significant anti- More recently, denosumab, a monoclonal antibody blocking the tumor activity with a possible suggestion of a survival benefit, 223Ra receptor activator of nuclear factor-κB (RANK) ligand, has also was subjected to a randomized, placebo-controlled, phase 3 trial gained FDA approval for the prevention of SREs in bone-metastatic (ALSYMPCA).471,472 This study enrolled men (n = 922) with symp- CRPC, based on the finding from a large randomized phase 3 trial.464 tomatic bone-metastatic CRPC, who had previously received RANK ligand is a member of the tumor necrosis factor family that docetaxel or were considered unfit for docetaxel, for treatment with binds to its receptor on immature and mature osteoclasts, promoting 223Ra (50 kBq/kg) or placebo given in six injections at 4-week inter- differentiation, activation, and survival of osteoclasts.465 yB blocking vals.t A a planned interim analysis, 50% of men treated with 223Ra the binding of RANK ligand to RANK, denosumab effectively inhib- versus 35% of men receiving placebo had received all six injections, its osteoclastic activity and thus osteoclast-mediated bone resorp- and the overall survival was superior for the 223Ra treatment arm (HR tion.466 Denosumab was developed for treatment of skeletal diseases = 0.695, 95% CI of 0.552 to 0.875; P = 0.0019). The overall survival mediatedy b osteoclasts, including metastatic bone disease from a advantage for 223Ra met the predetermined statistical boundary for variety of cancers, multiple myeloma, and hormonal therapy–induced stopping the trial early, and the Independent Data Monitoring Com- bone loss accompanying cancer treatment. mittee (IDMC) recommended halting the trial in June 2011 because Denosumab, given as 60 mg subcutaneously every 6 months, was of evidence of significant treatment benefit. initially studied in men (n = 1468) receiving ADT for nonmetastatic In subset analyses, men with a good performance status and men prostate cancer in a randomized, placebo-controlled, phase 3 trial.467 who had not previously been treated with docetaxel showed greater Denosumab therapy was associated with increased bone mineraliza- benefits, whereas prior treatment with bisphosphonates did not affect tion at all sites, with an increase in the bone mineral density of the outcome. Among the secondary endpoints, median time to first SRE lumbar spine of 5.6%, as compared with a loss 1.0% for placebo was significantly improved in the 223Ra treatment arm compared with treatment (P = 0.001). Men receiving denosumab along with ADT placebo (13.6 vs. 8.4 months; HR = 0.610, 95% CI of 0.461 to also had a decreased incidence of new vertebral fractures at 36 months 0.807; P = 0.0005), as was the time to alkaline phosphatase progres- (1.5% vs. 3.9% with placebo; HR = 0.38, 95% CI of 0.19 to 0.78; sion (HR = 0.163, 95% CI of 0.121 to 0.221; P < 0.00001) and the P = 0.006). time to PSA progression (HR = 0.671, 95% CI of 0.546 to 0.826; For men with prostate cancer bone metastases, a second phase 3 P = 0.0002). These results support a significant improvement in trial was undertaken, comparing denosumab, given as 120 mg sub- controlling metastatic bone disease with 223Ra. The safety of 223Ra cutaneously every 4 weeks, with zoledronic acid, given as 4 mg intra- administration was encouraging, with less adverse events in the 223Ra venously every 4 weeks.464 yThe primar end point of the trial was treatment arm and no worrisome toxicities ascribable to 223Ra expo- time to first SRE, including pathological fracture, need for radiation sure. This safety profile for 223Ra, especially in comparison with the therapy or surgery, and spinal cord compression. At the time of the bone-targeting β–emitters, may allow more liberal dosing and/or efficacy analysis, an improvement in time to first SRE for denosumab extended treatment periods. Also, if 223Ra can control bone metastases was evident (HR = 0.82, 95% CI of 0.71 to 0.95; P = 0.0002 for without injuring hematopoiesis in the bone marrow, combinations noninferiority; P = 0.008 for superiority). There were no differences with myelosuppressive chemotherapy, like docetaxel or cabazitaxel, in overall survival or in progression-free survival. As a result of this may be feasible. Each of these expanded uses of 223Ra awaits testing pivotal trial, denosumab gained approval by the FDA in November in controlled clinical trials. 2010 for use in men with bone involvement from CRPC. Common toxicities of denosumab include fatigue, nausea, hypophosphatemia, SUMMARY hypocalcemia (5% grade ≥3), and osteonecrosis of the jaw (2%). Therefore denosumab is a reasonable alternative to zoledronate for Although mortality from prostate cancer has declined over the past the prevention of SREs in patients with metastatic CRPC, and also few years, demographic trends, such as the general aging of the popu- has the advantage that it does not require dose adjustment or moni- lation, suggest that prostate cancer will remain one of the most toring for renal impairment. However, men treated with denosumab common health threats for men in the developed world. Widespread should undergo calcium supplementation, and should also have a implementation of prostate cancer screening, using the serum PSA, careful dental examination prior to initiating therapy. has resulted in a changing character of prostate cancer at its initial 89 153 223 presentation, with younger men being diagnosed at earlier prostate Strontium, Samarium, and Radium cancer stages than ever before. The use of serum PSA testing for In addition to the osteoclast-inhibitory maneuvers discussed above, disease activity monitoring has changed the character of prostate bone-seeking radiopharmaceuticals have also been used in the man- cancer throughout the rest of its natural history, with healthier men agement of patients with symptomatic bone-metastatic prostate having less prostate cancer at later stages of the disease than ever cancer.o T date, two such agents have been approved by the FDA: before. These changes have put new demands on improving prostate 89Sr and 153Sm. Both of these drugs are indicated for the palliative cancer treatment, whether offering active surveillance to selected men treatment of multifocal bone pain caused by widespread osseous with indolently progressive disease, minimizing the morbidity of local metastases, but neither drug has demonstrated a survival benefit when prostate cancer treatment, or continuing to improve the efficacy of given to patients with mCRPC.468 89Sr and 153Sm both emit β–par- systemic prostate cancer treatment. The androgen signaling axis ticles with track lengths up to a few millimeters resulting in collateral remains the major systemic treatment target for advanced prostate bone marrow toxicity when absorbed in areas of new bone formation. cancer, with new agents introduced to restrain ongoing androgen In contrast, α-particles appear to provide more dense ionizing radia- receptor activation in castration-resistant disease. tion (high linear energy transfer radiation) over a narrower range of <100 µm (corresponding to 2 to 10 tumor cell diameters), minimiz- ing myelotoxicity.469 223Ra, an α–emitting calcium mimic, has been subjected to intense scrutiny for the treatment of prostate cancer bone metastases. The agent has bone-seeking proclivity without requiring a carrier, has a suitable half-life (t1/2 = 11.4 days) allowing convenient dosing, and 219 469 has a safe short-lived daughter isotope ( Rn with t1/2 = 4.0 seconds). The complete reference list is available online at In addition, the total skeletal uptake of 223Ra in men with osteoblastic www.expertconsult.com. 1496 Part III: Specific Malignancies

REFERENCES

2. Barry MJ. Screening for prostate cancer—the from prostate cancer after radical prostatectomy. 366. Bolla M, Collette L, Blank L, et al. Long-term controversy that refuses to die. N Engl J Med N Engl J Med 2004;351(2):125–35. results with immediate androgen suppression and 2009;360(13):1351–4. 211. Andriole GL, Crawford ED, Grubb 3rd RL, et al. external irradiation in patients with locally 6. Walsh PC, Lepor H, Eggleston JC. Radical pros- Mortality results from a randomized prostate- advanced prostate cancer (an EORTC study): tatectomy with preservation of sexual function: cancer screening trial. N Engl J Med 2009; a phase III randomised trial. Lancet 2002; anatomical and pathological considerations. The 360(13):1310–9. 360(9327):103–6. Prostate 1983;4(5):473–85. 212. Schroder FH, Hugosson J, Roobol MJ, et al. 369. Jones CU, Hunt D, McGowan DG, et al. 10. Green SM, Mostaghel EA, Nelson PS. Androgen Screening and prostate-cancer mortality in a ran- Radiotherapy and short-term androgen depriva- action and metabolism in prostate cancer. Mol Cell domized European study. N Engl J Med 2009; tion for localized prostate cancer. N Engl J Med Endocrinol 2012;360(1-2):3–13. 360(13):1320–8. 2011;365(2):107–18. 20. Tomlins SA, Rhodes DR, Perner S, et al. Recurrent 213. Schroder FH, Hugosson J, Roobol MJ, et al. 390. Trock BJ, Han M, Freedland SJ, et al. Prostate fusion of TMPRSS2 and ETS transcription factor Prostate-cancer mortality at 11 years of follow-up. cancer-specific survival following salvage radio- genes in prostate cancer. Science 2005;310(5748): N Engl J Med 2012;366(11):981–90. therapy vs observation in men with biochemical 644–8. 244.e D Marzo AM, Platz EA, Sutcliffe S, et al. Inflam- recurrence after radical prostatectomy. JAMA 21. Rubin MA, Maher CA, Chinnaiyan AM. Common mation in prostate carcinogenesis. Nature Rev 2008;299(23):2760–9. gene rearrangements in prostate cancer. J Clin Cancer 2007;7(4):256–69. 420. Scher HI, Sawyers CL. Biology of progressive, Oncol 2011;29(27):3659–68. 248. Epstein JI, Allsbrook Jr WC, Amin MB, Egevad castration-resistant prostate cancer: directed thera- 23. Steinberg GD, Carter BS, Beaty TH, et al. Family LL. The 2005 International Society of Urological pies targeting the androgen-receptor signaling axis. history and the risk of prostate cancer. The Prostate Pathology (ISUP) Consensus Conference on J Clin Oncol 2005;23(32):8253–61. 1990;17(4):337–47. Gleason Grading of Prostatic Carcinoma. Am J 428. Maximum androgen blockade in advanced pros- 24. Lichtenstein P, Holm NV, Verkasalo PK, et al. Surg Pathol 2005;29(9):1228–42. tate cancer: an overview of 22 randomised trials Environmental and heritable factors in the causa- 250. Fox JJ, Morris MJ, Larson SM, et al. Developing with 3283 deaths in 5710 patients. Prostate tion of cancer— analyses of cohorts of twins from imaging strategies for castration resistant prostate Cancer Trialists’ Collaborative Group. Lancet Sweden, Denmark, and Finland. N Engl J Med cancer. Acta Oncol 2011;50(Suppl 1):39–48. 1995;346(8970):265–9. 2000;343(2):78–85. 257. Partin AW, Kattan MW, Subong EN, et al. Com- 430. Scher HI, Beer TM, Higano CS, et al. 42. Zheng SL, Sun J, Wiklund F, et al. Cumulative bination of prostate-specific antigen, clinical stage, Antitumour activity of MDV3100 in castration- association of five genetic variants with prostate and Gleason score to predict pathological stage of resistant prostate cancer: a phase 1-2 study. Lancet cancer. N Engl J Med 2008;358(9):910–9. localized prostate cancer. A multi-institutional 2010;375(9724):1437–46. 43. Hsing AW, Tsao L, Devesa SS. International update. JAMA 1997;277(18):1445–51. 434. de Bono JS, Logothetis CJ, Molina A, et al. trends and patterns of prostate cancer incidence 258. Han M, Partin AW, Zahurak M, et al. Abiraterone and increased survival in metastatic and mortality. International journal of cancer Biochemical (prostate specific antigen) recurrence prostate cancer. N Engl J Med 2011;364(21): 2000;85(1):60–7. probability following radical prostatectomy for 1995–2005. 66.e D Marzo AM, Marchi VL, Epstein JI, Nelson clinically localized prostate cancer. J Urol 2003; 449. Tannock IF, de Wit R, Berry WR, et al. Docetaxel WG. Proliferative inflammatory atrophy of the 169(2):517–23. plus prednisone or mitoxantrone plus prednisone prostate: implications for prostatic carcinogenesis. 268. Stamey TA, Yang N, Hay AR, et al. Prostate- for advanced prostate cancer. N Engl J Med Am J Pathol 1999;155(6):1985–92. specific antigen as a serum marker for adenocarci- 2004;351(15):1502–12. 86. Barbieri CE, Baca SC, Lawrence MS, et al. Exome noma of the prostate. N Engl J Med 1987;317(15): 450. Armstrong AJ, Garrett-Mayer ES, Yang YC, sequencing identifies recurrent SPOP, FOXA1 and 909–16. et al. A contemporary prognostic nomogram for MED12 mutations in prostate cancer. Nat Genet 269. D’Amico AV, Whittington R, Malkowicz SB, et al. men with hormone-refractory metastatic prostate 2012;44(6):685–9. Biochemical outcome after radical prostatectomy, cancer: a TAX327 study analysis. Clin Cancer Res 87. Lee WH, Morton RA, Epstein JI, et al. Cytidine external beam radiation therapy, or interstitial 2007;13(21):6396–403. methylation of regulatory sequences near the radiation therapy for clinically localized prostate 456. de Bono JS, Oudard S, Ozguroglu M, et al. pi-class glutathione S-transferase gene accompanies cancer. JAMA 1998;280(11):969–74. Prednisone plus cabazitaxel or mitoxantrone for human prostatic carcinogenesis. Proceedings of the 280. Bill-Axelson A, Holmberg L, Ruutu M, et al. metastatic castration-resistant prostate cancer National Academy of Sciences of the United States Radical prostatectomy versus watchful waiting in progressing after docetaxel treatment: a ran- of America 1994;91(24):11733–7. early prostate cancer. N Engl J Med 2011;364(18): domised open-label trial. Lancet 2010;376(9747): 148. Luo J, Zha S, Gage WR, et al. Alpha-methylacyl- 1708–17. 1147–54. coa racemase: a new molecular marker for prostate 304. Sanda MG, Dunn RL, Michalski J, et al. Quality 461. Kantoff PW, Higano CS, Shore ND, et al. cancer. Cancer Res 2002;62(8):2220–6. of life and satisfaction with outcome among Sipuleucel-T immunotherapy for castration- 165. Catalona WJ, Smith DS, Ratliff TL, et al. Mea- prostate-cancer survivors. N Engl J Med 2008; resistant prostate cancer. N Engl J Med 2010; surement of prostate-specific antigen in serum as a 358(12):1250–61. 363(5):411–22. screening test for prostate cancer. N Engl J Med 325. Zelefsky MJ, Fuks Z, Hunt M, et al. High-dose 462. Saad F, Gleason DM, Murray R, et al. A 1991;324(17):1156–61. intensity modulated radiation therapy for prostate randomized, placebo-controlled trial of zoledronic 181. Benson MC, Whang IS, Pantuck A, et al. Prostate cancer: early toxicity and biochemical outcome in acid in patients with hormone-refractory meta- specific antigen density: a means of distinguishing 772 patients. Int J Radiat Oncol Biol Phys static prostate carcinoma. J Natl Cancer Inst benign prostatic hypertrophy and prostate cancer. 2002;53(5):1111–6. 2002;94(19):1458–68. J Urol 1992;147(3 Pt 2):815–6. 332. Roach 3rd M, Hanks G, Thames Jr H, et al. Defin- 464. Fizazi K, Carducci M, Smith M, et al. Denosumab 184. Tosoian JJ, Trock BJ, Landis P, et al. Active ing biochemical failure following radiotherapy versus zoledronic acid for treatment of bone metas- surveillance program for prostate cancer: an update with or without hormonal therapy in men with tases in men with castration-resistant prostate of the Johns Hopkins experience. J Clin Oncol clinically localized prostate cancer: recommenda- cancer: a randomised, double-blind study. Lancet 2011;29(16):2185–90. tions of the RTOG-ASTRO Phoenix Consensus 2011;377(9768):813–22. 185. Carter HB, Pearson JD, Metter EJ, et al. Longitu- Conference. Int J Radiat Oncol Biol Phys 2006; 471. Nilsson S, Franzen L, Parker C, et al. dinal evaluation of prostate-specific antigen levels 65(4):965–74. Bone-targeted radium-223 in symptomatic, in men with and without prostate disease. JAMA 338. Wallner K, Merrick G, True L, et al. I-125 versus hormone-refractory prostate cancer: a randomised, 1992;267(16):2215–20. Pd-103 for low-risk prostate cancer: morbidity multicentre, placebo-controlled phase II study. 188. D’Amico AV, Chen MH, Roehl KA, Catalona WJ. outcomes from a prospective randomized multi- Lancet Oncol 2007;8(7):587–94. Preoperative PSA velocity and the risk of death center trial. Cancer J 2002;8(1):67–73. Prostate Cancer • CHAPTER 84 1496.e1

REFERENCES

1. Siegel R, Naishadham D, Jemal A. Cancer statis- 22. Morganti G, Gianferrari L, Cresseri A, et al. CAncer Prostate in Sweden Study. Cancer Res tics, 2012. CA Cancer J Clin 2012;62(1):10–29. Recherches clinicostastisiques et genetiques sur les 2004;64(8):2918–22. 2. Barry MJ. Screening for prostate cancer—the neoplasies de la prostate. Acta Genet 1956;6: 41. Kote-Jarai Z, Leongamornlert D, Saunders E, et al. controversy that refuses to die. N Engl J Med 304–5. BRCA2 is a moderate penetrance gene contribut- 2009;360(13):1351–4. 23. Steinberg GD, Carter BS, Beaty TH, et al. Family ing to young-onset prostate cancer: implications 3. A, Sakr W Grignon DJ, Crissman JD, et al. High history and the risk of prostate cancer. The Prostate for genetic testing in prostate cancer patients. Br J grade prostatic intraepithelial neoplasia (HGPIN) 1990;17(4):337–47. Cancer 2011;105(8):1230–4. and prostatic adenocarcinoma between the ages of 24. Lichtenstein P, Holm NV, Verkasalo PK, et al. 42. Zheng SL, Sun J, Wiklund F, et al. Cumulative 20-69: an autopsy study of 249 cases. In Vivo Environmental and heritable factors in the causa- association of five genetic variants with prostate 1994;8(3):439–43. tion of cancer—analyses of cohorts of twins from cancer. N Engl J Med 2008;358(9):910–9. 4. Brooks JD. Anatomy of the lower urinary tract and Sweden, Denmark, and Finland. N Engl J Med 43. Hsing AW, Tsao L, Devesa SS. International male genitalia. In: Walsh PC, editor. Campbell’s 2000;343(2):78–85. trends and patterns of prostate cancer incidence Urology, vol. 1. Philadelphia, PA: Saunders; 2002. 25. u Jin G, L L, Cooney KA, et al. Validation of pros- and mortality. International journal of cancer p. 41–80. tate cancer risk-related loci identified from 2000;85(1):60–7. 5. Walsh PC, Donker PJ. Impotence following genome-wide association studies using family- 44. Reddy S, Shapiro M, Morton Jr R, Brawley OW. radical prostatectomy: insight into etiology and based association analysis: evidence from the Inter- Prostate cancer in black and white Americans. prevention. J Urol. Sep 1982;128(3):492–7. national Consortium for Prostate Cancer Genetics Cancer Metastasis Rev 2003;22(1):83–6. 6. Walsh PC, Lepor H, Eggleston JC. Radical pros- (ICPCG). Hum Genet 2012;131(7):1095–103. 45. Whittemore AS, Kolonel LN, Wu AH, et al. tatectomy with preservation of sexual function: 26. Carpten J, Nupponen N, Isaacs S, et al. Germline Prostate cancer in relation to diet, physical activity, anatomical and pathological considerations. The mutations in the ribonuclease L gene in families ande body siz in blacks, whites, and Asians in the Prostate 1983;4(5):473–85. showing linkage with HPC1. Nat Genet 2002; United States and Canada. J Natl Cancer Inst 7. McNeal JE. The zonal anatomy of the prostate. 30(2):181–4. 1995;87(9):652–61. The Prostate 1981;2(1):35–49. 27.u X J, Zheng SL, Komiya A, et al. Germline muta- 46. Haenszel W, Kurihara M. Studies of Japanese 8. McNeal JE. Normal histology of the prostate. Am tions and sequence variants of the macrophage migrants. I. Mortality from cancer and other dis- J Surg Pathol 1988;12(8):619–33. scavenger receptor 1 gene are associated with pros- eases among Japanese in the United States. J Natl 9. Steers WD. 5alpha-reductase activity in the tate cancer risk. Nat Genet 2002;32(2):321–5. Cancer Inst 1968;40(1):43–68. prostate. Urology 2001;58(6 Suppl 1):17–24; 28. Zhou A, Hassel BA, Silverman RH. Expression 47. Shimizu H, Ross RK, Bernstein L, et al. Cancers discussion 24. cloning of 2-5A-dependent RNAase: a uniquely of the prostate and breast among Japanese and 10. Green SM, Mostaghel EA, Nelson PS. Androgen regulated mediator of interferon action. Cell white immigrants in Los Angeles County. Br J action and metabolism in prostate cancer. Mol Cell 1993;72(5):753–65. Cancer 1991;63(6):963–6. Endocrinol 2012;360(1-2):3–13. 29. Platt N, Gordon S. Is the class A macrophage 48. Giovannucci E, Rimm EB, Colditz GA, et al. A 11. Roche PJ, Hoare SA, Parker MG. A consensus scavenger receptor (SR-A) multifunctional?—The prospective study of dietary fat and risk of prostate DNA-binding site for the androgen receptor. Mol mouse’s tale. J Clin Invest 2001;108(5):649–54. cancer [see comments]. J Natl Cancer Inst Endocrinol 1992;6(12):2229–35. 30. Casey G, Neville PJ, Plummer SJ, et al. RNASEL 1993;85(19):1571–9. 12. Schuur ER, Henderson GA, Kmetec LA, et al. Arg462Gln variant is implicated in up to 13% of 49. Gann PH, Hennekens CH, Sacks FM, et al. Prostate-specific antigen expression is regulated by prostate cancer cases. Nat Genet 2002. Prospective study of plasma fatty acids and risk an upstream enhancer. J Biol Chem 1996;271(12): 31. Dejager S, Mietus-Snyder M, Friera A, Pitas RE. of prostate cancer. J Natl Cancer Inst 1994;86(4): 7043–51. Dominant negative mutations of the scavenger 281–6. 13. Goldstein AS, Stoyanova T, Witte ON. Primitive receptor. Native receptor inactivation by expression 50. Le Marchand L, Kolonel LN, Wilkens LR, et al. origins of prostate cancer: in vivo evidence for of truncated variants. J Clin Invest 1993;92(2): Animal fat consumption and prostate cancer: a prostate-regenerating cells and prostate cancer- 894–902. prospective study in Hawaii. Epidemiology initiating cells. Mol Oncol 2010;4(5):385–96. 32. Zhou A, Paranjape J, Brown TL, et al. Interferon 1994;5(3):276–82. 14. Peehl DM, Rubin JS. Keratinocyte growth factor: action and apoptosis are defective in mice devoid 51.e Kniz MG, Salmon CP, Mehta SS, Felton JS. an androgen-regulated mediator of stromal- of 2’,5’-oligoadenylate-dependent. RNase L. Embo Analysis of cooked muscle meats for heterocyclic epithelial interactions in the prostate. World J Urol J 1997;16(21):6355–63. aromatic amine carcinogens. Mutat Res 1997; 1995;13(5):312–7. 33. Suzuki H, Kurihara Y, Takeya M, et al. A role for 376(1-2):129–34. 15. Planz B, Wang Q, Kirley SD, et al. Androgen macrophage scavenger receptors in atherosclerosis 52. Lijinsky W, Shubik P. Benzo(a)pyrene and other responsiveness of stromal cells of the human pros- and susceptibility to infection. Nature 1997; polynuclear hydrocarbons in charcoal-broiled tate: regulation of cell proliferation and keratino- 386(6622):292–6. meat. Science (New York, N.Y) 1964;145:53–5. cyte growth factor by androgen. J Urol 34. Peiser L, Gough PJ, Kodama T, Gordon S. Macro- 53. , Shirai T Sano M, Tamano S, et al. The prostate: 1998;160(5):1850–5. phage class A scavenger receptor-mediated phago- a target for carcinogenicity of 2-amino-1-methyl- 16. Marker PC, Donjacour AA, Dahiya R, Cunha GR. cytosis of Escherichia coli: role of cell heterogeneity, 6- phenylimidazo[4,5-b]pyridine (PhIP) derived Hormonal, cellular, and molecular control of microbial strain, and culture conditions in vitro. from cooked foods. Cancer Res 1997;57(2): prostatic development. Dev Biol 2003;253(2): Infect Immun 2000;68(4):1953–63. 195–8. 165–74. 35. Thomas CA, Li Y, Kodama T, et al. Protection 54. Chan JM, Stampfer MJ, Ma J, et al. Dairy 17. Oesterling JE, Hauzeur CG, Farrow GM. from lethal gram-positive infection by macrophage products, calcium, and prostate cancer risk in Small cell anaplastic carcinoma of the prostate: scavenger receptor-dependent phagocytosis. J Exp the Physicians’ Health Study. Am J Clin Nutr a clinical, pathological and immunohistological Med 2000;191(1):147–56. 2001;74(4):549–54. study of 27 patients. J Urol 1992;147(3 Pt 2): 36. Sun J, Wiklund F, Zheng SL, et al. Sequence 55. H, Gann P Ma J, Giovannucci E, et al. Lower 804–7. variants in Toll-like receptor gene cluster (TLR6- prostate cancer risk in men with elevated plasma 18.e D Marzo AM, Nelson WG, Meeker AK, Coffey TLR1-TLR10) and prostate cancer risk. J Natl lycopene levels: results of a prospective analysis. DS. Stem cell features of benign and malignant Cancer Inst 2005;97(7):525–32. Cancer Res 1999;59(6):1225–30. prostate epithelial cells. J Urol 1998;160(6 Pt 2): 37. Lindmark F, Zheng SL, Wiklund F, et al. 56. Cohen JH, Kristal AR, Stanford JL. Fruit and 2381–92. H6D polymorphism in macrophage-inhibitory vegetable intakes and prostate cancer risk. J Natl 19. van Leenders G, Dijkman H, Hulsbergen-van de cytokine-1 gene associated with prostate cancer. Cancer Inst 2000;92(1):61–8. Kaa C, et al. Demonstration of intermediate cells J Natl Cancer Inst 2004;96(16):1248–54. 57. Klein EA, Thompson Jr IM, Tangen CM, et al. during human prostate epithelial differentiation in 38. Lindmark F, Zheng SL, Wiklund F, et al. Vitamin E and the risk of prostate cancer: the situ and in vitro using triple-staining confocal Interleukin-1 receptor antagonist haplotype associ- Selenium and Vitamin E Cancer Prevention Trial scanning microscopy. Lab Invest 2000;80(8): ated with prostate cancer risk. Br J Cancer 2005; (SELECT). JAMA 2011;306(14):1549–56. 1251–8. 93(4):493–7. 58. Gardner WA, Bennett BD. The prostate overview: 20. Tomlins SA, Rhodes DR, Perner S, et al. Recurrent 39.u X J, Lowey J, Wiklund F, et al. The interaction recent insights and speculations. In: Weinstein RS, fusion of TMPRSS2 and ETS transcription factor of four genes in the inflammation pathway signifi- GarnderA, W editors. Pathology and pathobiology genes in prostate cancer. Science 2005;310(5748): cantly predicts prostate cancer risk. Cancer Epide- of the urinary bladder and prostate. Baltimore: 644–8. miol Biomarkers Prev 2005;14(11 Pt 1):2563–8. Williams and Wilkens; 1992. p. 129–48. 21. Rubin MA, Maher CA, Chinnaiyan AM. Common 40. Zheng SL, Augustsson-Balter K, Chang B, et al. 59. Giovannucci E. Medical history and etiology gene rearrangements in prostate cancer. J Clin Sequence variants of toll-like receptor 4 are associ- of prostate cancer. Epidemiol Rev 2001;23(1): Oncol 2011;29(27):3659–68. ated with prostate cancer risk: results from the 159–62. 1496.e2 Part III: Specific Malignancies

60. Hoekx L, Jeuris W, Van Marck E, Wyndaele JJ. molecular subtype of prostate cancer. Cancer Res 96. Bhatia-Gaur R, Donjacour AA, Sciavolino PJ, Elevated serum prostate specific antigen (PSA) 2006;66(7):3396–400. et al. Roles for Nkx3.1 in prostate development related to asymptomatic prostatic inflammation. 79. Haffner MC, Aryee MJ, Toubaji A, et al. Androgen- and. cancer Genes Dev 1999;13(8):966–77. Acta Urol Belg 1998;66(3):1–2. induced TOP2B-mediated double-strand breaks 97. Abdulkadir SA, Magee JA, Peters TJ, et al. 61. Roberts RO, Lieber MM, Rhodes T, et al. and prostate cancer gene rearrangements. Nat Conditional loss of Nkx3.1 in adult mice induces Prevalence of a physician-assigned diagnosis of Genet 2010;42(8):668–75. prostatic intraepithelial neoplasia. Molecular and prostatitis: the Olmsted County Study of Urinary 80. Haffner MC, De Marzo AM, Meeker AK, et al. cellular biology 2002;22(5):1495–503. Symptoms and Health Status Among Men. Transcription-induced DNA double strand breaks: 98. Emmert-Buck MR, Vocke CD, Pozzatti RO, et al. Urology 1998;51(4):578–84. both oncogenic force and potential therapeutic Allelic loss on chromosome 8p12-21 in microdis- 62. Hayes RB, Pottern LM, Strickler H, et al. Sexual target? Clin Cancer Res 2011;17(12):3858–64. sected prostatic intraepithelial neoplasia. Cancer behaviour, STDs and risks for prostate cancer. Br 81. Cerveira N, Ribeiro FR, Peixoto A, et al. Res 1995;55(14):2959–62. J Cancer 2000;82(3):718–25. TMPRSS2-ERG gene fusion causing ERG overex- 99. Li J, Yen C, Liaw D, et al. PTEN, a putative 63. Dennis LK, Dawson DV. Meta-analysis of pression precedes chromosome copy number protein tyrosine phosphatase gene mutated in measures of sexual activity and prostate cancer. changes in prostate and paired HGPIN human brain, breast, and prostate cancer. Science Epidemiology 2002;13(1):72–9. lesions. Neoplasia (New York, N.Y.) 2006;8(10): (New York, N.Y.) 1997;275(5308):1943–7. 64., Xia Y Zweier JL. Superoxide and peroxynitrite 826–32. 100. Steck PA, Pershouse MA, Jasser SA, et al. generation from inducible nitric oxide synthase 82. Hermans KG, van Marion R, van Dekken H, Identification of a candidate tumour suppressor in macrophages. Proceedings of the National et al. TMPRSS2:ERG fusion by translocation or gene, MMAC1, at chromosome 10q23.3 that is Academy of Sciences of the United States of interstitial deletion is highly relevant in androgen- mutated in multiple advanced cancers. Nat Genet America 1997;94(13):6954–8. dependent prostate cancer, but is bypassed in late- 1997;15(4):356–62. 65. Eiserich JP, Hristova M, Cross CE, et al. Formation stage androgen receptor-negative prostate cancer. 101. Teng DH, Hu R, Lin H, et al. MMAC1/PTEN of nitric oxide-derived inflammatory oxidants by Cancer Res 2006;66(22):10658–63. mutations in primary tumor specimens and tumor myeloperoxidase in neutrophils. Nature 1998; 83. Nam RK, Sugar L, Wang Z, et al. Expression of cell lines. Cancer Res 1997;57(23):5221–5. 391(6665):393–7. TMPRSS2 ERG Gene Fusion in Prostate Cancer 102. Myers MP, Pass I, Batty IH, et al. The lipid phos- 66.e D Marzo AM, Marchi VL, Epstein JI, Nelson Cells is an Important Prognostic Factor for Cancer phatase activity of PTEN is critical for its tumor WG. Proliferative inflammatory atrophy of the Progression. Cancer biology & therapy 2007;6(1). supressor function. Proceedings of the National prostate: implications for prostatic carcinogenesis. 84. Petrovics G, Liu A, Shaheduzzaman S, et al. Academy of Sciences of the United States of Am J Pathol 1999;155(6):1985–92. Frequent overexpression of ETS-related gene-1 America 1998;95(23):13513–8. 67. Franks LM. Atrophy and hyperplasia in the (ERG1) in prostate cancer transcriptome. Onco- 103. Myers MP, Stolarov JP, Eng C, et al. P-TEN, prostate proper. J Pathol and Bacteriol 1954;68: gene 2005;24(23):3847–52. the tumor suppressor from human chromosome 617–21. 85. Tomlins SA, Rhodes DR, Yu J, et al. The role of 10q23, is a dual- specificity phosphatase. Proceed- 68.e D Marzo AM, et al. A working group classifica- SPINK1 in ETS rearrangement-negative prostate ings of the National Academy of Sciences of the tion of focal prostate atrophy lesions. Am J Surg cancers. Cancer cell 2008;13(6):519–28. United States of America 1997;94(17):9052–7. PatholAm J Surg Pathol 2006;In press. 86. Barbieri CE, Baca SC, Lawrence MS, et al. Exome 104. Maehama T, Dixon JE. The tumor suppressor, 69. Nakayama M, Bennett CJ, Hicks JL, et al. sequencing identifies recurrent SPOP, FOXA1 and PTEN/MMAC1, dephosphorylates the lipid Hypermethylation of the human glutathione MED12 mutations in prostate cancer. Nat Genet second messenger, phosphatidylinositol 3,4,5- S-transferase-pi gene (GSTP1) CpG island is 2012;44(6):685–9. trisphosphate. J Biol Chem 1998;273(22): present in a subset of proliferative inflammatory 87. Lee WH, Morton RA, Epstein JI, et al. Cytidine 13375–8. atrophy lesions but not in normal or hyperplastic methylation of regulatory sequences near the 105. Cairns P, Okami K, Halachmi S, et al. Frequent epithelium of the prostate: a detailed study using pi-class glutathione S-transferase gene accompanies inactivation of PTEN/MMAC1 in primary pros- laser-capture microdissection. Am J Pathol human prostatic carcinogenesis. Proceedings of the tate. cancer Cancer Res 1997;57(22):4997–5000. 2003;163(3):923–33. National Academy of Sciences of the United States 106. Suzuki H, Freije D, Nusskern DR, et al. Interfocal 70. Shiraishi T, Watanabe M, Matsuura H, et al. The of America 1994;91(24):11733–7. heterogeneity of PTEN/MMAC1 gene alterations frequency of latent prostatic carcinoma in young 88. Nakayama M, Gonzalgo ML, Yegnasubramanian in multiple metastatic prostate cancer tissues. males: the Japanese experience. In Vivo 1994;8(3): S, et al. GSTP1 CpG island hypermethylation as Cancer Res 1998;58(2):204–9. 445–7. a molecular biomarker for prostate cancer. J Cell 107. McMenamin ME, Soung P, Perera S, et al. Loss of 71. Yatani R, Shiraishi T, Nakakuki K, et al. Trends in Biochem 2004;91(3):540–52. PTEN expression in paraffin-embedded primary frequency of latent prostate carcinoma in Japan 89. The effect of vitamin E and beta carotene on the prostate cancer correlates with high Gleason score from 1965- 1979 to 1982-1986. J Natl Cancer Inst incidence of lung cancer and other cancers in male and advanced stage. Cancer Res 1999;59(17): 1988;80(9):683–7. smokers. The Alpha-Tocopherol, Beta Carotene 4291–6. 72. Yatani R, Chigusa I, Akazaki K, et al. Geographic Cancer Prevention Study Group. N Engl J Med 108. Podsypanina K, Ellenson LH, Nemes A, et al. pathology of latent prostatic carcinoma. Interna- 1994;330(15):1029–35. Mutation of Pten/Mmac1 in mice causes neoplasia tional journal of cancer 1982;29(6):611–6. 90. Henderson CJ, Smith AG, Ure J, et al. Increased in multiple organ systems. Proceedings of the 73. Berger MF, Lawrence MS, Demichelis F, et al. The skin tumorigenesis in mice lacking pi class gluta- National Academy of Sciences of the United States genomic complexity of primary human prostate thione S- transferases. Proceedings of the National of America 1999;96(4):1563–8. cancer. Nature 2011;470(7333):214–20. Academy of Sciences of the United States of 109.i D Cristofano A, Pesce B, Cordon-Cardo C, 74. Yegnasubramanian S, Wu Z, Haffner MC, et al. America 1998;95(9):5275–80. Pandolfi. PP Pten is essential for embryonic Chromosome-wide mapping of DNA methylation 91. Nelson CP, Kidd LC, Sauvageot J, et al. development and tumour suppression. Nat Genet patterns in normal and malignant prostate cells Protection against 2-hydroxyamino-1-methyl-6- 1998;19(4):348–55. reveals pervasive methylation of gene-associated phenylimidazo[4,5- b]pyridine cytotoxicity and 110. Kim MJ, Cardiff RD, Desai N, et al. Cooperativity and conserved intergenic sequences. BMC genom- DNA adduct formation in human prostate by of Nkx3.1 and Pten loss of function in a mouse ics 2011;12:313. glutathione S-transferase P1. Cancer Res 2001; model of prostate carcinogenesis. Proceedings of 75. Isaacs JT, Coffey DS. Adaptation versus 61(1):103–9. the National Academy of Sciences of the United selection as the mechanism responsible for the 92. Brooks JD, Weinstein M, Lin X, et al. CG island States of America 2002;99(5):2884–9. relapse of prostatic cancer to androgen ablation methylation changes near the GSTP1 gene in pros- 111. Cordon-Cardo C, Koff A, Drobnjak M, et al. Dis- therapy as studied in the Dunning R-3327-H tatic intraepithelial neoplasia. Cancer Epidemiol tinct altered patterns of p27KIP1 gene expression adenocarcinoma. Cancer Res 1981;41(12 Pt Biomarkers Prev 1998;7(6):531–6. in benign prostatic hyperplasia and prostatic carci- 1):5070–5. 93. Bieberich CJ, Fujita K, He WW, Jay G. noma. J Natl Cancer Inst 1998;90(17):1284–91. 76. Isaacs JT, Wake N, Coffey DS, Sandberg AA. Prostate-specific and androgen-dependent expres- 112. , Guo Y Sklar GN, Borkowski A, Kyprianou N. Genetic instability coupled to clonal selection as a sion of a novel homeobox gene. J Biol Chem Loss of the cyclin-dependent kinase inhibitor mechanism for tumor progression in the Dunning 1996;271(50):31779–82. p27(Kip1) protein in human prostate cancer cor- R-3327 rat prostatic adenocarcinoma system. 94. Steadman DJ, Giuffrida D, Gelmann EP. DNA- relates with tumor grade. Clin Cancer Res Cancer Res 1982;42(6):2353–71. binding sequence of the human prostate-specific 1997;3(12t P 1):2269–74. 77. Perner S, Demichelis F, Beroukhim R, et al. homeodomain protein NKX3.1. Nucleic acids 113. Kibel AS, Faith DA, Bova GS, Isaacs WB. Loss TMPRSS2:ERG Fusion-Associated Deletions research 2000;28(12):2389–95. of heterozygosity at 12P12-13 in primary and Provide Insight into the Heterogeneity of Prostate 95. Chen H, Nandi AK, Li X, Bieberich CJ. NKX-3.1 metastatic prostate adenocarcinoma. J Urol Cancer. Cancer Res 2006;66(17):8337–41. interacts with prostate-derived Ets factor and regu- 2000;164(1):192–6. 78. Tomlins SA, Mehra R, Rhodes DR, et al. lates the activity of the PSA promoter. Cancer Res 114. Graff JR, Konicek BW, McNulty AM, et al. TMPRSS2:ETV4 gene fusions define a third 2002;62(2):338–40. Increased AKT activity contributes to prostate Prostate Cancer • CHAPTER 84 1496.e3

cancer progression by dramatically accelerating prostate cancers compared to benign prostatic 154. Chin L, Artandi SE, Shen Q, et al. p53 deficiency prostate tumor growth and diminishing p27Kip1 hyperplasia. J Urol 2001;166(6):2171–7. rescues the adverse effects of telomere loss and expression. J Biol Chem 2000;275(32):24500–5. 134. Welsh JB, Sapinoso LM, Su AI, et al. Analysis of cooperates with telomere dysfunction to accelerate 115. Gottschalk AR, Basila D, Wong M, et al. p27Kip1 gene expression identifies candidate markers and carcinogenesis. Cell 1999;97(4):527–38. is required for PTEN-induced G1 growth arrest. pharmacological targets in prostate cancer. Cancer 155. Sommerfeld HJ, Meeker AK, Piatyszek MA, et al. Cancer Res 2001;61(5):2105–11. Res 2001;61(16):5974–8. Telomerase activity: a prevalent marker of malig- 116. Nakamura N, Ramaswamy S, Vazquez F, et al. 135. Magee JA, Araki T, Patil S, et al. Expression profil- nant human prostate tissue. Cancer Res 1996; Forkhead transcription factors are critical effectors ing reveals hepsin overexpression in prostate 56(1):218–22. of cell death and cell cycle arrest downstream of cancer. Cancer Res 2001;61(15):5692–6. 156. Meeker AK, Gage WR, Hicks JL, et al. Telomere PTEN. Molecular and cellular biology 2000; 136. Luo J, Duggan DJ, Chen Y, et al. Human prostate length assessment in human archival tissues: com- 20(23):8969–82. cancer and benign prostatic hyperplasia: molecular bined telomere fluorescence in situ hybridization 117.i D Cristofano A, De Acetis M, Koff A, et al. dissectiony b gene expression profiling. Cancer Res and immunostaining. Am J Pathol 2002; Pten and p27KIP1 cooperate in prostate cancer 2001;61(12):4683–8. 160(4):1259–68. tumor suppression in the mouse. Nat Genet 137. Waghray A, Schober M, Feroze F, et al. Identifica- 157. Meeker AK, Hicks JL, Platz EA, et al. Telomere 2001;27(2):222–4. tion of differentially expressed genes by serial shortening is an early somatic DNA alteration 118. Eisenberger MA, Blumenstein BA, Crawford ED, analysis of gene expression in human prostate in human prostate tumorigenesis. Cancer Res et al. Bilateral orchiectomy with or without fluta- cancer. Cancer Res 2001;61(10):4283–6. 2002;62(22):6405–9. mide for metastatic prostate cancer. N Engl J Med 138. Nelson PS, Han D, Rochon Y, et al. Comprehen- 158. Smith DS, Catalona WJ. Interexaminer variability 1998;339(15):1036–42. sive analyses of prostate gene expression: conver- of digital rectal examination in detecting prostate 119. Crawford ED, Eisenberger MA, McLeod DG, gence of expressed sequence tag databases, cancer. Urology 1995;45(1):70–4. et al. A controlled trial of leuprolide with and transcript profiling and proteomics. Electrophore- 159. Ellis WJ, Chetner MP, Preston SD, Brawer MK. without flutamide in prostatic carcinoma. N Engl sis 2000;21(9):1823–31. [pii]. Diagnosis of prostatic carcinoma: the yield of J Med 1989;321(7):419–24. 139.u X J, Stolk JA, Zhang X, et al. Identification of serum prostate specific antigen, digital rectal exam- 120. Feldman BJ, Feldman D. The development of differentially expressed genes in human prostate ination and transrectal ultrasonography. J Urol androgen-independent prostate cancer. Nature cancer using subtraction and microarray. Cancer 1994;152(5 Pt 1):1520–5. reviews. Cancer 2001;1(1):34–45. Res 2000;60(6):1677–82. 160. Cooner WH, Mosley BR, Rutherford Jr CL, et al. 121. van der Kwast TH, Schalken J, Ruizeveld de 140. Walker MG, Volkmuth W, Sprinzak E, et al. Prostate cancer detection in a clinical urological Winter JA, et al. Androgen receptors in endocrine- Prediction of gene function by genome-scale practicey b ultrasonography, digital rectal examina- therapy-resistant human prostate cancer. Interna- expression analysis: prostate cancer-associated tion and prostate specific antigen. J Urol. Jun tional journal of cancer 1991;48(2):189–93. genes. Genome research 1999;9(12):1198–203. 1990;143(6):1146–52; discussion 1152–44. 122. Koivisto P, Kononen J, Palmberg C, et al. 141. Huang GM, Ng WL, Farkas J, et al. Prostate 161. Catalona WJ, Richie JP, Ahmann FR, et al. Com- Androgen receptor gene amplification: a possible cancer expression profiling by cDNA sequencing parison of digital rectal examination and serum molecular mechanism for androgen deprivation analysis. Genomics 1999;59(2):178–86. prostate specific antigen in the early detection of therapy failure in prostate cancer. Cancer Res 142. Rhodes DR, Barrette TR, Rubin MA, et al. prostate cancer: results of a multicenter clinical 1997;57(2):314–9. Meta-analysis of microarrays: interstudy validation trial of 6,630 men. J Urol 1994;151(5):1283–90. 123. Tan J, Sharief Y, Hamil KG, et al. Dehydroepi- of gene expression profiles reveals pathway dys- 162. Thompson IM, Rounder JB, Teague JL, et al. androsterone activates mutant androgen receptors regulation in prostate cancer. Cancer Res 2002; Impact of routine screening for adenocarcinoma expressed in the androgen-dependent human pros- 62(15):4427–33. of the prostate on stage distribution. J Urol tate cancer xenograft CWR22 and LNCaP cells. 143. Tsuji A, Torres-Rosado A, Arai T, et al. Hepsin, a 1987;137(3):424–6. Mol Endocrinol 1997;11(4):450–9. cell membrane-associated protease. Characteriza- 163. Epstein JI, Walsh PC, Carmichael M, Brendler 124. Veldscholte J, Voorhorst-Ogink MM, Bolt-de Vries tion, tissue distribution, and gene localization. CB. Pathologic and clinical findings to predict J, et al. Unusual specificity of the androgen recep- J Biol Chem 1991;266(25):16948–53. tumor extent of nonpalpable (stage T1c) prostate tor in the human prostate tumor cell line LNCaP: 144. Klezovitch O, Chevillet J, Mirosevich J, et al. cancer. JAMA 1994;271(5):368–74. high affinity for progestagenic and estrogenic Hepsin promotes prostate cancer progression and 164. Schroder FH, van der Maas P, Beemsterboer P, steroids. Biochim Biophys Acta 1990;1052(1): metastasis. Cancer cell 2004;6(2):185–95. et al. Evaluation of the digital rectal examination 187–94. 145. Schmitz W, Albers C, Fingerhut R, Conzelmann as a screening test for prostate cancer. Rotterdam 125. Culig Z, Hobisch A, Cronauer MV, et al. Mutant E. Purification and characterization of an alpha- section of the European Randomized Study of androgen receptor detected in an advanced-stage methylacyl-CoA racemase from human liver. Eur J Screening for Prostate Cancer. J Natl Cancer Inst prostatic carcinoma is activated by adrenal andro- Biochem 1995;231(3):815–22. 1998;90(23):1817–23. gens and progesterone. Mol Endocrinol 1993; 146. Jiang Z, Woda BA, Rock KL, et al. P504S: a new 165. Catalona WJ, Smith DS, Ratliff TL, et al. Mea- 7(12):1541–50. molecular marker for the detection of prostate car- surement of prostate-specific antigen in serum as a 126. Shi XB, Ma AH, Xia L, et al. Functional analysis of cinoma. Am J Surg PatholAm J Surg Pathol screening test for prostate cancer. N Engl J Med 44 mutant androgen receptors from human pros- 2001;25(11):1397–404. 1991;324(17):1156–61. tate cancer. Cancer Res 2002;62(5):1496–502. 147. Ferdinandusse S, Denis S, Clayton PT, et al. 166. Gosselaar C, Roobol MJ, Roemeling S, 127. Sadar MD, Gleave ME. Ligand-independent acti- Mutations in the gene encoding peroxisomal Schroder FH. The role of the digital rectal vation of the androgen receptor by the differentia- alpha-methylacyl-CoA racemase cause adult-onset examination in subsequent screening visits in the tion agent butyrate in human prostate cancer cells. sensory motor neuropathy. Nat Genet 2000; European randomized study of screening for Cancer Res 2000;60(20):5825–31. 24(2):188–91. prostate cancer (ERSPC), Rotterdam. Eur Urol 128. Craft N, Shostak Y, Carey M, Sawyers CL. A 148. Luo J, Zha S, Gage WR, et al. Alpha-methylacyl- 2008;54(3):581–8. mechanism for hormone-independent prostate coa racemase: a new molecular marker for prostate 167. Lilja H. Biology of prostate-specific antigen. cancer through modulation of androgen receptor cancer. Cancer Res 2002;62(8):2220–6. Urology 2003;62(5 Suppl 1):27–33. signalingy b the HER-2/neu tyrosine kinase. 149. Varambally S, Dhanasekaran SM, Zhou M, et al. 168. Oesterling JE, Jacobsen SJ, Chute CG, et al. Serum Nature medicine 1999;5(3):280–5. The polycomb group protein EZH2 is involved prostate-specific antigen in a community-based 129. Hobisch A, Eder IE, Putz T, et al. Interleukin-6 in progression of prostate cancer. Nature 2002; population of healthy men. Establishment of age- regulates prostate-specific protein expression in 419(6907):624–9. specific reference ranges. JAMA 1993;270(7): prostate carcinoma cells by activation of the andro- 150. Greider CW, Blackburn EH. Identification of 860–4. gen receptor. Cancer Res 1998;58(20):4640–5. a specific telomere terminal transferase activity 169. Klein LT, Lowe FC. The effects of prostatic manip- 130. Nazareth LV, Weigel NL. Activation of the human in Tetrahymena extracts. Cell 1985;43(2 Pt 1): ulation on prostate-specific antigen levels. Urol androgen receptor through a protein kinase A 405–13. Clin North Am 1997;24(2):293–7. signaling pathway. J Biol Chem 1996;271(33): 151. Maser RS, DePinho RA. Connecting chromo- 170. Guess HA, Heyse JF, Gormley GJ. The effect 19900–7. somes, crisis, and cancer. Science 2002;297(5581): of finasteride on prostate-specific antigen in men 131. Dhanasekaran SM, Barrette TR, Ghosh D, et al. 565–9. with benign prostatic hyperplasia. The Prostate Delineation of prognostic biomarkers in prostate 152. O’Hagan RC, Chang S, Maser RS, et al. Telomere 1993;22(1):31–7. cancer. Nature 2001;412(6849):822–6. dysfunction provokes regional amplification and 171. Gann PH, Hennekens CH, Stampfer MJ. A 132. Luo JH, Yu YP, Cieply K, et al. Gene expression deletion in cancer genomes. Cancer cell 2002; prospective evaluation of plasma prostate-specific analysis of prostate cancers. Mol Carcinog 2002; 2(2):149–55. antigen for detection of prostatic cancer. JAMA 33(1):25–35. 153. Hackett JA, Feldser DM, Greider CW. Telomere 1995;273(4):289–94. 133. Stamey TA, Warrington JA, Caldwell MC, et al. dysfunction increases mutation rate and genomic 172. Fang J, Metter EJ, Landis P, et al. Low levels of Molecular genetic profiling of Gleason grade 4/5 instability. Cell 2001;106(3):275–86. prostate-specific antigen predict long-term risk of 1496.e4 Part III: Specific Malignancies

prostate cancer: results from the Baltimore Longi- life-threatening prostate cancer during window of imaging in the diagnosis of prostate cancer. Int J tudinal Study of Aging. Urology 2001;58(3): curability. Urology 2007;70(4):685–90. Urol 2012;19(7):602–13. 411–6. 191. Loeb S, Metter EJ, Kan D, et al. Prostate-specific 209. Etzioni R, Tsodikov A, Mariotto A, et al. Quantify- 173. Lilja H, Cronin AM, Dahlin A, et al. Prediction of antigen velocity (PSAV) risk count improves the ing the role of PSA screening in the US prostate significant prostate cancer diagnosed 20 to 30 years specificity of screening for clinically significant cancer mortality decline. Cancer Causes Control later with a single measure of prostate-specific prostate cancer. BJU Int 2012;109(4):508–13; 2008;19(2):175–81. antigen at or before age 50. Cancer 2011;117(6): discussion 513–504. 210. Collin SM, Martin RM, Metcalfe C, et al. 1210–9. 192. Roddam AW, Duffy MJ, Hamdy FC, et al. Use of Prostate-cancer mortality in the USA and UK in 174. Schroder FH. Stratifying risk—the U.S. Preventive prostate-specific antigen (PSA) isoforms for the 1975-2004: an ecological study. Lancet Oncol Services Task Force and prostate-cancer screening. detection of prostate cancer in men with a PSA 2008;9(5):445–52. N Engl J Med 2011;365(21):1953–5. level of 2-10 ng/ml: systematic review and meta- 211. Andriole GL, Crawford ED, Grubb 3rd RL, et al. 175. Zhu X, Albertsen PC, Andriole GL, et al. analysis. Eur Urol 2005;48(3):386–99; discussion Mortality results from a randomized prostate- Risk-based prostate cancer screening. Eur Urol 398–389. cancer screening trial. N Engl J Med 2009; 2012;61(4):652–61. 193. Catalona WJ, Southwick PC, Slawin KM, et al. 360(13):1310–9. 176. Thompson IM, Ankerst DP, Chi C, et al. Operat- Comparison of percent free PSA, PSA density, and 212. Schroder FH, Hugosson J, Roobol MJ, et al. ing characteristics of prostate-specific antigen in age-specific PSA cutoffs for prostate cancer detec- Screening and prostate-cancer mortality in a ran- men with an initial PSA level of 3.0 ng/ml or tion and staging. Urology 2000;56(2):255–60. domized European study. N Engl J Med 2009; lower. JAMA 2005;294(1):66–70. 194. Mikolajczyk SD, Marker KM, Millar LS, et al. 360(13):1320–8. 177. Thompson IM, Ankerst DP, Chi C, et al. Assessing A truncated precursor form of prostate-specific 213. Schroder FH, Hugosson J, Roobol MJ, et al. prostate cancer risk: results from the Prostate antigen is a more specific serum marker of prostate Prostate-cancer mortality at 11 years of follow-up. Cancer Prevention Trial. J Natl Cancer Inst cancer. Cancer Res 2001;61(18):6958–63. N Engl J Med 2012;366(11):981–90. 2006;98(8):529–34. 195. Mikolajczyk SD, Catalona WJ, Evans CL, et al. 214. Andriole GL, Crawford ED, Grubb 3rd RL, et al. 178. van Vugt HA, Roobol MJ, Kranse R, et al. Proenzyme forms of prostate-specific antigen in Prostate cancer screening in the randomized Prediction of prostate cancer in unscreened men: serum improve the detection of prostate cancer. Prostate, Lung, Colorectal, and Ovarian Cancer external validation of a risk calculator. Eur J Cancer Clinical chemistry 2004;50(6):1017–25. Screening Trial: mortality results after 13 years of 2011;47(6):903–9. 196. Le BV, Griffin CR, Loeb S, et al. [-2]Proenzyme follow-up. J Natl Cancer Inst 2012;104(2): 179. Lepor H, Wang B, Shapiro E. Relationship prostate specific antigen is more accurate than total 125–32. between prostatic epithelial volume and serum and free prostate specific antigen in differentiating 215. Miller AB. New data on prostate-cancer mortality prostate-specific antigen levels. Urology 1994; prostate cancer from benign disease in a prospec- after PSA screening. N Engl J Med 2012;366(11): 44(2):199–205. tive prostate cancer screening study. J Urol 1047–8. 180. Benson MC, Whang IS, Olsson CA, et al. The use 2010;183(4):1355–9. 216. Chou R, LeFevre ML. Prostate cancer screening— of prostate specific antigen density to enhance the 197. Sokoll LJ, Sanda MG, Feng Z, et al. A prospective, the evidence, the recommendations, and the clini- predictive value of intermediate levels of serum multicenter, National Cancer Institute Early cal implications. JAMA 2011;306(24):2721–2. prostate specific antigen. J Urol 1992;147(3 Pt 2): Detection Research Network study of [-2]proPSA: 217. McNaughton-Collins MF, Barry MJ. One man at 817–21. improving prostate cancer detection and correlat- a time—resolving the PSA controversy. N Engl J 181. Benson MC, Whang IS, Pantuck A, et al. Prostate ing with cancer aggressiveness. Cancer Epidemiol Med 2011;365(21):1951–3. specific antigen density: a means of distinguishing Biomarkers Prev 2010;19(5):1193–200. 218. Ganz PA, Barry JM, Burke W, et al. National Insti- benign prostatic hypertrophy and prostate cancer. 198. Bussemakers MJ, van Bokhoven A, Verhaegh GW, tutes of Health State-of-the-Science Conference: J Urol 1992;147(3 Pt 2):815–6. et al. DD3: a new prostate-specific gene, highly rolee of activ surveillance in the management of 182. Djavan B, Zlotta A, Kratzik C, et al. PSA, PSA overexpressed in prostate cancer. Cancer Res men with localized prostate cancer. Ann Intern density, PSA density of transition zone, free/total 1999;59(23):5975–9. Med 2012;156(8):591–5. PSA ratio, and PSA velocity for early detection of 199. Hessels D, Schalken JA. The use of PCA3 in the 219. Bardia A, Platz EA, Yegnasubramanian S, et al. prostate cancer in men with serum PSA 2.5 to diagnosis of prostate cancer. Nature reviews. Anti-inflammatory drugs, antioxidants, and pros- 4.0 ng/mL. Urology 1999;54(3):517–22. Urology 2009;6(5):255–61. tate cancer prevention. Current opinion in phar- 183. Djavan B, Zlotta AR, Remzi M, et al. Total and 200. Auprich M, Bjartell A, Chun FK, et al. Contem- macology 2009;9(4):419–26. transition zone prostate volume and age: how do porary role of prostate cancer antigen 3 in the 220. Prevention of cancer in the next millennium: they affect the utility of PSA-based diagnostic management of prostate cancer. Eur Urol 2011; Report of the Chemoprevention Working Group parameters for early prostate cancer detection? 60(5):1045–54. to the American Association for . Urology 1999;54(5):846–52. 201. Haese A, de la Taille A, van Poppel H, et al. Clini- Cancer Res 1999;59(19):4743–58. 184. Tosoian JJ, Trock BJ, Landis P, et al. Active cal utility of the PCA3 urine assay in European 221. Thompson IM, Goodman PJ, Tangen CM, et al. surveillance program for prostate cancer: an update men scheduled for repeat biopsy. Eur Urol The influence of finasteride on the development of of the Johns Hopkins experience. J Clin Oncol 2008;54(5):1081–8. prostate cancer. N Engl J Med 2003;349(3): 2011;29(16):2185–90. 202. Baden J, Green G, Painter J, et al. Multicenter 215–24. 185. Carter HB, Pearson JD, Metter EJ, et al. Longitu- evaluation of an investigational prostate cancer 222. Andriole GL, Bostwick DG, Brawley OW, et al. dinal evaluation of prostate-specific antigen levels methylation assay. J Urol 2009;182(3):1186–93. Effect of dutasteride on the risk of prostate cancer. in men with and without prostate disease. JAMA 203. Tomlins SA, Aubin SM, Siddiqui J, et al. N Engl J Med 2010;362(13):1192–202. 1992;267(16):2215–20. Urine TMPRSS2:ERG fusion transcript stratifies 223. Theoret MR, Ning YM, Zhang JJ, et al. The 186. Berger AP, Deibl M, Strasak A, et al. Large-scale prostate cancer risk in men with elevated serum risks and benefits of 5alpha-reductase inhibitors study of clinical impact of PSA velocity: long-term PSA. Science translational medicine 2011;3(94): for prostate-cancer prevention. N Engl J Med PSA kinetics as method of differentiating men with 94ra72. 2011;365(2):97–9. from those without prostate cancer. Urology 204. Etzioni R, Kooperberg C, Pepe M, et al. 224. Hardell L, Degerman A, Tomic R, et al. Levels 2007;69(1):134–8. Combining biomarkers to detect disease with of selenium in plasma and glutathione peroxidase 187. Etzioni RD, Howlader N, Shaw PA, et al. application to prostate cancer. Biostatistics 2003; in erythrocytes in patients with prostate cancer or Long-term effects of finasteride on prostate 4(4):523–38. benign hyperplasia. Eur J Cancer Prev 1995;4(1): specific antigen levels: results from the prostate 205. Boczko J, Messing E, Dogra V. Transrectal sonog- 91–5. cancer prevention trial. J Urol 2005;174(3): raphy in prostate evaluation. Radiol Clin North 225. Chan JM, Stampfer MJ, Ma J, et al. Supplemental 877–81. Am 2006;44(5):679–87, viii. vitamin E intake and prostate cancer risk in a 188. D’Amico AV, Chen MH, Roehl KA, Catalona WJ. 206. Loeb S, Carter HB, Berndt SI, et al. Complications larget cohor of men in the United States. Cancer Preoperative PSA velocity and the risk of death after prostate biopsy: data from SEER-Medicare. Epidemiol Biomarkers Prev 1999;8(10):893–9. from prostate cancer after radical prostatectomy. J Urol 2011;186(5):1830–4. 226. Brooks JD, Metter EJ, Chan DW, et al. Plasma N Engl J Med 2004;351(2):125–35. 207. Taylor AK, Zembower TR, Nadler RB, et al. selenium level before diagnosis and the risk of 189. Carter HB, Ferrucci L, Kettermann A, et al. Targeted antimicrobial prophylaxis using rectal prostate cancer development. J Urol 2001;166(6): Detection of life-threatening prostate cancer with swab cultures in men undergoing transrectal ultra- 2034–8. prostate-specific antigen velocity during a window sound guided prostate biopsy is associated with 227. Kristal AR, Stanford JL, Cohen JH, et al. Vitamin of. curability J Natl Cancer Inst 2006;98(21): reduced incidence of postoperative infectious com- and mineral supplement use is associated with 1521–7. plications and cost of care. J Urol 2012;187(4): reduced risk of prostate cancer. Cancer Epidemiol 190. Carter HB, Kettermann A, Ferrucci L, et al. 1275–9. Biomarkers Prev 1999;8(10):887–92. Prostate-specific antigen velocity risk count 208. Kumar V, Jagannathan NR, Thulkar S, Kumar R. 228. Helzlsouer KJ, Huang HY, Alberg AJ, et al. assessment: a new concept for detection of Prebiopsy magnetic resonance spectroscopy and Association between alpha-tocopherol, Prostate Cancer • CHAPTER 84 1496.e5

gamma-tocopherol, selenium, and subsequent cancer: biopsy and radical prostatectomy speci- 266. Pinto F, Totaro A, Palermo G, et al. Imaging in prostate cancer. J Natl Cancer Inst 2000; mens. Eur Urol 2012;62(1):20–39. prostate cancer staging: present role and future 92(24):2018–23. 248. Epstein JI, Allsbrook Jr WC, Amin MB, Egevad perspectives. Urol Int 2012;88(2):125–36. 229. Nomura AM, Lee J, Stemmermann GN, Combs LL. The 2005 International Society of Urological 267. Ellis RJ, Kaminsky DA, Zhou EH, et al. Jr. GF Serum selenium and subsequent risk of pros- Pathology (ISUP) Consensus Conference on Ten-year outcomes: the clinical utility of single tate. cancer Cancer Epidemiol Biomarkers Prev Gleason Grading of Prostatic Carcinoma. Am J photon emission computed tomography/computed 2000;9(9):883–7. Surg Pathol 2005;29(9):1228–42. tomography capromab pendetide (Prostascint) in a 230. Yoshizawa K, Willett WC, Morris SJ, et al. Study 249. Casimiro S, Guise TA, Chirgwin J. The critical role cohort diagnosed with localized prostate cancer. of prediagnostic selenium level in toenails and the of the bone microenvironment in cancer metasta- Int J Radiat Oncol Biol Phys 2011;81(1):29–34. risk of advanced prostate cancer. J Natl Cancer Inst ses. Mol Cell Endocrinol 2009;310(1-2):71–81. 268. Stamey TA, Yang N, Hay AR, et al. 1998;90(16):1219–24. 250. Fox JJ, Morris MJ, Larson SM, et al. Developing Prostate-specific antigen as a serum marker for 231. Klein EA, Thompson IM, Lippman SM, et al. imaging strategies for castration resistant prostate adenocarcinoma of the prostate. N Engl J Med SELECT: the next prostate cancer prevention trial. cancer. Acta Oncol 2011;50 Suppl 1:39–48. 1987;317(15):909–16. Selenum and Vitamin E Cancer Prevention Trial. 251. Even-Sapir E, Metser U, Mishani E, et al. The 269. D’Amico AV, Whittington R, Malkowicz SB, et al. J Urol 2001;166(4):1311–5. detection of bone metastases in patients with high- Biochemical outcome after radical prostatectomy, 232. Lippman SM, Klein EA, Goodman PJ, et al. Effect risk prostate cancer: 99mTc-MDP Planar bone external beam radiation therapy, or interstitial of selenium and vitamin E on risk of prostate scintigraphy, single- and multi-field-of-view radiation therapy for clinically localized prostate cancer and other cancers: the Selenium and SPECT, 18F-fluoride PET, and 18F-fluoride PET/ cancer. JAMA 1998;280(11):969–74. Vitamin E Cancer Prevention Trial (SELECT). CT. J Nucl Med 2006;47(2):287–97. 270. Cooperberg MR, Carroll PR, Klotz L. Active sur- JAMA 2009;301(1):39–51. 252. Rubin MA, Putzi M, Mucci N, et al. Rapid veillance for prostate cancer: progress and promise. 233. Duffield-Lillico AJ, Dalkin BL, Reid ME, et al. (“warm”) autopsy study for procurement of J Clin Oncol 2011;29(27):3669–76. Selenium supplementation, baseline plasma sele- metastatic prostate cancer. Clin Cancer Res 2000; 271. Mohler JL. The 2010 NCCN clinical practice nium status and incidence of prostate cancer: an 6(3):1038–45. guidelines in oncology on prostate cancer. J Natl analysis of the complete treatment period of the 253. Shah RB, Mehra R, Chinnaiyan AM, et al. Compr Canc Netw 2010;8(2):145. Nutritional Prevention of Cancer Trial. BJU Int Androgen-independent prostate cancer is a hetero- 272. Moreno JG, Croce CM, Fischer R, et al. Detection 2003;91(7):608–12. geneous group of diseases: lessons from a rapid of hematogenous micrometastasis in patients with 234. DeMarzo AM, Nelson WG, Isaacs WB, Epstein JI. autopsy program. Cancer Res 2004;64(24): prostate cancer. Cancer Res 1992;52(21):6110–2. Pathological and molecular aspects of prostate 9209–16. 273. Ts’o PO, Pannek J, Wang ZP, et al. Detection of cancer. Lancet 2003;361(9361):955–64. 254., Liu W Laitinen S, Khan S, et al. Copy number intact prostate cancer cells in the blood of men 235. Epstein JI. Diagnostic criteria of limited adenocar- analysis indicates monoclonal origin of lethal with prostate cancer. Urology 1997;49(6):881–5. cinoma of the prostate on needle biopsy. Hum metastatic prostate cancer. Nat Med 2009;15(5): 274. Bastian PJ, Palapattu GS, Lin X, et al. Preoperative Pathol 1995;26(2):223–9. 559–65. serum DNA GSTP1 CpG island hypermethyl- 236. Baisden BL, Kahane H, Epstein JI. Perineural inva- 255. Yegnasubramanian S, Haffner MC, Zhang Y, ation and the risk of early prostate-specific antigen sion, mucinous fibroplasia, and glomerulations: et al. DNA hypomethylation arises later in recurrence following radical prostatectomy. Clin diagnostic features of limited cancer on prostate prostate cancer progression than CpG island Cancer Res 2005;11(11):4037–43. needle biopsy. Am J Surg Pathol 1999;23(8): hypermethylation and contributes to metastatic 275.d Allar WJ, Matera J, Miller MC, et al. Tumor 918–24. tumor heterogeneity. Cancer Res 2008;68(21): cells circulate in the peripheral blood of all major 237. Rubin MA, Zhou M, Dhanasekaran SM, et al. 8954–67. carcinomas but not in healthy subjects or patients alpha-Methylacyl coenzyme A racemase as a tissue 256. Partin AW, Yoo J, Carter HB, et al. The use with nonmalignant diseases. Clin Cancer Res biomarker for prostate cancer. JAMAJAMA of prostate specific antigen, clinical stage and 2004;10(20):6897–904. 2002;287(13):1662–70. Gleasone scor to predict pathological stage in men 276. Danila DC, Fleisher M, Scher HI. Circulating 238. McNeal JE, Bostwick DG. Intraductal dysplasia: a with localized prostate cancer. J Urol 1993; tumor cells as biomarkers in prostate cancer. premalignant lesion of the prostate. Hum Pathol 150(1):110–4. Clin Cancer Res 2011;17(12):3903–12. 1986;17(1):64–71. 257. Partin AW, Kattan MW, Subong EN, et al. Com- 277. Economos C, Morrissey C, Vessella RL. Circulat- 239. Wills ML, Hamper UM, Partin AW, Epstein JI. bination of prostate-specific antigen, clinical stage, ing tumor cells as a marker of response: implica- Incidence of high-grade prostatic intraepithelial and Gleason score to predict pathological stage of tions for determining treatment efficacy and neoplasia in sextant needle biopsy specimens. localized prostate cancer. A multi-institutional evaluating new agents. Current Opin Urol. May Urology 1997;49(3):367–73. update. JAMA 1997;277(18):1445–51. 2012;22(3):190–6. 240. Haggman MJ, Macoska JA, Wojno KJ, Oesterling 258. Han M, Partin AW, Zahurak M, et al. 278. Carter HB. Management of low (favourable)-risk JE. The relationship between prostatic intraepithe- Biochemical (prostate specific antigen) recurrence prostate cancer. BJU Int 2011. lial neoplasia and prostate cancer: critical issues. probability following radical prostatectomy for 279. Parker C. Active surveillance: towards a new para- J Urol 1997;158(1):12–22. clinically localized prostate cancer. J Urol 2003; digm in the management of early prostate cancer. 241. O’Shaughnessy JA, Kelloff GJ, Gordon GB, et al. 169(2):517–23. Lancet Oncol 2004;5(2):101–6. Treatment and prevention of intraepithelial neo- 259. D’Amico AV, Whittington R, Malkowicz SB, et al. 280. Bill-Axelson A, Holmberg L, Ruutu M, et al. plasia: an important target for accelerated new Predicting prostate specific antigen outcome Radical prostatectomy versus watchful waiting agent development. Clin Cancer Res 2002;8(2): preoperatively in the prostate specific antigen era. in early prostate cancer. N Engl J Med 2011; 314–46. J Urol 2001;166(6):2185–8. 364(18):1708–17. 242. Lee MC, Moussa AS, Zaytoun O, et al. Using 260. Lughezzani G, Briganti A, Karakiewicz PI, et al. 281. Wilt TJ, Brawer MK, Barry MJ, et al. The Prostate a saturation biopsy scheme increases cancer Predictive and prognostic models in radical prosta- cancer Intervention Versus Observation Trial:VA/ detection during repeat biopsy in men with high- tectomy candidates: a critical analysis of the litera- NCI/AHRQ Cooperative Studies Program #407 grade prostatic intra-epithelial neoplasia. Urology ture. Eur Urol 2010;58(5):687–700. (PIVOT): design and baseline results of a random- 2011;78(5):1115–9. 261. Shariat SF, Kattan MW, Vickers AJ, et al. Critical ized controlled trial comparing radical prostatec- 243. Kawachi MH, Bahnson RR, Barry M, et al. review of prostate cancer predictive tools. Future tomy to watchful waiting for men with clinically NCCN clinical practice guidelines in oncology: Oncol 2009;5(10):1555–84. localized prostate cancer. Contemp Clin Trials prostate cancer early detection. J Natl Compr Canc 262. Purohit RS, Shinohara K, Meng MV, Carroll PR. 2009;30(1):81–7. Netw 2010;8(2):240–62. Imaging clinically localized prostate cancer. Urol 282. Carter HB, Walsh PC, Landis P, Epstein JI. 244.e D Marzo AM, Platz EA, Sutcliffe S, et al. Inflam- Clin North Am 2003;30(2):279–93. Expectant management of nonpalpable prostate mation in prostate carcinogenesis. Nature Rev 263. Oesterling JE. Using PSA to eliminate the staging cancer with curative intent: preliminary results. Cancer 2007;7(4):256–69. radionuclide bone scan. Significant economic J Urol 2002;167(3):1231–4. 245. Shah R, Mucci NR, Amin A, et al. Postatrophic implications. Urol Clin North Am 1993;20(4): 283. Choo R, Klotz L, Danjoux C, et al. Feasibility hyperplasia of the prostate gland: neoplastic pre- 705–11. study: watchful waiting for localized low to inter- cursor or innocent bystander? Am J Pathol 264. Hofer C, Kubler H, Hartung R, et al. Diagnosis mediate grade prostate carcinoma with selective 2001;158(5):1767–73. and monitoring of urological tumors using posi- delayed intervention based on prostate specific 246. Gleason DF, Mellinger GT. Prediction of prognosis tron emission tomography. Eur Urol 2001;40(5): antigen, histological and/or clinical progression. for prostatic adenocarcinoma by combined histo- 481–7. J Urol 2002;167(4):1664–9. logical grading and clinical staging. J Urol 1974; 265. Harisinghani MG, Barentsz J, Hahn PF, et al. 284. Dahabreh IJ, Chung M, Balk EM, et al. 111(1):58–64. Noninvasive detection of clinically occult lymph- Active surveillance in men with localized prostate 247. Fine SW, Amin MB, Berney DM, et al. A contem- node metastases in prostate cancer. N Engl J Med cancer: a systematic review. Ann Intern Med porary update on pathology reporting for prostate 2003;348(25):2491–9. 2012;156(8):582–90. 1496.e6 Part III: Specific Malignancies

285. Stattin P, Holmberg E, Johansson JE, et al. prostate-cancer survivors. N Engl J Med 2008; 325. Zelefsky MJ, Fuks Z, Hunt M, et al. High-dose Outcomes in localized prostate cancer: National 358(12):1250–61. intensity modulated radiation therapy for prostate Prostate Cancer Register of Sweden follow-up 305. Walsh PC. Anatomic radical retropubic prostatec- cancer: early toxicity and biochemical outcome in study. J Natl Cancer Inst 2010;102(13):950–8. tomy. In: Walsh PC, editor. Campbell’s Urology, 772 patients. Int J Radiat Oncol Biol Phys 286. Parker C, Muston D, Melia J, et al. A model of the vol. 4. Philadelphia, PA: Saunders; 2002. 2002;53(5):1111–6. natural history of screen-detected prostate cancer, p. 3107–30. 326. Zelefsky MJ, Eid JF. Elucidating the etiology of and the effect of radical treatment on overall sur- 306. Geary ES, Dendinger TE, Freiha FS, Stamey TA. erectile dysfunction after definitive therapy for vival.r B J Cancer 2006;94(10):1361–8. Incontinence and vesical neck strictures following prostatic cancer. Int J Radiat Oncol Biol Phys 287. Eggener SE, Scardino PT, Walsh PC, et al. Predict- radical retropubic prostatectomy. Urology 1995; 1998;40(1):129–33. ing 15-year prostate cancer specific mortality 45(6):1000–6. 327. Fisch BM, Pickett B, Weinberg V, Roach M. Dose after radical prostatectomy. J Urol 2011;185(3): 307. Steiner MS. Continence-preserving anatomic of radiation received by the bulb of the penis cor- 869–75. radical retropubic prostatectomy. Urology relates with risk of impotence after three- 288. Shappley 3rd WV, Kenfield SA, Kasperzyk JL, 2000;55(3):427–35. dimensional conformal radiotherapy for prostate et al. Prospective study of determinants and 308. Walsh PC, Marschke PL. Intussusception of cancer. Urology 2001;57(5):955–9. outcomes of deferred treatment or watchful the reconstructed bladder neck leads to earlier 328. Bagshaw MA, Cox RS, Ray GR. Status of radiation waiting among men with prostate cancer in a continence after radical prostatectomy. Urology treatment of prostate cancer at Stanford University. nationwide cohort. J Clin Oncol 2009; 2002;59(6):934–8. NCI Monogr 1988;7:47–60. 27(30):4980–5. 309. Dubbelman YD, Dohle GR, Schroder FH. 329. Zelefsky MJ, McKee AB, Lee H, Leibel SA. Effi- 289. Cooperberg MR, Broering JM, Carroll PR. Sexual function before and after radical retropubic cacy of oral sildenafil in patients with erectile dys- Time trends and local variation in primary treat- prostatectomy: A systematic review of prognostic function after radiotherapy for carcinoma of the ment of localized prostate cancer. J Clin Oncol indicators for a successful outcome. Eur Urol prostate. Urology 1999;53(4):775–8. 2010;28(7):1117–23. 2006;50(4):711–8; discussion 718–20. 330. Zagars GK. The prognostic significance of a single 290. Cooperberg MR, Broering JM, Kantoff PW, 310. Huang GJ, Sadetsky N, Penson DF. Health related serum prostate-specific antigen value beyond six Carroll PR. Contemporary trends in low risk pros- quality of life for men treated for localized prostate months after radiation therapy for adenocarcinoma tate cancer: risk assessment and treatment. J Urol cancer with long-term followup. J Urol 2010; of the prostate. Int J Radiat Oncol Biol Phys 2007;178(3 Pt 2):S14–19. 183(6):2206–12. 1993;27(1):39–45. 291. Hamilton AS, Albertsen PC, Johnson TK, et al. 311. Mulhall JP, Bella AJ, Briganti A, et al. Erectile 331. Sartor CI, Strawderman MH, Lin XH, et al. Rate Trends in the treatment of localized prostate cancer function rehabilitation in the radical prostatectomy of PSA rise predicts metastatic versus local recur- using supplemented cancer registry data. BJU Int patient. J Sex Med 2010;7(4 Pt 2):1687–98. rence after definitive radiotherapy. Int J Radiat 2011;107(4):576–84. 312. Han M, Partin AW, Pound CR, et al. Long-term Oncol Biol Phys 1997;38(5):941–7. 292. Klotz L, Zhang L, Lam A, et al. Clinical results of biochemical disease-free and cancer-specific sur- 332. Roach 3rd M, Hanks G, Thames Jr H, et al. Defin- long-term follow-up of a large, active surveillance vival following anatomic radical retropubic prosta- ing biochemical failure following radiotherapy cohort with localized prostate cancer. J Clin Oncol tectomy. The 15-year Johns Hopkins experience. with or without hormonal therapy in men with 2010;28(1):126–31. Urol Clin North Am 2001;28(3):555–65. clinically localized prostate cancer: recommenda- 293. Lane JA, Hamdy FC, Martin RM, et al. Latest 313. Antonarakis ES, Feng Z, Trock BJ, et al. The tions of the RTOG-ASTRO Phoenix Consensus results from the UK trials evaluating prostate natural history of metastatic progression in men Conference. Int J Radiat Oncol Biol Phys cancer screening and treatment: the CAP and with prostate-specific antigen recurrence after 2006;65(4):965–74. ProtecT studies. Eur J Cancer 2010;46(17): radical prostatectomy: long-term follow-up. BJU 333. Consensus statement: guidelines for PSA following 3095–101. Int 2012;109(1):32–9. radiation therapy. American Society for Therapeu- 294. Bechis SK, Carroll PR, Cooperberg MR. Impact 314. Roentgen WC. Proceedings of the Wurzburg tic Radiology and Oncology Consensus Panel. Int of age at diagnosis on prostate cancer treatment Phisico-Medical Society. December 28 1895. J Radiat Oncol Biol Phys 1997;37(5):1035–41. and survival. J Clin Oncol 2011;29(2):235–41. 315. Curie MS. Recherches sur les substances radioac- 334. Pollack A, Zagars GK, Starkschall G, et al. Prostate 295. Mettlin CJ, Murphy GP, Ho R, Menck HR. The tives. In: Faculte des Sciences de Paris pour obtenir cancer radiation dose response: results of the M. National Cancer Data Base report on longitudinal le grade de docteur es science physiques. 2nd ed. D. Anderson phase III randomized trial. Int J observations on prostate cancer. Cancer 1996; Paris: Gauthier-Villas; 1904. Radiat Oncol Biol Phys 2002;53(5):1097–105. 77(10):2162–6. 316. Young HH, Frontz WA. Some new methods in the 335. Zelefsky MJ, Leibel SA, Gaudin PB, et al. Dose 296. Barbash GI, Glied SA. New technology and health treatment of carcinoma of the lower genito-urinary escalation with three-dimensional conformal radia- care costs—the case of robot-assisted surgery. tract with radium. J Urol 1917;1:505–41. tion therapy affects the outcome in prostate cancer. N Engl J Med 2010;363(8):701–4. 317. Barringer BS. Phases of the pathology, diagnosis Int J Radiat Oncol Biol Phys 1998;41(3): 297. Boorjian SA, Eastham JA, Graefen M, et al. A and treatment of cancer of the prostate. J Urol 491–500. critical analysis of the long-term impact of radical 1928:407–11. 336. Zelefsky MJ, Fuks Z, Hunt M, et al. High prostatectomy on cancer control and function out- 318. George FW, Carlton CE, Dykhuizen RF, Dillon dose radiation delivered by intensity modulated comes. Eur Urol 2012;61(4):664–75. JR. Cobalt-60 telecurietherapy in the definitive conformal radiotherapy improves the outcome of 298. Barry MJ, Gallagher PM, Skinner JS, Fowler Jr FJ. treatment of carcinoma of the prostate: A prelimi- localized prostate cancer. J Urol 2001;166(3): Adverse effects of robotic-assisted laparoscopic nary report. J Urol 1965;93:102–9. 876–81. versus open retropubic radical prostatectomy 319. Kaplan HS, Bagshaw MA. The Stanford medical 337. Pollack A, Smith LG, von Eschenbach AC. Exter- among a nationwide random sample of medicare- linear accelerator III. Application to clinical prob- nal beam radiotherapy dose response characteristics age men. J Clin Oncol 2012;30(5):513–8. lems of Radiation Therapy. Stanford Med Bull of 1127 men with prostate cancer treated in 299. Duffey B, Varda B, Konety B. Quality of evidence 1957;15:141–51. the PSA era. Int J Radiat Oncol Biol Phys toe compar outcomes of open and robot-assisted 320. Bagshaw MA, Kaplan HS, Sagerman RH. Linear 2000;48(2):507–12. laparoscopic prostatectomy. Current urology Accelerator Supervoltage Radiotherapy VII. Carci- 338. Wallner K, Merrick G, True L, et al. I-125 versus reports 2011;12(3):229–36. noma of the Prostate. Radiology 1965;85:121–9. Pd-103 for low-risk prostate cancer: morbidity 300. Vickers AJ. Great meaningless questions in 321. Del Regato JA. Radiotherapy in the conservative outcomes from a prospective randomized multi- urology: which is better, open, laparoscopic, or treatment of operable and locally inoperable carci- center trial. Cancer J 2002;8(1):67–73. robotic radical prostatectomy? Urology 2011; noma of the prostate. Radiology 1967;88:761–6. 339. Martinez AA, Pataki I, Edmundson G, et al. Phase 77(5):1025–6. 322. Fowler JE Jr, Braswell NT, Pandey P, et al. Experi- II prospective study of the use of conformal high- 301. Begg CB, Riedel ER, Bach PB, et al. Variations in ence with radical prostatectomy and radiation dose-rate brachytherapy as monotherapy for the morbidity after radical prostatectomy. N Engl J therapy for localized prostate cancer at a Veterans treatment of favorable stage prostate cancer: a fea- Med 2002;346(15):1138–44. Affairs Medical Center. J Urol 1995;153:1026– sibility report. Int J Radiat Oncol Biol Phys 302. Walsh PC, Marschke P, Ricker D, Burnett AL. 31. 2001;49(1):61–9. Patient-reported urinary continence and sexual 323. Zelefsky MJ, Cowen D, Fuks Z, et al. Long term 340. Yoshioka Y, Nose T, Yoshida K, et al. High-dose- function after anatomic radical prostatectomy. tolerance of high dose three-dimensional confor- rate interstitial brachytherapy as a monotherapy for Urology 2000;55(1):58–61. mal radiotherapy in patients with localized prostate localized prostate cancer: treatment description 303. Walsh PC. Radical prostatectomy for localized carcinoma. Cancer 1999;85(11):2460–8. and preliminary results of a phase I/II clinical trial. prostate cancer provides durable cancer control 324. Hanks GE, Hanlon AL, Schultheiss TE, et al. Int J Radiat Oncol Biol Phys 2000;48(3): with excellent quality of life: a structured debate. Dose escalation with 3D conformal treatment: 675–81. J Urol 2000;163(6):1802–7. five year outcomes, treatment optimization, and 341. Deger S, Boehmer D, Turk I, et al. High dose 304. Sanda MG, Dunn RL, Michalski J, et al. Quality future directions. Int J Radiat Oncol Biol Phys rate brachytherapy of localized prostate cancer. Eur of life and satisfaction with outcome among 1998;41(3):501–10. Urol 2002;41(4):420–6. Prostate Cancer • CHAPTER 84 1496.e7

342. Zelefsky MJ, Kuban DA, Levy LB, et al. Multi- implantation for stage T1/T2 prostatic carcinoma. stages T1 to 2 adenocarcinoma of the prostate: institutional analysis of long-term outcome for J Clin Oncol 1996;14(2):449–53. new insights into outcome from repeat biopsy stages T1-T2 prostate cancer treated with perma- 360. Stock RG, Kao J, Stone NN. Penile erectile func- and prostate specific antigen followup. J Urol nent seed implantation. Int J Radiat Oncol Biol tion after permanent radioactive seed implantation 1994;152(5 Pt 2):1806–12. Phys 2007;67(2):327–33. for treatment of prostate cancer. J Urol 2001; 377. Paulson DF. Impact of radical prostatectomy in the 343. Davis BJ, Pisansky TM, Wilson TM, et al. The 165(2):436–9. management of clinically localized disease. J Urol radial distance of extraprostatic extension of pros- 361. Merrick GS, Butler WM, Wallner KE, et al. The 1994;152(5 Pt 2):1826–30. tate carcinoma: implications for prostate brachy- importance of radiation doses to the penile bulb 378. Valicenti RK, Gomella LG, Ismail M, et al. therapy. Cancer 1999;85(12):2630–7. vs. crura in the development of postbrachytherapy The efficacy of early adjuvant radiation therapy 344. Sylvester JE, Grimm PD, Blasko JC, et al. 15-Year erectile dysfunction. Int J Radiat Oncol Biol Phys for pT3N0 prostate cancer: a matched-pair analy- biochemical relapse free survival in clinical Stage 2002;54(4):1055–62. sis. Int J Radiat Oncol Biol Phys 1999;45(1): T1-T3 prostate cancer following combined exter- 362. Merrick GS, Wallner KE, Butler WM. Manage- 53–8. nal beam radiotherapy and brachytherapy; Seattle ment of sexual dysfunction after prostate brachy- 379. Petrovich Z, Lieskovsky G, Stein JP, et al. Com- experience. Int J Radiat Oncol Biol Phys therapy. Oncology (Huntingt) 2003;17(1):52–62; parison of surgery alone with surgery and adjuvant 2007;67(1):57–64. discussion 62, 67–70, 73. radiotherapy for pT3N0 prostate cancer. BJU Int 345. Stone NN, Stock RG. Prostate brachytherapy in 363. Slater JD, Rossi Jr CJ, Yonemoto LT, et al. Proton 2002;89(6):604–11. patients with prostate volumes >/= 50 cm3: dosi- therapy for prostate cancer: the initial Loma Linda 380. Taylor NKJ, Kuban DA, et al. Adjuvant and metric analysis of implant quality. Int J Radiat University experience. Int J Radiat Oncol Biol Salvage Radiotherapy After Radical Prostatectomy Oncol Biol Phys 2000;46(5):1199–204. Phys 2004;59(2):348–52. For Prostate Cancer. Int J Radiat Oncol Biol Phys 346. Merrick GS, Butler WM, Dorsey AT, Lief JH. 364. Zietman AL, DeSilvio ML, Slater JD, et al. Com- 2003;56(3):755–63. Effect of prostate size and isotope selection on dosi- parison of conventional-dose vs high-dose confor- 381. Thompson Jr IM, Tangen CM, Paradelo J, et al. metric quality following permanent seed implanta- mal radiation therapy in clinically localized Adjuvant radiotherapy for pathologically advanced tion. Tech Urol 2001;7(3):233–40. adenocarcinoma of the prostate: a randomized prostate cancer: a randomized clinical trial. JAMA 347. Terk MD, Stock RG, Stone NN. Identification controlled trial. JAMA 2005;294(10):1233–9. 2006;296(19):2329–35. of patients at increased risk for prolonged urinary 365. Bolla M, Gonzalez D, Warde P, et al. Improved 382. Bottke D, Wiegel T. Adjuvant radiotherapy after retention following radioactive seed implantation survival in patients with locally advanced prostate radical prostatectomy: indications, results and side of the prostate. J Urol 1998;160(4):1379–82. cancer treated with radiotherapy and goserelin. N effects. Urol Int 2007;78(3):193–7. 348. Merrick GS, Butler WM, Lief JH, Dorsey AT. Engl J MedN Engl J Med 1997;337(5):295–300. 383. Pound CR, Partin AW, Eisenberger MA, et al. Temporal resolution of urinary morbidity follow- 366. Bolla M, Collette L, Blank L, et al. Long-term Natural history of progression after PSA elevation ing prostate brachytherapy. Int J Radiat Oncol Biol results with immediate androgen suppression and following radical prostatectomy. JAMA 1999; Phys 2000;47(1):121–8. external irradiation in patients with locally 281(17):1591–7. 349. Landis D, Wallner K, Locke J, et al. Late Urinary advanced prostate cancer (an EORTC study): 384. Lu-Yao GL, Potosky AL, Albertsen PC, et al. Function After Prostate Brachytherapy. Brachy- a phase III randomised trial. Lancet 2002; Follow-up prostate cancer treatments after radical therapy 2002;1:21. 360(9327):103–6. prostatectomy: a population-based study. J Natl 350. Wallner K, Lee H, Wasserman S, Dattoli M. Low 367. Pilepich MV, Caplan R, Byhardt RW, et al. Phase Cancer Inst 1996;88(3-4):166–73. risk of urinary incontinence following prostate III trial of androgen suppression using goserelin in 385. Partin AW, Pearson JD, Landis PK, et al. Evalua- brachytherapy in patients with a prior transurethral unfavorable- prognosis carcinoma of the prostate tion of serum prostate-specific antigen velocity prostate resection. Int J Radiat Oncol Biol Phys treated with definitive radiotherapy: report of after radical prostatectomy to distinguish local 1997;37(3):565–9. Radiation Therapy Oncology Group Protocol recurrence from distant metastases. Urology 351. Merrick GS, Butler WM, Wallner KE, et al. 85-31. J Clin Oncol 1997;15(3):1013–21. 1994;43(5):649–59. Prostate-specific antigen spikes after permanent 368. D’Amico AV, Schultz D, Loffredo M, et al. Bio- 386.x Co JD, Gallagher MJ, Hammond EH, et al. Con- prostate brachytherapy. Int J Radiat Oncol Biol chemical outcome following external beam radia- sensus statements on radiation therapy of prostate Phys 2002;54(2):450–6. tion therapy with or without androgen suppression cancer: guidelines for prostate re-biopsy after radia- 352. Kleinberg L, Wallner K, Roy J, et al. therapy for clinically localized prostate cancer. tion and for radiation therapy with rising prostate- Treatment-related symptoms during the first year JAMA 2000;284(10):1280–3. specific antigen levels after radical prostatectomy. following transperineal 125I prostate implantation. 369. Jones CU, Hunt D, McGowan DG, et al. Radio- American Society for Therapeutic Radiology and Int J Radiat Oncol Biol Phys 1994;28(4): therapy and short-term androgen deprivation for Oncology Consensus Panel. J Clin Oncol 985–90. localized prostate cancer. N Engl J Med 1999;17(4):1155. 353. Ragde H, Blasko JC, Grimm PD, et al. Interstitial 2011;365(2):107–18. 387. Song DY, Thompson TL, Ramakrishnan V, et al. iodine-125 radiation without adjuvant therapy in 370. Gleave ME, Goldenberg SL, Chin JL, et al. Ran- Salvage radiotherapy for rising or persistent PSA the treatment of clinically localized prostate carci- domized comparative study of 3 versus 8-month after radical prostatectomy. Urology 2002;60(2): noma. Cancer 1997;80(3):442–53. neoadjuvant hormonal therapy before radical pros- 281–7. 354. Talcott JA, Clark JA, Stark PC, Mitchell SP. tatectomy: biochemical and pathological effects. 388. Cadeddu JA, Partin AW, DeWeese TL, Walsh PC. Long-term treatment related complications of J Urol 2001;166(2):500–6; discussion 506–7. Long-term results of radiation therapy for prostate brachytherapy for early prostate cancer: a survey of 371. Blank KR, Whittington R, Arjomandy B, et al. cancer recurrence following radical prostatectomy. patients previously treated. J Urol 2001;166(2): Neoadjuvant androgen deprivation prior to trans- J Urol 1998;159(1):173–7; discussion 177–8. 494–9. perineal prostate brachytherapy: smaller volumes, 389. Stephenson AJ, Shariat SF, Zelefsky MJ, et al. 355. Benoit RM, Naslund MJ, Cohen JK. Complica- less morbidity. Cancer J Sci Am 1999;5(6): Salvage radiotherapy for recurrent prostate cancer tions after prostate brachytherapy in the Medicare 370–3. after radical prostatectomy. JAMA 2004;291(11): population. Urology 2000;55(1):91–6. 372. Potters L, Torre T, Ashley R, Leibel S. Examining 1325–32. 356. Zelefsky MJ, Hollister T, Raben A, et al. Five-year the role of neoadjuvant androgen deprivation in 390. Trock BJ, Han M, Freedland SJ, et al. Prostate biochemical outcome and toxicity with transperi- patients undergoing prostate brachytherapy. J Clin cancer-specific survival following salvage radio- neal- CT planned permanent I-125 prostate Oncol 2000;18(6):1187–92. therapy vs observation in men with biochemical implantation for patients with localized prostate 373. Kupelian PA, Katcher J, Levin HS, Klein EA. Stage recurrence after radical prostatectomy. JAMA cancer. Int J Radiat Oncol Biol Phys 2000; T1-2 prostate cancer: a multivariate analysis of 2008;299(23):2760–9. 47(5):1261–6. factors affecting biochemical and clinical failures 391. Corn BW, Winter K, Pilepich MV. Does androgen 357. Lawton CA, DeSilvio M, Lee WR, et al. Results of after radical prostatectomy. Int J Radiat Oncol Biol suppression enhance the efficacy of postoperative a phase II trial of transrectal ultrasound-guided Phys 1997;37(5):1043–52. irradiation? A secondary analysis of RTOG 85-31. permanent radioactive implantation of the prostate 374. Grossfeld GD, Tigrani VS, Nudell D, et al. Radiation Therapy Oncology Group. Urology fore definitiv management of localized adenocarci- Management of a positive surgical margin after 1999;54(3):495–502. noma of the prostate (radiation therapy oncology radical prostatectomy: decision analysis. J Urol 392. Taylor CD, Elson P, Trump DL. Importance of group 98-05). Int J Radiat Oncol Biol Phys 2000;164(1):93–9; discussion 100. continued testicular suppression in hormone- 2007;67(1):39–47. 375. Anscher MS, Prosnitz LR. Multivariate analysis of refractory prostate cancer. J Clin Oncol 358. Stock RG, Stone NN, Iannuzzi C. Sexual potency factors predicting local relapse after radical 1993;11(11):2167–72. following interactive ultrasound-guided brachy- prostatectomy—possible indications for postoper- 393. Van Cangh PJ, Richard F, Lorge F, et al. therapy for prostate cancer. Int J Radiat Oncol Biol ative radiotherapy. Int J Radiat Oncol Biol Phys Adjuvant radiation therapy does not cause urinary Phys 1996;35(2):267–72. 1991;21(4):941–7. incontinence after radical prostatectomy: results 359. Wallner K, Roy J, Harrison L. Tumor control and 376. Zietman AL, Shipley WU, Coen JJ. Radical pros- of a prospective randomized study. J Urol 1998; morbidity following transperineal iodine 125 tatectomy and radical radiation therapy for clinical 159(1):164–6. 1496.e8 Part III: Specific Malignancies

394. Formenti SC, Lieskovsky G, Skinner D, et al. prostatectomy: 25-year follow-up. J Clin Oncol 428. Maximum androgen blockade in advanced pros- Update on impact of moderate dose of adjuvant 2009;27(15S). tate cancer: an overview of 22 randomised trials radiation on urinary continence and sexual potency 411. D’Amico AV, Moul JW, Carroll PR, et al. Surro- with 3283 deaths in 5710 patients. Prostate Cancer in prostate cancer patients treated with nerve- gate end point for prostate cancer-specific mortal- Trialists’ Collaborative Group. Lancet 1995; sparing prostatectomy. Urology 2000;56(3): ity after radical prostatectomy or radiation therapy. 346(8970):265–9. 453–8. J Natl Cancer Inst 2003;95(18):1376–83. 429. Chen Y, Clegg NJ, Scher HI. Anti-androgens and 395. Bastasch MD, Teh BS, Mai WY, et al. Post-nerve- 412. Hussain M, Goldman B, Tangen C, et al. Prostate- androgen-depleting therapies in prostate cancer: sparing prostatectomy, dose-escalated intensity- specific antigen progression predicts overall sur- new agents for an established target. Lancet Oncol modulated radiotherapy: effect on erectile function. vival in patients with metastatic prostate cancer: 2009;10(10):981–91. Int J Radiat Oncol Biol Phys 2002;54(1):101–6. data from Southwest Oncology Group Trials 9346 430. Scher HI, Beer TM, Higano CS, et al. Antitumour 396. Katz MS, Zelefsky MJ, Venkatraman ES, et al. (Intergroup Study 0162) and 9916. J Clin Oncol activity of MDV3100 in castration-resistant pros- Predictors of biochemical outcome with salvage 2009;27(15):2450–6. tate cancer: a phase 1-2 study. Lancet 2010; conformal radiotherapy after radical prostatectomy 413. Scher HI, Eisenberger M, D’Amico AV, et al. 375(9724):1437–46. for prostate cancer. J Clin Oncol 2003;21(3): Eligibility and outcomes reporting guidelines for 431.e D Bono JS, Fizazi K, Saad F, et al. Primary, 483–9. clinical trials for patients in the state of a rising secondary, and quality-of-life endpoint results 397. DeWeese TL, Song DY. Current evidence for prostate-specific antigen: recommendations from from the phase III AFFIRM study of MDV3100, the role of combined androgen suppression and the Prostate-Specific Antigen Working Group. an androgen receptor signaling inhibitor. J Clin radiation in the treatment of adenocarcinoma of J Clin Oncol 2004;22(3):537–56. Oncol 2012;30:(suppl; abstr 4519). the prostate. Urology 2000;55(2):169–74. 414. Nelson JB, Love W, Chin JL, et al. Phase 3, ran- 432. Rathkopf DE, Danila DC, Slovin SF, et al. A first- 398. Del Regato J. Radiotherapy for carcinoma of the domized, controlled trial of atrasentan in patients in-human, open-label, phase I/II safety, pharmaco- prostate. A report from the Committee for the with nonmetastatic, hormone-refractory prostate kinetic, and proof-of-concept study of ARN-509 Cooperative Study of Radiotherapy for Carcinoma cancer. Cancer 2008;113(9):2478–87. in patients with progressive advanced castration- of the Prostate 1968. 415. Smith MR, Kabbinavar F, Saad F, et al. Natural resistant prostate cancer (CRPC). J Clin Oncol 399. Neglia WJ, Hussey DH, Johnson DE. Megavoltage history of rising serum prostate-specific antigen in 2011;29:(suppl; abstr TPS190). radiation therapy for carcinoma of the prostate. Int men with castrate nonmetastatic prostate cancer. 433. Mostaghel EA, Page ST, Lin DW, et al. Intrapros- J Radiat Oncol Biol Phys 1977;2(9-10):873–83. J Clin Oncol 2005;23(13):2918–25. tatic androgens and androgen-regulated gene 400. van der Werf-Messing B, Sourek-Zikova V, Blonk 416. Smith MR, Cook R, Lee KA, Nelson JB. Disease expression persist after testosterone suppression: DI. Localized advanced carcinoma of the prostate: and host characteristics as predictors of time to first therapeutic implications for castration-resistant radiation therapy versus hormonal therapy. Int J bone metastasis and death in men with progressive prostate cancer. Cancer Res 2007;67(10): Radiat Oncol Biol Phys 1976;1(11-12):1043–8. castration-resistant nonmetastatic prostate cancer. 5033–41. 401. Green N, Bodner H, Broth E, et al. Improved Cancer 2011;117(10):2077–85. 434. de Bono JS, Logothetis CJ, Molina A, et al. control of bulky prostate carcinoma with sequen- 417. Eisenberger MA, Blumenstein BA, Crawford ED, Abiraterone and increased survival in metastatic tial estrogen and radiation therapy. Int J Radiat et al. Bilateral orchiectomy with or without fluta- prostate cancer. N Engl J Med 2011;364(21): Oncol Biol Phys 1984;10(7):971–6. mide for metastatic prostate cancer. N Engl J Med 1995–2005. 402. Mukamel E, Servadio C, Lurie H. Combined 1998;339(15):1036–42. 435. Vasaitis TS, Bruno RD, Njar VC. CYP17 inhibi- external radiotherapy and hormonal therapy for 418. Hussain M, Tangen CM, Higano C, et al. Absolute tors for prostate cancer therapy. J Steroid Biochem localized carcinoma of the prostate. The Prostate prostate-specific antigen value after androgen Mol Biol 2011;125(1-2):23–31. 1983;4(3):283–7. deprivation is a strong independent predictor of 436. Byar DP, Corle DK. Hormone therapy for prostate 403. Pilepich MV, Krall JM, Sause WT, et al. Prognostic survival in new metastatic prostate cancer: Data cancer: results of the Veterans Administration factors in carcinoma of the prostate—analysis of from Southwest Oncology Group trial 9346 (INT- Cooperative Urological Research Group studies. RTOG study 75-06. Int J Radiat Oncol Biol Phys 0162). J Clin Oncol 2006;24(24):3984–90. NCI Monogr 1988;(7):165–70. 1987;13(3):339–49. 419. Makarov DV, Humphreys EB, Mangold LA, et al. 437. Immediate versus deferred treatment for advanced 404. Pilepich MV, Winter K, John MJ, et al. Phase III The natural history of men treated with deferred prostatic cancer: initial results of the Medical radiation therapy oncology group (RTOG) trial androgen deprivation therapy in whom metastatic Research Council Trial. The Medical Research 86-10 of androgen deprivation adjuvant to defini- prostate cancer developed following radical prosta- Council Prostate Cancer Working Party Investiga- tive radiotherapy in locally advanced carcinoma of tectomy. J Urol 2008;179(1):156–61; discussion tors Group. British journal of urology 1997; the prostate. Int J Radiat Oncol Biol Phys 161-152. 79(2):235–46. 2001;50(5):1243–52. 420. Scher HI, Sawyers CL. Biology of progressive, 438. Messing EM, Manola J, Sarosdy M, et al. Immedi- 405. Lawton CA, Winter K, Murray K, et al. Updated castration-resistant prostate cancer: directed thera- ate hormonal therapy compared with observation results of the phase III Radiation Therapy Oncol- pies targeting the androgen-receptor signaling axis. after radical prostatectomy and pelvic lymphade- ogy Group (RTOG) trial 85-31 evaluating the J Clin Oncol 2005;23(32):8253–61. nectomy in men with node-positive prostate potential benefit of androgen suppression follow- 421. Chen CD, Welsbie DS, Tran C, et al. Molecular cancer. N Engl J Med 1999;341(24):1781–8. ingd standar radiation therapy for unfavorable determinants of resistance to antiandrogen therapy. 439. Saylor PJ, Smith MR. Adverse effects of androgen prognosis carcinoma of the prostate. Int J Radiat Nat Med 2004;10(1):33–9. deprivation therapy: defining the problem and pro- Oncol Biol Phys 2001;49(4):937–46. 422. Kelly WK, Scher HI. Prostate specific antigen moting health among men with prostate cancer. 406. Hanks GE, Lu JD, Machtay M, et al. RTOG decline after antiandrogen withdrawal: the fluta- J Natl Compr Canc Netw 2010;8(2):211–23. protocol 92-02: a phase III trial of the use of long mide withdrawal syndrome. J Urol. Mar 1993; 440. Akakura K, Bruchovsky N, Goldenberg SL, et al. term androgen suppression following neoadjuvant 149(3):607–9. Effects of intermittent androgen suppression hormonal cytoreduction and radiotherapy in 423.u H R, Lu C, Mostaghel EA, et al. Distinct tran- on androgen-dependent tumors. Apoptosis and locally advanced carcinoma of the prostate. scriptional programs mediated by the ligand- serum prostate-specific antigen. Cancer 1993; (Abstract). Int J Radiat Oncol Biol Phys dependent full-length androgen receptor and its 71(9):2782–90. 2000;48(Suppl):112. splice variants in castration-resistant prostate 441. Russo P, Liguori G, Heston WD, et al. Effects of 407. Widmark A, Klepp O, Solberg A, et al. Endocrine cancer. Cancer Res 2012;72(14):3457–62. intermittent diethylstilbestrol diphosphate admin- treatment, with or without radiotherapy, in locally 424. Montgomery RB, Mostaghel EA, Vessella R, et al. istration on the R3327 rat prostatic carcinoma. advanced prostate cancer (SPCG-7/SFUO-3): an Maintenance of intratumoral androgens in meta- Cancer Res 1987;47(22):5967–70. open randomised phase III trial. Lancet 2009; static prostate cancer: a mechanism for castration- 442. Conti PD, Atallah AN, Arruda H, et al. Intermit- 373(9660):301–8. resistant tumor growth. Cancer Res 2008;68(11): tent versus continuous androgen suppression for 408. Partin AW, Hanks GE, Klein EA, et al. Prostate- 4447–54. prostatic cancer. Cochrane Database Syst Rev specific antigen as a marker of disease activity in 425. Thompson IM, Zeidman EJ, Rodriguez FR. 2007(4):CD005009. prostate cancer. Oncology (Huntingt) 2002;16(9): Sudden death due to disease flare with luteinizing 443. Oefelein MG. Health related quality of life using 1218–24; discussion 1224, 1227-18 passim. hormone-releasing hormone agonist therapy for serum testosterone as the trigger to re-dose long 409. Partin AW, Hanks GE, Klein EA, et al. Prostate- carcinoma of the prostate. J Urol 1990;144(6): acting depot luteinizing hormone-releasing specific antigen as a marker of disease activity in 1479–80. hormone agonists in patients with prostate cancer. prostate cancer. Oncology (Huntingt) 426.x Co RL, Crawford ED. Estrogens in the treatment J Urol 2003;169(1):251–5. 2002;16(8):1024–38, 1042; discussion 1042, of prostate cancer. J Urol 1995;154(6):1991–8. 444. Klotz L, O’Callaghan CJ, Ding K, et al. A 1047–1028, 1051. 427. Labrie F, Dupont A, Giguere M, et al. Advantages phase III randomized trial comparing intermittent 410. Antonarakis ES, Trock BJ, Feng Z, et al. The of the combination therapy in previously untreated versus continuous androgen suppression for natural history of metastatic progression in men and treated patients with advanced prostate cancer. patients with PSA progression after radical therapy: with PSA-recurrent prostate cancer after radical J Steroid Biochem 1986;25(5B):877–83. NCICG CT PR.7/SWOG JPR.7/CTSU JPR.7/ Prostate Cancer • CHAPTER 84 1496.e9

UK Intercontinental Trial CRUKE/01/013. J Clin 454. Paller CJ, Antonarakis ES. Cabazitaxel: a novel skeletal complications in patients with metastatic Oncol 2011;29: (suppl 7; abstr 3). second-line treatment for metastatic castration- hormone-refractory prostate cancer. J Natl Cancer 445. Hussain M, Tangen CM, Higano CS, et al. Inter- resistant prostate cancer. Drug Design Devel Ther Inst 2004;96(11):879–82. mittent (IAD) versus continuous androgen depri- 2011;5:117–24. 464. Fizazi K, Carducci M, Smith M, et al. Denosumab vation (CAD) in hormone sensitive metastatic 455. Mita AC, Denis LJ, Rowinsky EK, et al. Phase I versus zoledronic acid for treatment of bone metas- prostate cancer (HSM1PC) patients (pts): Results and pharmacokinetic study of XRP6258 (RPR tases in men with castration-resistant prostate of S9346 (INT-0162), an international phase III 116258A), a novel taxane, administered as a cancer: a randomised, double-blind study. Lancet trial. J Clin Oncol 2012;30:(suppl; abstr 4). 1-hour infusion every 3 weeks in patients with 2011;377(9768):813–22. 446. Jordan MA, Wilson L. Microtubules as a target for advanced solid tumors. Clin Cancer Res 2009; 465. Vallet S, Smith MR, Raje N. Novel bone-targeted anticancer drugs. Nature reviews. Cancer 2004; 15(2):723–30. strategies in oncology. Clin Cancer Res 4(4):253–65. 456. de Bono JS, Oudard S, Ozguroglu M, et al. 2010;16(16):4084–93. 447. Platz EA, Yegnasubramanian S, Liu JO, et al. Prednisone plus cabazitaxel or mitoxantrone 466. Brown JM, Corey E, Lee ZD, et al. Osteoprote- A novel two-stage, transdisciplinary study identi- for metastatic castration-resistant prostate cancer gerin and rank ligand expression in prostate cancer. fies digoxin as a possible drug for prostate cancer progressing after docetaxel treatment: a ran- Urology 2001;57(4):611–6. treatment. Cancer Discov 2011;1(1):68–77. domised open-label trial. Lancet 2010;376(9747): 467. Smith MR, Egerdie B, Hernandez Toriz N, 448. Darshan MS, Loftus MS, Thadani-Mulero M, 1147–54. et al. Denosumab in men receiving androgen- et al. Taxane-induced blockade to nuclear accumu- 457. Drake CG. Prostate cancer as a model for tumour deprivation therapy for prostate cancer. N Engl J lation of the androgen receptor predicts clinical immunotherapy. Nat Rev Immunol 2010;10(8): Med 2009;361(8):745–55. responses in metastatic prostate cancer. Cancer Res 580–93. 468. Goyal J, Antonarakis ES. Bone-targeting radio- 2011;71(18):6019–29. 458. Antonarakis ES, Drake CG. Current status of pharmaceuticals for the treatment of prostate 449. Tannock IF, de Wit R, Berry WR, et al. Docetaxel immunological therapies for prostate cancer. Curr cancer with bone metastases. Cancer letters plus prednisone or mitoxantrone plus prednisone Opin Urol 2010;20(3):241–6. 2012;323(2):135–46. for advanced prostate cancer. N Engl J Med 459. Small EJ, Fratesi P, Reese DM, et al. Immuno- 469. Nilsson S, Larsen RH, Fossa SD, et al. First clinical 2004;351(15):1502–12. therapy of hormone-refractory prostate cancer with experience with alpha-emitting radium-223 in the 450. Armstrong AJ, Garrett-Mayer ES, Yang YC, et al. antigen-loaded dendritic cells. J Clin Oncol treatment of skeletal metastases. Clin Cancer Res A contemporary prognostic nomogram for men 2000;18(23):3894–903. 2005;11(12):4451–9. with hormone-refractory metastatic prostate 460. Higano CS, Schellhammer PF, Small EJ, et al. Inte- 470. Bruland OS, Nilsson S, Fisher DR, Larsen RH. cancer: a TAX327 study analysis. Clin Cancer Res grated data from 2 randomized, double-blind, High-linear energy transfer irradiation targeted to 2007;13(21):6396–403. placebo-controlled, phase 3 trials of active cellular skeletal metastases by the alpha-emitter 223Ra: 451. Petrylak DP, Tangen CM, Hussain MH, et al. immunotherapy with sipuleucel-T in advanced adjuvant or alternative to conventional modalities? Docetaxel and estramustine compared with mito- prostate cancer. Cancer 2009;115(16):3670–9. Clin Cancer Res 2006;12(20 Pt 2):6250s–7s. xantrone and prednisone for advanced refractory 461. Kantoff PW, Higano CS, Shore ND, et al. 471. Nilsson S, Franzen L, Parker C, et al. Bone- prostate cancer. N Engl J Med 2004;351(15): Sipuleucel-T immunotherapy for castration- targeted radium-223 in symptomatic, hormone- 1513–20. resistant prostate cancer. N Engl J Med 2010; refractory prostate cancer: a randomised, 452. Beer TM, Garzotto M, Henner WD, et al. Inter- 363(5):411–22. multicentre, placebo-controlled phase II study. mittent chemotherapy in metastatic androgen- 462. , Saad F Gleason DM, Murray R, et al. A random- Lancet Oncol 2007;8(7):587–94. independent prostate cancer. Br J Cancer 2003; ized, placebo-controlled trial of zoledronic acid in 472. Parker P, Nilsson S, Heinrich D, et al. Updated 89(6):968–70. patients with hormone-refractory metastatic pros- analysis of the phase III, double-blind, random- 453. Meulenbeld HJ, Hamberg P, de Wit R. Chemo- tate carcinoma. J Natl Cancer Inst 2002;94(19): ized, multinational study of radium-223 chloride therapy in patients with castration-resistant pros- 1458–68. in castration-resistant prostate cancer (CRPC) tate. cancer Eur J Cancer 2009;45(Suppl 1): 463. , Saad F Gleason DM, Murray R, et al. Long-term patients with bone metastases (ALSYMPCA). 161–71. efficacy of zoledronic acid for the prevention of J Clin Oncol 2012;30:(suppl; abstr LBA4512)